1 Background

Researchers have assessed the proteome in different regions of the heart for 3 patients (identifiers 3, 4, and 8). For each patient they sampled the left atrium (LA), right atrium (RA), left ventricle (LV) and the right ventricle (RV). The data are a small subset of the public dataset PXD006675 on PRIDE.

Suppose that researchers are mainly interested in comparing the ventricular to the atrial proteome. Particularly, they would like to compare the left atrium to the left ventricle, the right atrium to the right ventricle, the average ventricular vs atrial proteome and if ventricular vs atrial proteome shifts differ between left and right heart region.

2 Data

We first import the peptides.txt file. This is the file that contains your peptide-level intensities. For a MaxQuant search [6], this peptides.txt file can be found by default in the “path_to_raw_files/combined/txt/” folder from the MaxQuant output, with “path_to_raw_files” the folder where raw files were saved. In this tutorial, we will use a MaxQuant peptides file from MaxQuant that can be found in the data tree of the SGA2020 github repository https://github.com/statOmics/SGA2020/tree/data/quantification/heart .

To import the data we use the QFeatures package.

We generate the object peptideRawFile with the path to the peptideRaws.txt file. Using the grepEcols function, we find the columns that contain the expression data of the peptideRaws in the peptideRaws.txt file.

library(tidyverse)
library(limma)
library(QFeatures)
library(msqrob2)
library(plotly)

peptidesFile <- "https://raw.githubusercontent.com/statOmics/SGA2020/data/quantification/heart/peptides.txt"

ecols <- MSnbase::grepEcols(
  peptidesFile,
  "Intensity ",
  split = "\t")

pe <- readQFeatures(
  table = peptidesFile,
  fnames = 1,
  ecol = ecols,
  name = "peptideRaw", sep="\t")

pe
## An instance of class QFeatures containing 1 assays:
##  [1] peptideRaw: SummarizedExperiment with 31319 rows and 12 columns
pe[["peptideRaw"]]
## class: SummarizedExperiment 
## dim: 31319 12 
## metadata(0):
## assays(1): ''
## rownames(31319): AAAAAAAAAK AAAAAAAAEQQSSNGPVK ... YYTPVPCESATAK
##   YYTYLIMNK
## rowData names(91): Sequence N.term.cleavage.window ...
##   Oxidation..M..site.IDs MS.MS.Count
## colnames(12): Intensity.LA3 Intensity.LA4 ... Intensity.RV4
##   Intensity.RV8
## colData names(0):

We will make use from data wrangling functionalities from the tidyverse package. The %>% operator allows us to pipe the output of one function to the next function.

colData(pe)$location <- substr(
  colnames(pe[["peptideRaw"]]),
  11,
  11) %>%
  unlist %>%
  as.factor

colData(pe)$tissue <- substr(
    colnames(pe[["peptideRaw"]]),
    12,
    12) %>%
    unlist %>%
    as.factor

colData(pe)$patient <- substr(
  colnames(pe[["peptideRaw"]]),
  13,
  13) %>%
  unlist %>%
  as.factor

We calculate how many non zero intensities we have per peptide and this will be useful for filtering.

rowData(pe[["peptideRaw"]])$nNonZero <- rowSums(assay(pe[["peptideRaw"]]) > 0)

Peptides with zero intensities are missing peptides and should be represent with a NA value rather than 0.

pe <- zeroIsNA(pe, "peptideRaw") # convert 0 to NA

2.1 Data exploration

We can inspect the missingness in our data with the plotNA() function provided with MSnbase. 63% of all peptide intensities are missing and for some peptides we do not even measure a signal in any sample. The missingness is similar across samples.

MSnbase::plotNA(assay(pe[["peptideRaw"]])) +
  xlab("Peptide index (ordered by data completeness)")

3 Preprocessing

This section preforms standard preprocessing for the peptide data. This include log transformation, filtering and summarisation of the data.

3.1 Log transform the data

pe <- logTransform(pe, base = 2, i = "peptideRaw", name = "peptideLog")
limma::plotDensities(assay(pe[["peptideLog"]]))

3.2 Filtering

3.2.1 Handling overlapping protein groups

In our approach a peptide can map to multiple proteins, as long as there is none of these proteins present in a smaller subgroup.

pe <- filterFeatures(pe,
  ~ Proteins %in% smallestUniqueGroups(rowData(pe[["peptideLog"]])$Proteins)
)

3.2.2 Remove reverse sequences (decoys) and contaminants

We now remove the contaminants, peptides that map to decoy sequences, and proteins which were only identified by peptides with modifications.

First look to the names of the variables for the peptide features

pe[["peptideLog"]] %>%
  rowData %>%
  names
##  [1] "Sequence"                "N.term.cleavage.window" 
##  [3] "C.term.cleavage.window"  "Amino.acid.before"      
##  [5] "First.amino.acid"        "Second.amino.acid"      
##  [7] "Second.last.amino.acid"  "Last.amino.acid"        
##  [9] "Amino.acid.after"        "A.Count"                
## [11] "R.Count"                 "N.Count"                
## [13] "D.Count"                 "C.Count"                
## [15] "Q.Count"                 "E.Count"                
## [17] "G.Count"                 "H.Count"                
## [19] "I.Count"                 "L.Count"                
## [21] "K.Count"                 "M.Count"                
## [23] "F.Count"                 "P.Count"                
## [25] "S.Count"                 "T.Count"                
## [27] "W.Count"                 "Y.Count"                
## [29] "V.Count"                 "U.Count"                
## [31] "O.Count"                 "Length"                 
## [33] "Missed.cleavages"        "Mass"                   
## [35] "Proteins"                "Leading.razor.protein"  
## [37] "Start.position"          "End.position"           
## [39] "Gene.names"              "Protein.names"          
## [41] "Unique..Groups."         "Unique..Proteins."      
## [43] "Charges"                 "PEP"                    
## [45] "Score"                   "Identification.type.LA3"
## [47] "Identification.type.LA4" "Identification.type.LA8"
## [49] "Identification.type.LV3" "Identification.type.LV4"
## [51] "Identification.type.LV8" "Identification.type.RA3"
## [53] "Identification.type.RA4" "Identification.type.RA8"
## [55] "Identification.type.RV3" "Identification.type.RV4"
## [57] "Identification.type.RV8" "Fraction.Average"       
## [59] "Fraction.Std..Dev."      "Fraction.1"             
## [61] "Fraction.2"              "Fraction.3"             
## [63] "Fraction.4"              "Fraction.5"             
## [65] "Fraction.6"              "Fraction.7"             
## [67] "Fraction.8"              "Fraction.100"           
## [69] "Experiment.LA3"          "Experiment.LA4"         
## [71] "Experiment.LA8"          "Experiment.LV3"         
## [73] "Experiment.LV4"          "Experiment.LV8"         
## [75] "Experiment.RA3"          "Experiment.RA4"         
## [77] "Experiment.RA8"          "Experiment.RV3"         
## [79] "Experiment.RV4"          "Experiment.RV8"         
## [81] "Intensity"               "Reverse"                
## [83] "Potential.contaminant"   "id"                     
## [85] "Protein.group.IDs"       "Mod..peptide.IDs"       
## [87] "Evidence.IDs"            "MS.MS.IDs"              
## [89] "Best.MS.MS"              "Oxidation..M..site.IDs" 
## [91] "MS.MS.Count"             "nNonZero"

No information on decoys.

pe <- filterFeatures(pe, ~ Potential.contaminant != "+")

3.2.3 Remove peptides of proteins that were only identified with modified peptides

I will skip this step for the moment. Large protein groups file needed for this.

3.2.4 Drop peptides that were only identified in one sample

We keep peptides that were observed at last twice.

pe <- filterFeatures(pe, ~ nNonZero >= 2)
nrow(pe[["peptideLog"]])
## [1] 17432

We keep 17432 peptides after filtering.

3.3 Quantile normalize the data

pe <- normalize(pe, i = "peptideLog", method = "quantiles", name = "peptideNorm")

3.4 Explore quantile normalized data

After quantile normalisation the density curves for all samples coincide.

limma::plotDensities(assay(pe[["peptideNorm"]]))

This is more clearly seen is a boxplot.

boxplot(assay(pe[["peptideNorm"]]), col = palette()[-1],
       main = "Peptide distribtutions after normalisation", ylab = "intensity")

We can visualize our data using a Multi Dimensional Scaling plot, eg. as provided by the limma package.

limma::plotMDS(assay(pe[["peptideNorm"]]),
  col = colData(pe)$location:colData(pe)$tissue %>%
    as.numeric,
  labels = colData(pe) %>%
    rownames %>%
    substr(start = 11, stop = 13)
  )

The first axis in the plot is showing the leading log fold changes (differences on the log scale) between the samples.

3.5 Summarization to protein level

We use robust summarization in aggregateFeatures. This is the default workflow of aggregateFeatures so you do not have to specifiy the argument fun. However, because we compare methods we have included the fun argument to show the summarization method explicitely.

pe <- aggregateFeatures(pe,
 i = "peptideNorm",
 fcol = "Proteins",
 na.rm = TRUE,
 name = "proteinRobust",
 fun = MsCoreUtils::robustSummary)
## Your quantitative and row data contain missing values. Please read the
## relevant section(s) in the aggregateFeatures manual page regarding the
## effects of missing values on data aggregation.
plotMDS(assay(pe[["proteinRobust"]]),
  col = colData(pe)$location:colData(pe)$tissue %>%
    as.numeric,
  labels = colData(pe) %>%
    rownames %>%
    substr(start = 11, stop = 13)
)

4 Data Analysis

4.1 Estimation

We model the protein level expression values using msqrob. By default msqrob2 estimates the model parameters using robust regression.

pe <- msqrob(
  object = pe,
  i = "proteinRobust",
  formula = ~ location*tissue + patient)

4.2 Inference

First, we extract the parameter names of the model.

getCoef(rowData(pe[["proteinRobust"]])$msqrobModels[[2]])
##       (Intercept)         locationR           tissueV          patient4 
##       26.33779939        0.28826213        0.20946392        0.46536955 
##          patient8 locationR:tissueV 
##       -0.02608046       -0.05550111
L <- makeContrast(
  c(
    "tissueV = 0",
    "tissueV + locationR:tissueV = 0",
    "tissueV + 0.5*locationR:tissueV = 0","locationR:tissueV = 0"),
  parameterNames =
    rowData(pe[["proteinRobust"]])$msqrobModels[[2]] %>%
    getCoef %>%
    names
  )


pe <- hypothesisTest(object = pe, i = "proteinRobust", contrast = L, overwrite=TRUE)

4.3 Evaluate results contrast \(\log_2 FC_{V-A}^L\)

4.3.1 Volcano-plot

volcanoLeft <- ggplot(rowData(pe[["proteinRobust"]])$"tissueV + locationR:tissueV",
                 aes(x = logFC, y = -log10(pval), color = adjPval < 0.05)) +
 geom_point(cex = 2.5) +
 scale_color_manual(values = alpha(c("black", "red"), 0.5)) + theme_minimal()
volcanoLeft

4.3.2 Heatmap

We first select the names of the proteins that were declared signficant.

sigNamesLeft <- rowData(pe[["proteinRobust"]])$tissueV %>%
 rownames_to_column("proteinRobust") %>%
 filter(adjPval<0.05) %>%
 pull(proteinRobust)
heatmap(assay(pe[["proteinRobust"]])[sigNamesLeft, ])

There are 211 proteins significantly differentially expressed at the 5% FDR level.

rowData(pe[["proteinRobust"]])$tissueV %>%
  cbind(.,rowData(pe[["proteinRobust"]])$Protein.names) %>%
  na.exclude %>%
  filter(adjPval<0.05) %>%
  arrange(pval)  %>%
  knitr::kable(.)
logFC se df t pval adjPval rowData(pe[[“proteinRobust”]])$Protein.names
P08590 7.566945 0.4227679 9.117912 17.898582 0.0000000 0.0000417 Myosin light chain 3
P12883 4.333125 0.3637861 9.255194 11.911187 0.0000006 0.0006480 Myosin-7
P10916 6.908674 0.5190748 7.385413 13.309594 0.0000020 0.0013463 Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
O75368 -2.290376 0.2718512 9.251939 -8.425109 0.0000123 0.0046575 SH3 domain-binding glutamic acid-rich-like protein
P46821 -2.182822 0.2654404 9.385413 -8.223396 0.0000137 0.0046575 Microtubule-associated protein 1B;MAP1B heavy chain;MAP1 light chain LC1
Q6UWY5 -3.253229 0.3888996 9.170135 -8.365215 0.0000138 0.0046575 Olfactomedin-like protein 1
Q8N474 -3.304647 0.3784419 7.847514 -8.732243 0.0000261 0.0070102 Secreted frizzled-related protein 1
O95865 -2.158932 0.2871753 9.385413 -7.517818 0.0000288 0.0070102 N(G),N(G)-dimethylarginine dimethylaminohydrolase 2
Q9ULL5-3 -3.386308 0.3993822 7.893242 -8.478865 0.0000311 0.0070102 Proline-rich protein 12
P02452 -3.226193 0.4112622 8.367424 -7.844614 0.0000392 0.0070838 Collagen alpha-1(I) chain
O94875-10 2.321238 0.3122508 8.958355 7.433891 0.0000406 0.0070838 Sorbin and SH3 domain-containing protein 2
Q16647 -2.787698 0.3824272 9.156725 -7.289485 0.0000422 0.0070838 Prostacyclin synthase
P29622 -2.114870 0.2991501 9.385413 -7.069595 0.0000474 0.0070838 Kallistatin
P14854 2.300663 0.3037112 8.346841 7.575168 0.0000514 0.0070838 Cytochrome c oxidase subunit 6B1
P05546 -1.915671 0.2708975 9.198639 -7.071573 0.0000523 0.0070838 Heparin cofactor 2
P21810 -3.380254 0.4548500 8.304055 -7.431580 0.0000609 0.0077217 Biglycan
P36955 -2.323620 0.3325722 8.456893 -6.986813 0.0000872 0.0097521 Pigment epithelium-derived factor
P23083 -4.274293 0.5581240 7.385413 -7.658322 0.0000912 0.0097521 Ig heavy chain V-I region V35
P13533 -4.313925 0.6516590 9.115028 -6.619911 0.0000915 0.0097521 Myosin-6
Q15113 -2.755021 0.4253583 9.188121 -6.476942 0.0001043 0.0097521 Procollagen C-endopeptidase enhancer 1
Q9UBG0 -2.576210 0.3963719 9.131671 -6.499476 0.0001044 0.0097521 C-type mannose receptor 2
P00325 -2.108814 0.3251595 9.141096 -6.485476 0.0001057 0.0097521 Alcohol dehydrogenase 1B
P07451 -1.841539 0.2910138 9.385413 -6.328012 0.0001136 0.0100264 Carbonic anhydrase 3
P51888 -3.199549 0.4165978 6.959924 -7.680186 0.0001217 0.0102934 Prolargin
P24844 -2.551801 0.4140400 9.330669 -6.163176 0.0001427 0.0112127 Myosin regulatory light polypeptide 9
Q53GQ0 -2.430853 0.3948274 9.334954 -6.156748 0.0001436 0.0112127 Very-long-chain 3-oxoacyl-CoA reductase
Q06828 -4.209189 0.6775919 9.003303 -6.211983 0.0001564 0.0116347 Fibromodulin
Q8TBQ9 -2.761806 0.4223033 8.170120 -6.539863 0.0001643 0.0116347 Protein kish-A
P51884 -2.402234 0.3614104 7.936878 -6.646831 0.0001672 0.0116347 Lumican
P35442 -2.334260 0.3655617 8.385413 -6.385405 0.0001735 0.0116347 Thrombospondin-2
Q9UL18 -2.602312 0.3982234 8.037138 -6.534804 0.0001777 0.0116347 Protein argonaute-1
Q96LL9 -2.426640 0.3958291 8.842792 -6.130526 0.0001858 0.0117873 DnaJ homolog subfamily C member 30
P18428 -2.002578 0.3365444 9.013977 -5.950411 0.0002139 0.0131587 Lipopolysaccharide-binding protein
P08294 -2.756458 0.4335622 7.979491 -6.357699 0.0002212 0.0132069 Extracellular superoxide dismutase [Cu-Zn]
P36021 -3.138301 0.5174695 8.385413 -6.064707 0.0002493 0.0136858 Monocarboxylate transporter 8
P02743 -2.273778 0.3999916 9.385413 -5.684565 0.0002568 0.0136858 Serum amyloid P-component;Serum amyloid P-component(1-203)
Q8WWA0 -5.806975 0.9532620 8.244689 -6.091688 0.0002588 0.0136858 Intelectin-1
Q92736-2 -3.330740 0.5744993 8.908498 -5.797640 0.0002706 0.0136858 Ryanodine receptor 2
O60760 -3.500029 0.5842390 8.385413 -5.990748 0.0002715 0.0136858 Hematopoietic prostaglandin D synthase
Q9UGT4 -2.283615 0.4020386 9.193722 -5.680088 0.0002789 0.0136858 Sushi domain-containing protein 2
Q14764 -1.625976 0.2901417 9.385413 -5.604074 0.0002855 0.0136858 Major vault protein
O95980 -2.552421 0.4176977 7.980660 -6.110688 0.0002889 0.0136858 Reversion-inducing cysteine-rich protein with Kazal motifs
Q92508 4.071001 0.5712249 6.385413 7.126791 0.0002899 0.0136858 Piezo-type mechanosensitive ion channel component 1
Q9BW30 -2.738684 0.4828316 9.049210 -5.672131 0.0002988 0.0137863 Tubulin polymerization-promoting protein family member 3
P12110 -2.136456 0.3667316 8.535409 -5.825667 0.0003078 0.0138861 Collagen alpha-2(VI) chain
P40261 -2.306727 0.4169709 9.340024 -5.532105 0.0003196 0.0141028 Nicotinamide N-methyltransferase
P05997 -3.068864 0.5429778 8.864434 -5.651913 0.0003308 0.0141028 Collagen alpha-2(V) chain
Q9P2B2 -2.047509 0.3731311 9.385413 -5.487374 0.0003335 0.0141028 Prostaglandin F2 receptor negative regulator
Q9NZ01 -2.346040 0.4161143 8.691035 -5.637970 0.0003618 0.0148853 Very-long-chain enoyl-CoA reductase
P46060 -1.970642 0.3436046 8.385413 -5.735204 0.0003666 0.0148853 Ran GTPase-activating protein 1
P31994-2 -1.655566 0.3017732 8.992524 -5.486128 0.0003882 0.0152351 Low affinity immunoglobulin gamma Fc region receptor II-b
O14967 -2.393131 0.4223134 8.430438 -5.666718 0.0003903 0.0152351 Calmegin
P00748 -2.003056 0.3702529 9.091376 -5.409968 0.0004128 0.0156430 Coagulation factor XII;Coagulation factor XIIa heavy chain;Beta-factor XIIa part 1;Coagulation factor XIIa light chain
Q07954 -1.674832 0.3146216 9.385413 -5.323322 0.0004161 0.0156430 Prolow-density lipoprotein receptor-related protein 1;Low-density lipoprotein receptor-related protein 1 85 kDa subunit;Low-density lipoprotein receptor-related protein 1 515 kDa subunit;Low-density lipoprotein receptor-related protein 1 intracellular domain
Q9UBB5 2.673301 0.4015137 6.385413 6.658059 0.0004277 0.0157858 Methyl-CpG-binding domain protein 2
O43677 -2.758090 0.4792076 7.933870 -5.755523 0.0004396 0.0159350 NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial
Q92604 -2.270281 0.4316583 9.345516 -5.259442 0.0004605 0.0163992 Acyl-CoA:lysophosphatidylglycerol acyltransferase 1
Q8NAT1 -1.416451 0.2751694 9.385413 -5.147559 0.0005298 0.0181178 Protein O-linked-mannose beta-1,4-N-acetylglucosaminyltransferase 2
O00264 -1.999242 0.3827164 9.079390 -5.223821 0.0005311 0.0181178 Membrane-associated progesterone receptor component 1
Q92621 -1.755581 0.3415656 9.385413 -5.139808 0.0005355 0.0181178 Nuclear pore complex protein Nup205
Q8WZA9 -1.502201 0.2907398 9.101344 -5.166822 0.0005690 0.0186760 Immunity-related GTPase family Q protein
Q9BXN1 -2.670923 0.5132981 8.937487 -5.203455 0.0005742 0.0186760 Asporin
Q14195-2 -2.527278 0.4943182 9.262403 -5.112654 0.0005796 0.0186760 Dihydropyrimidinase-related protein 3
O00180 -4.096722 0.7724957 8.385413 -5.303229 0.0006215 0.0197142 Potassium channel subfamily K member 1
Q8TBP6 -1.893243 0.3673308 8.851865 -5.154053 0.0006323 0.0197464 Solute carrier family 25 member 40
Q9GZY4 -3.167768 0.5759744 7.703311 -5.499842 0.0006539 0.0198708 Cytochrome c oxidase assembly factor 1 homolog
P41240 -1.569148 0.3075870 8.922337 -5.101476 0.0006615 0.0198708 Tyrosine-protein kinase CSK
Q9NY15 -2.177423 0.4377625 9.336638 -4.973981 0.0006860 0.0198708 Stabilin-1
Q96C86 -1.515572 0.3020943 9.145534 -5.016883 0.0006878 0.0198708 m7GpppX diphosphatase
P02747 -2.680914 0.4712559 7.138784 -5.688871 0.0006937 0.0198708 Complement C1q subcomponent subunit C
P06858 1.795244 0.3596173 9.218266 4.992094 0.0006950 0.0198708 Lipoprotein lipase
O43464 -1.900721 0.3799226 9.072346 -5.002915 0.0007184 0.0201585 Serine protease HTRA2, mitochondrial
O14980 -1.230352 0.2498369 9.382448 -4.924620 0.0007249 0.0201585 Exportin-1
Q8WY22 -1.839442 0.3608464 8.385413 -5.097577 0.0008064 0.0221211 BRI3-binding protein
P04083 -1.524538 0.3158141 9.385413 -4.827329 0.0008320 0.0225191 Annexin A1
P48681 -1.330081 0.2756444 9.321612 -4.825351 0.0008507 0.0227223 Nestin
P02775 -1.952126 0.4075050 9.385413 -4.790435 0.0008772 0.0229385 Platelet basic protein;Connective tissue-activating peptide III;TC-2;Connective tissue-activating peptide III(1-81);Beta-thromboglobulin;Neutrophil-activating peptide 2(74);Neutrophil-activating peptide 2(73);Neutrophil-activating peptide 2;TC-1;Neutrophil-activating peptide 2(1-66);Neutrophil-activating peptide 2(1-63)
Q7L4S7 -1.747450 0.3202677 7.157555 -5.456217 0.0008814 0.0229385 Protein ARMCX6
P46063 -1.386912 0.2873890 9.154885 -4.825907 0.0008948 0.0229922 ATP-dependent DNA helicase Q1
A6NMZ7 -2.267329 0.4773591 9.385413 -4.749734 0.0009302 0.0232949 Collagen alpha-6(VI) chain
Q5NDL2 -2.337629 0.4766026 8.686198 -4.904777 0.0009340 0.0232949 EGF domain-specific O-linked N-acetylglucosamine transferase
P56539 -2.051918 0.4159611 8.553679 -4.932956 0.0009410 0.0232949 Caveolin-3
Q9UNW9 4.097053 0.8545595 9.054127 4.794344 0.0009650 0.0236026 RNA-binding protein Nova-2
P01699 -4.025961 0.6965009 6.314916 -5.780266 0.0009792 0.0236632 Ig lambda chain V-I region VOR
Q9HAV4 -2.205274 0.4388018 7.987893 -5.025671 0.0010243 0.0244630 Exportin-5
Q92681 -2.153054 0.4353071 8.133279 -4.946057 0.0010730 0.0253280 Regulatory solute carrier protein family 1 member 1
P49207 -1.534829 0.3249990 8.970773 -4.722565 0.0010949 0.0255013 60S ribosomal protein L34
P50552 -1.523119 0.3245142 9.074476 -4.693535 0.0011055 0.0255013 Vasodilator-stimulated phosphoprotein
Q5VIR6-4 -1.755057 0.3758054 9.130015 -4.670123 0.0011243 0.0256432 Vacuolar protein sorting-associated protein 53 homolog
Q96H79 -3.021670 0.5420367 6.334231 -5.574659 0.0011785 0.0265817 Zinc finger CCCH-type antiviral protein 1-like
O75828 -1.641739 0.3592450 9.385413 -4.569971 0.0012087 0.0269634 Carbonyl reductase [NADPH] 3
O15230 -1.415011 0.3058820 9.044210 -4.626004 0.0012277 0.0270900 Laminin subunit alpha-5
Q5M9N0 -3.537066 0.7427497 8.350040 -4.762123 0.0012639 0.0275884 Coiled-coil domain-containing protein 158
P04196 -1.917181 0.3881943 7.683140 -4.938714 0.0012797 0.0276358 Histidine-rich glycoprotein
Q53GG5-2 -2.923374 0.6214767 8.429675 -4.703916 0.0013308 0.0282214 PDZ and LIM domain protein 3
Q6SZW1 -2.563687 0.5126523 7.385413 -5.000831 0.0013346 0.0282214 Sterile alpha and TIR motif-containing protein 1
Q15274 -1.928288 0.3958755 7.757883 -4.870945 0.0013525 0.0283041 Nicotinate-nucleotide pyrophosphorylase [carboxylating]
Q9BXR6 -2.352662 0.5252419 9.382448 -4.479196 0.0013831 0.0283325 Complement factor H-related protein 5
Q9ULC3 -1.674808 0.3626400 8.669265 -4.618376 0.0013874 0.0283325 Ras-related protein Rab-23
Q9Y5U8 -3.988833 0.8897580 9.327097 -4.483053 0.0013957 0.0283325 Mitochondrial pyruvate carrier 1
P34932 -1.163429 0.2608932 9.385413 -4.459407 0.0014232 0.0286058 Heat shock 70 kDa protein 4
Q9BUF5 -1.934378 0.4345654 9.217423 -4.451293 0.0015060 0.0298342 Tubulin beta-6 chain
Q8TDB6 -1.611315 0.3613218 9.153547 -4.459500 0.0015138 0.0298342 E3 ubiquitin-protein ligase DTX3L
P45877 -1.259792 0.2861984 9.343571 -4.401814 0.0015676 0.0305974 Peptidyl-prolyl cis-trans isomerase C
P04003 -1.479053 0.3338506 9.090898 -4.430283 0.0016066 0.0310601 C4b-binding protein alpha chain
P06727 -1.358368 0.3048521 8.884167 -4.455826 0.0016384 0.0312643 Apolipoprotein A-IV
P09619 -1.675728 0.3807310 9.154490 -4.401345 0.0016479 0.0312643 Platelet-derived growth factor receptor beta
Q8N5M1 -2.022143 0.4573254 8.937206 -4.421672 0.0016958 0.0316965 ATP synthase mitochondrial F1 complex assembly factor 2
Q6YN16 1.527167 0.3496754 9.222955 4.367385 0.0017019 0.0316965 Hydroxysteroid dehydrogenase-like protein 2
P01042 -2.256316 0.4659486 7.210294 -4.842414 0.0017231 0.0317986 Kininogen-1;Kininogen-1 heavy chain;T-kinin;Bradykinin;Lysyl-bradykinin;Kininogen-1 light chain;Low molecular weight growth-promoting factor
P08582 -1.663860 0.3857501 9.299314 -4.313310 0.0018093 0.0329078 Melanotransferrin
P30405 -1.540274 0.3587630 9.385413 -4.293290 0.0018252 0.0329078 Peptidyl-prolyl cis-trans isomerase F, mitochondrial
P14550 -1.394080 0.3100035 8.301450 -4.496981 0.0018318 0.0329078 Alcohol dehydrogenase [NADP(+)]
Q9UQ35 -1.367511 0.3203946 9.385413 -4.268208 0.0018958 0.0334035 Serine/arginine repetitive matrix protein 2
P36551 -1.338543 0.3106105 9.112223 -4.309393 0.0019078 0.0334035 Oxygen-dependent coproporphyrinogen-III oxidase, mitochondrial
P14555 -4.594903 0.9455710 6.867951 -4.859396 0.0019377 0.0334035 Phospholipase A2, membrane associated
Q08945 -2.071352 0.4670698 8.385413 -4.434781 0.0019453 0.0334035 FACT complex subunit SSRP1
P24311 1.725765 0.4048607 9.295713 4.262615 0.0019540 0.0334035 Cytochrome c oxidase subunit 7B, mitochondrial
P02461 -3.597666 0.8096938 8.323445 -4.443242 0.0019581 0.0334035 Collagen alpha-1(III) chain
Q9H1E5 -1.388829 0.3280259 9.385413 -4.233902 0.0019969 0.0337811 Thioredoxin-related transmembrane protein 4
O00303 -1.477605 0.3444231 9.008150 -4.290088 0.0020156 0.0338155 Eukaryotic translation initiation factor 3 subunit F
Q9Y6X5 -1.411435 0.3280595 8.750753 -4.302375 0.0021171 0.0348421 Bis(5-adenosyl)-triphosphatase ENPP4
P15924 1.274221 0.3034579 9.350459 4.199004 0.0021231 0.0348421 Desmoplakin
O75746 -1.578482 0.3695373 8.893946 -4.271509 0.0021327 0.0348421 Calcium-binding mitochondrial carrier protein Aralar1
P05455 -1.204229 0.2854061 9.178555 -4.219353 0.0021455 0.0348421 Lupus La protein
Q2TAA5 -1.319245 0.3143146 9.249693 -4.197212 0.0021804 0.0349673 GDP-Man:Man(3)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase
P04004 -1.633973 0.3854552 8.981078 -4.239073 0.0021876 0.0349673 Vitronectin;Vitronectin V65 subunit;Vitronectin V10 subunit;Somatomedin-B
P01031 -1.322378 0.3017394 8.183937 -4.382518 0.0022165 0.0351530 Complement C5;Complement C5 beta chain;Complement C5 alpha chain;C5a anaphylatoxin;Complement C5 alpha chain
Q5JPH6 3.506017 0.7033283 6.212234 4.984894 0.0022530 0.0354450 Probable glutamate–tRNA ligase, mitochondrial
P49458 -2.320823 0.5006356 7.120983 -4.635753 0.0022768 0.0354450 Signal recognition particle 9 kDa protein
P04209 1.316898 0.3151619 9.167154 4.178483 0.0022873 0.0354450 Ig lambda chain V-II region NIG-84
Q04721 1.531039 0.3675191 9.201253 4.165877 0.0023123 0.0355608 Neurogenic locus notch homolog protein 2;Notch 2 extracellular truncation;Notch 2 intracellular domain
Q9UKS6 1.443688 0.3439564 8.943424 4.197299 0.0023485 0.0358449 Protein kinase C and casein kinase substrate in neurons protein 3
Q9BTV4 -1.810463 0.4381260 9.284468 -4.132288 0.0023862 0.0361484 Transmembrane protein 43
O75348 -1.846417 0.4493725 9.377764 -4.108879 0.0024210 0.0364041 V-type proton ATPase subunit G 1
Q12996 -1.667403 0.3663886 7.207709 -4.550913 0.0024442 0.0364833 Cleavage stimulation factor subunit 3
P60468 -1.522924 0.3550773 8.241407 -4.288994 0.0024787 0.0367280 Protein transport protein Sec61 subunit beta
Q6ZSY5 -1.520789 0.3699133 9.170791 -4.111204 0.0025292 0.0370388 Protein phosphatase 1 regulatory subunit 3F
P62760 -1.929645 0.4686939 9.120970 -4.117068 0.0025362 0.0370388 Visinin-like protein 1
Q14019 -3.973669 0.8363384 6.385413 -4.751270 0.0026690 0.0387005 Coactosin-like protein
Q13478 -1.620268 0.3970937 8.994941 -4.080316 0.0027600 0.0397356 Interleukin-18 receptor 1
P01034 -1.689330 0.4126063 8.837162 -4.094289 0.0028058 0.0401104 Cystatin-C
Q53T59 -1.852124 0.4344248 7.876061 -4.263395 0.0028487 0.0402275 HCLS1-binding protein 3
P02776 -1.748717 0.4069507 7.718405 -4.297123 0.0028536 0.0402275 Platelet factor 4;Platelet factor 4, short form
P26447 -1.877769 0.4593883 8.774968 -4.087542 0.0028764 0.0402690 Protein S100-A4
Q9Y2Z0 -1.757978 0.4412870 9.385413 -3.983751 0.0029317 0.0405660 Suppressor of G2 allele of SKP1 homolog
O75475 -1.951060 0.4885410 9.296501 -3.993647 0.0029426 0.0405660 PC4 and SFRS1-interacting protein
Q1KMD3 -1.494563 0.3712572 9.051770 -4.025682 0.0029575 0.0405660 Heterogeneous nuclear ribonucleoprotein U-like protein 2
P01024 -1.148297 0.2873908 9.197920 -3.995596 0.0029972 0.0408343 Complement C3;Complement C3 beta chain;C3-beta-c;Complement C3 alpha chain;C3a anaphylatoxin;Acylation stimulating protein;Complement C3b alpha chain;Complement C3c alpha chain fragment 1;Complement C3dg fragment;Complement C3g fragment;Complement C3d fragment;Complement C3f fragment;Complement C3c alpha chain fragment 2
P54577 -1.309794 0.3255176 8.964139 -4.023729 0.0030257 0.0409480 Tyrosine–tRNA ligase, cytoplasmic;Tyrosine–tRNA ligase, cytoplasmic, N-terminally processed
P54652 -1.585922 0.3969039 9.007166 -3.995732 0.0031255 0.0420185 Heat shock-related 70 kDa protein 2
P25311 -1.476798 0.3658030 8.673237 -4.037141 0.0031737 0.0422552 Zinc-alpha-2-glycoprotein
Q9UK22 -1.968951 0.4285590 6.372396 -4.594351 0.0031847 0.0422552 F-box only protein 2
O94919 -1.158582 0.2941090 9.248102 -3.939294 0.0032331 0.0425105 Endonuclease domain-containing 1 protein
P03950 -2.214295 0.5408135 8.216113 -4.094379 0.0032737 0.0425105 Angiogenin
O15111 -1.770061 0.4097076 7.141811 -4.320302 0.0033195 0.0425105 Inhibitor of nuclear factor kappa-B kinase subunit alpha
P07357 -1.154912 0.2950375 9.290174 -3.914458 0.0033303 0.0425105 Complement component C8 alpha chain
O15116 -3.262825 0.6533382 5.390877 -4.994083 0.0033442 0.0425105 U6 snRNA-associated Sm-like protein LSm1
Q13641 -2.094962 0.4829370 7.050947 -4.337963 0.0033469 0.0425105 Trophoblast glycoprotein
Q9BS26 -1.226358 0.3132596 9.249914 -3.914830 0.0033564 0.0425105 Endoplasmic reticulum resident protein 44
Q14011 -2.439155 0.5991974 8.231467 -4.070703 0.0033715 0.0425105 Cold-inducible RNA-binding protein
P12814 -1.726195 0.4239901 8.144626 -4.071308 0.0034446 0.0431638 Alpha-actinin-1
P25940 -1.680300 0.4292504 9.043783 -3.914499 0.0035074 0.0436810 Collagen alpha-3(V) chain
Q9UBI9 -2.822134 0.6797511 7.613412 -4.151717 0.0035670 0.0441523 Headcase protein homolog
Q96PK6 -1.284104 0.3320346 9.148490 -3.867380 0.0036883 0.0448514 RNA-binding protein 14
Q7LBR1 -2.851457 0.7432377 9.385413 -3.836534 0.0036895 0.0448514 Charged multivesicular body protein 1b
P07384 -1.106938 0.2881747 9.333139 -3.841205 0.0037006 0.0448514 Calpain-1 catalytic subunit
O60262 -1.514780 0.3809638 8.388576 -3.976177 0.0037118 0.0448514 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7
Q86VU5 1.574090 0.4112246 9.385413 3.827810 0.0037405 0.0449299 Catechol O-methyltransferase domain-containing protein 1
Q13636 -3.085924 0.6708563 5.941397 -4.599978 0.0037856 0.0452041 Ras-related protein Rab-31
O43143 -1.010978 0.2650086 9.289616 -3.814887 0.0038896 0.0458869 Pre-mRNA-splicing factor ATP-dependent RNA helicase DHX15
P20774 -2.236773 0.5631895 8.210882 -3.971618 0.0039003 0.0458869 Mimecan
P08311 -1.326822 0.3393339 8.579011 -3.910077 0.0039106 0.0458869 Cathepsin G
A8MTT3 -3.368826 0.8032193 7.070471 -4.194155 0.0039754 0.0461448 Protein CEBPZOS
Q9HB40 -2.173414 0.4870876 6.179009 -4.462060 0.0039780 0.0461448 Retinoid-inducible serine carboxypeptidase
O60476 -2.858033 0.6987082 7.449546 -4.090453 0.0040536 0.0462919 Mannosyl-oligosaccharide 1,2-alpha-mannosidase IB
Q96CS3 -1.329185 0.3488970 9.119924 -3.809678 0.0040557 0.0462919 FAS-associated factor 2
Q04941 -1.954543 0.5132443 9.127049 -3.808212 0.0040591 0.0462919 Proteolipid protein 2
Q8NFQ8 -1.244891 0.3112852 7.843418 -3.999198 0.0041168 0.0466119 Torsin-1A-interacting protein 2
Q9Y3B4 -1.254563 0.3315970 9.218746 -3.783396 0.0041429 0.0466119 Splicing factor 3B subunit 6
O00567 -2.329642 0.6192522 9.376799 -3.762024 0.0041560 0.0466119 Nucleolar protein 56
Q9UKX3 2.040096 0.5408257 9.208912 3.772187 0.0042241 0.0471152 Myosin-13
P56199 -1.282712 0.3337866 8.647866 -3.842911 0.0042549 0.0471986 Integrin alpha-1
P14543 -1.384551 0.3678338 9.204669 -3.764065 0.0042816 0.0472368 Nidogen-1
Q9Y2D4 -1.989829 0.5205860 8.653139 -3.822287 0.0043830 0.0479403 Exocyst complex component 6B
Q6P1N0 -1.699604 0.4098304 6.936107 -4.147091 0.0043979 0.0479403 Coiled-coil and C2 domain-containing protein 1A
Q8NBF2 -1.164826 0.3132700 9.379760 -3.718280 0.0044515 0.0479403 NHL repeat-containing protein 2
P62745 -1.495470 0.3945560 8.788016 -3.790261 0.0044705 0.0479403 Rho-related GTP-binding protein RhoB
Q14254 -1.392125 0.3457572 7.385413 -4.026309 0.0044916 0.0479403 Flotillin-2
Q9Y287 -1.918702 0.5175377 9.385413 -3.707366 0.0045246 0.0479403 Integral membrane protein 2B;BRI2, membrane form;BRI2 intracellular domain;BRI2C, soluble form;Bri23 peptide
P49773 -1.295274 0.3495513 9.385413 -3.705532 0.0045377 0.0479403 Histidine triad nucleotide-binding protein 1
Q9BVC6 -1.637083 0.4433031 9.341936 -3.692921 0.0046665 0.0479403 Transmembrane protein 109
P08670 -1.482725 0.3924566 8.643328 -3.778060 0.0046928 0.0479403 Vimentin
P50991 -1.786149 0.4735903 8.685140 -3.771507 0.0046981 0.0479403 T-complex protein 1 subunit delta
P23434 1.126822 0.3062675 9.385413 3.679208 0.0047316 0.0479403 Glycine cleavage system H protein, mitochondrial
Q6IC98 -1.126652 0.3015080 8.888308 -3.736724 0.0047525 0.0479403 GRAM domain-containing protein 4
Q8IXW5 3.388152 0.8332024 7.009655 4.066422 0.0047569 0.0479403 Putative RNA polymerase II subunit B1 CTD phosphatase RPAP2
Q6P587 5.677610 1.3549193 6.518479 4.190368 0.0047840 0.0479403 Acylpyruvase FAHD1, mitochondrial
P01008 -1.547192 0.4205447 9.310907 -3.679019 0.0047975 0.0479403 Antithrombin-III
P04843 -2.051639 0.5456574 8.660976 -3.759939 0.0048046 0.0479403 Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit 1
Q96FJ2 1.591193 0.4148520 8.139895 3.835568 0.0048186 0.0479403 Dynein light chain 2, cytoplasmic
Q7Z3T8 -1.576843 0.4157303 8.413206 -3.792946 0.0048217 0.0479403 Zinc finger FYVE domain-containing protein 16
P51665 -1.274787 0.3456226 9.194991 -3.688379 0.0048292 0.0479403 26S proteasome non-ATPase regulatory subunit 7
P80723 -1.638540 0.4231920 7.910668 -3.871858 0.0048319 0.0479403 Brain acid soluble protein 1
O95486 -1.500300 0.4068449 9.187800 -3.687646 0.0048413 0.0479403 Protein transport protein Sec24A
Q14258 -1.359986 0.3561261 8.157903 -3.818833 0.0049155 0.0483626 E3 ubiquitin/ISG15 ligase TRIM25
P04275 -1.054100 0.2849243 8.991784 -3.699577 0.0049316 0.0483626 von Willebrand factor;von Willebrand antigen 2
Q16082 -1.361982 0.3713096 9.207589 -3.668050 0.0049745 0.0485490 Heat shock protein beta-2
P32119 -1.348354 0.3464470 7.636769 -3.891950 0.0050302 0.0488581 Peroxiredoxin-2
P05060 -2.649749 0.6720512 7.305570 -3.942778 0.0051268 0.0495588 Secretogranin-1;PE-11;GAWK peptide;CCB peptide
Q9HCB6 -1.808880 0.4871150 8.648303 -3.713455 0.0051666 0.0497073 Spondin-1

4.4 Evaluate results contrast \(\log_2 FC_{V-A}^R\)

4.4.1 Volcano-plot

volcanoRight <- ggplot(rowData(pe[["proteinRobust"]])$"tissueV + locationR:tissueV",
                 aes(x = logFC, y = -log10(pval), color = adjPval < 0.05)) +
 geom_point(cex = 2.5) +
 scale_color_manual(values = alpha(c("black", "red"), 0.5)) + theme_minimal()
volcanoRight

4.4.2 Heatmap

We first select the names of the proteins that were declared signficant.

sigNamesRight <- rowData(pe[["proteinRobust"]])$"tissueV + locationR:tissueV" %>%
 rownames_to_column("proteinRobust") %>%
 filter(adjPval<0.05) %>%
 pull(proteinRobust)
heatmap(assay(pe[["proteinRobust"]])[sigNamesRight, ])

There are 94 proteins significantly differentially expressed at the 5% FDR level.

rowData(pe[["proteinRobust"]])$"tissueV + locationR:tissueV"  %>%
  cbind(.,rowData(pe[["proteinRobust"]])$Protein.names) %>%
  na.exclude %>%
  filter(adjPval<0.05) %>%
  arrange(pval) %>%
  knitr::kable(.)
logFC se df t pval adjPval rowData(pe[[“proteinRobust”]])$Protein.names
P08590 5.358077 0.4191438 9.117912 12.783387 0.0000004 0.0008046 Myosin light chain 3
P06858 3.329246 0.3542730 9.218266 9.397404 0.0000051 0.0051277 Lipoprotein lipase
P02776 -2.841711 0.3443690 7.718405 -8.251937 0.0000430 0.0194907 Platelet factor 4;Platelet factor 4, short form
P35442 -3.207091 0.4221143 8.385413 -7.597683 0.0000491 0.0194907 Thrombospondin-2
O75368 -1.844075 0.2686680 9.251939 -6.863771 0.0000643 0.0194907 SH3 domain-binding glutamic acid-rich-like protein
P54652 -2.725246 0.4112417 9.007166 -6.626871 0.0000959 0.0194907 Heat shock-related 70 kDa protein 2
Q9ULD0 -3.507028 0.3938799 6.128068 -8.903799 0.0000993 0.0194907 2-oxoglutarate dehydrogenase-like, mitochondrial
A6NMZ7 -3.065958 0.4773591 9.385413 -6.422751 0.0001012 0.0194907 Collagen alpha-6(VI) chain
Q6UWY5 -2.469667 0.3813094 9.170135 -6.476806 0.0001053 0.0194907 Olfactomedin-like protein 1
P21810 -2.994207 0.4377152 8.304055 -6.840536 0.0001110 0.0194907 Biglycan
P05546 -1.750184 0.2755089 9.198639 -6.352548 0.0001204 0.0194907 Heparin cofactor 2
P13533 -4.083951 0.6439331 9.115028 -6.342197 0.0001269 0.0194907 Myosin-6
P29622 -1.862155 0.2991501 9.385413 -6.224819 0.0001290 0.0194907 Kallistatin
Q06828 -4.135476 0.6523980 9.003303 -6.338886 0.0001344 0.0194907 Fibromodulin
P46821 -1.622963 0.2654404 9.385413 -6.114227 0.0001481 0.0200375 Microtubule-associated protein 1B;MAP1B heavy chain;MAP1 light chain LC1
P28066 -2.170776 0.3390487 8.500773 -6.402548 0.0001604 0.0203510 Proteasome subunit alpha type-5
Q9UGT4 -2.466535 0.4090800 9.193722 -6.029468 0.0001792 0.0213941 Sushi domain-containing protein 2
Q6PCB0 -2.300792 0.3926118 9.198450 -5.860221 0.0002211 0.0249365 von Willebrand factor A domain-containing protein 1
P35625 -3.979204 0.6344156 7.962134 -6.272235 0.0002447 0.0261405 Metalloproteinase inhibitor 3
P60468 -2.454190 0.4052019 8.241407 -6.056708 0.0002697 0.0268819 Protein transport protein Sec61 subunit beta
Q15327 -2.221783 0.3961366 9.280457 -5.608627 0.0002957 0.0268819 Ankyrin repeat domain-containing protein 1
Q14764 -1.616256 0.2901417 9.385413 -5.570573 0.0002985 0.0268819 Major vault protein
Q69YU5 3.220843 0.5625486 8.841525 5.725448 0.0003046 0.0268819 Uncharacterized protein C12orf73
Q9P2B2 -2.045271 0.3731311 9.385413 -5.481374 0.0003362 0.0281811 Prostaglandin F2 receptor negative regulator
P48163 -2.953929 0.4964480 7.960353 -5.950127 0.0003486 0.0281811 NADP-dependent malic enzyme
Q92930 -2.803127 0.4638105 7.597170 -6.043690 0.0003777 0.0281811 Ras-related protein Rab-8B
P48681 -1.493328 0.2771541 9.321612 -5.388078 0.0003901 0.0281811 Nestin
P01031 -1.652659 0.2888520 8.183937 -5.721472 0.0004077 0.0281811 Complement C5;Complement C5 beta chain;Complement C5 alpha chain;C5a anaphylatoxin;Complement C5 alpha chain
O43677 -2.965485 0.5101963 7.933870 -5.812438 0.0004121 0.0281811 NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial
P02775 -2.169029 0.4075050 9.385413 -5.322705 0.0004165 0.0281811 Platelet basic protein;Connective tissue-activating peptide III;TC-2;Connective tissue-activating peptide III(1-81);Beta-thromboglobulin;Neutrophil-activating peptide 2(74);Neutrophil-activating peptide 2(73);Neutrophil-activating peptide 2;TC-1;Neutrophil-activating peptide 2(1-66);Neutrophil-activating peptide 2(1-63)
P30711 -2.323525 0.4343764 9.018645 -5.349105 0.0004597 0.0301015 Glutathione S-transferase theta-1
Q96FN9 -2.647962 0.4831404 8.385413 -5.480729 0.0004988 0.0308425 Probable D-tyrosyl-tRNA(Tyr) deacylase 2
P11586 2.011996 0.3618415 7.881516 5.560434 0.0005632 0.0308425 C-1-tetrahydrofolate synthase, cytoplasmic;Methylenetetrahydrofolate dehydrogenase;Methenyltetrahydrofolate cyclohydrolase;Formyltetrahydrofolate synthetase;C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed
Q9H1K0 -2.283648 0.3962045 7.385413 -5.763812 0.0005668 0.0308425 Rabenosyn-5
P30405 -1.828202 0.3587630 9.385413 -5.095848 0.0005693 0.0308425 Peptidyl-prolyl cis-trans isomerase F, mitochondrial
Q09161 2.423061 0.3818259 6.358037 6.345983 0.0005705 0.0308425 Nuclear cap-binding protein subunit 1
Q5NDL2 -2.704579 0.5131644 8.686198 -5.270394 0.0005771 0.0308425 EGF domain-specific O-linked N-acetylglucosamine transferase
Q9BZH6 3.420486 0.6371741 8.367230 5.368213 0.0005773 0.0308425 WD repeat-containing protein 11
O00180 -4.755346 0.8920012 8.385413 -5.331098 0.0006003 0.0309185 Potassium channel subfamily K member 1
P00748 -1.948996 0.3807404 9.091376 -5.118963 0.0006092 0.0309185 Coagulation factor XII;Coagulation factor XIIa heavy chain;Beta-factor XIIa part 1;Coagulation factor XIIa light chain
Q00G26 1.936681 0.3542707 7.788675 5.466670 0.0006541 0.0319953 Perilipin-5
P23142 -2.819044 0.5094029 7.590129 -5.534018 0.0006620 0.0319953 Fibulin-1
P10916 2.903591 0.5190748 7.385413 5.593783 0.0006814 0.0321678 Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
Q9UHG2 -3.305283 0.6492888 8.796297 -5.090620 0.0007015 0.0323665 ProSAAS;KEP;Big SAAS;Little SAAS;Big PEN-LEN;PEN;Little LEN;Big LEN
Q9BW30 -2.326316 0.4679439 9.049210 -4.971357 0.0007561 0.0336366 Tubulin polymerization-promoting protein family member 3
P18428 -1.701410 0.3439009 9.013977 -4.947385 0.0007905 0.0336366 Lipopolysaccharide-binding protein
Q5JPH6 3.243753 0.5340074 6.212234 6.074360 0.0007941 0.0336366 Probable glutamate–tRNA ligase, mitochondrial
Q9BUH6 -1.516414 0.3086486 9.115985 -4.913078 0.0008018 0.0336366 Protein PAXX
P12883 1.752389 0.3596357 9.255194 4.872678 0.0008119 0.0336366 Myosin-7
P35052 -1.955749 0.3694381 7.703314 -5.293847 0.0008301 0.0337017 Glypican-1;Secreted glypican-1
Q8N474 -2.161723 0.4158032 7.847514 -5.198911 0.0008754 0.0348447 Secreted frizzled-related protein 1
Q99983 -3.574620 0.6431377 6.904704 -5.558094 0.0008937 0.0348873 Osteomodulin
P04004 -1.932935 0.4008337 8.981078 -4.822288 0.0009496 0.0354254 Vitronectin;Vitronectin V65 subunit;Vitronectin V10 subunit;Somatomedin-B
P62857 -2.138437 0.4200464 7.956911 -5.090954 0.0009561 0.0354254 40S ribosomal protein S28
O15061 -1.702821 0.3601514 9.385413 -4.728071 0.0009598 0.0354254 Synemin
P08603 -1.493256 0.3168082 9.385413 -4.713438 0.0009804 0.0355379 Complement factor H
Q9NRG4 2.553079 0.5223003 8.385413 4.888143 0.0010578 0.0376713 N-lysine methyltransferase SMYD2
Q96KC8 -2.528784 0.5175266 8.321700 -4.886287 0.0010840 0.0379395 DnaJ homolog subfamily C member 1
P23434 1.413938 0.3062675 9.385413 4.616676 0.0011287 0.0383884 Glycine cleavage system H protein, mitochondrial
Q04760 2.216188 0.4645453 8.599181 4.770661 0.0011516 0.0383884 Lactoylglutathione lyase
P02452 -2.007037 0.4158054 8.367424 -4.826865 0.0011535 0.0383884 Collagen alpha-1(I) chain
P24298 1.963174 0.4165267 8.623072 4.713201 0.0012356 0.0398590 Alanine aminotransferase 1
Q15113 -1.988509 0.4330474 9.188121 -4.591895 0.0012370 0.0398590 Procollagen C-endopeptidase enhancer 1
P50453 -1.422449 0.3086989 9.052869 -4.607886 0.0012567 0.0398605 Serpin B9
P04275 -1.362325 0.2963324 8.991784 -4.597287 0.0012986 0.0405566 von Willebrand factor;von Willebrand antigen 2
Q7L4S7 -2.547761 0.5017188 7.157555 -5.078066 0.0013409 0.0412425 Protein ARMCX6
Q86WV6 -1.336643 0.2979661 9.239827 -4.485891 0.0014229 0.0424928 Stimulator of interferon genes protein
Q92604 -1.925795 0.4331202 9.345516 -4.446330 0.0014664 0.0424928 Acyl-CoA:lysophosphatidylglycerol acyltransferase 1
Q9HCB6 -2.416374 0.5273097 8.648303 -4.582457 0.0014674 0.0424928 Spondin-1
P82663 -1.935089 0.4352236 9.302714 -4.446194 0.0014834 0.0424928 28S ribosomal protein S25, mitochondrial
Q6PI78 1.948479 0.4338791 9.040261 4.490835 0.0014919 0.0424928 Transmembrane protein 65
Q8TDB4 -2.860288 0.5377313 6.330306 -5.319177 0.0015176 0.0424928 Protein MGARP
P01611 -2.219411 0.5030754 9.385413 -4.411687 0.0015281 0.0424928 Ig kappa chain V-I region Wes
Q15274 -2.178586 0.4620144 7.757883 -4.715407 0.0016427 0.0426894 Nicotinate-nucleotide pyrophosphorylase [carboxylating]
P08294 -1.898191 0.4077813 7.979491 -4.654924 0.0016454 0.0426894 Extracellular superoxide dismutase [Cu-Zn]
Q9BSD7 2.950896 0.6028017 7.080846 4.895302 0.0017057 0.0426894 Cancer-related nucleoside-triphosphatase
Q9Y6X5 -1.544960 0.3471001 8.750753 -4.451051 0.0017123 0.0426894 Bis(5-adenosyl)-triphosphatase ENPP4
Q6YN16 1.546774 0.3546814 9.222955 4.361023 0.0017180 0.0426894 Hydroxysteroid dehydrogenase-like protein 2
P01303 -2.163300 0.4894155 8.890312 -4.420171 0.0017214 0.0426894 Pro-neuropeptide Y;Neuropeptide Y;C-flanking peptide of NPY
P51888 -1.946837 0.3954667 6.959924 -4.922884 0.0017365 0.0426894 Prolargin
P07360 -1.547962 0.3489250 8.752393 -4.436374 0.0017475 0.0426894 Complement component C8 gamma chain
P04350 -2.838038 0.5777244 6.967833 -4.912443 0.0017514 0.0426894 Tubulin beta-4A chain
P24844 -1.783615 0.4121116 9.330669 -4.327990 0.0017561 0.0426894 Myosin regulatory light polypeptide 9
Q9UL26 7.923835 1.7917216 8.784585 4.422470 0.0017665 0.0426894 Ras-related protein Rab-22A
P07357 -1.256415 0.2926092 9.290174 -4.293832 0.0018671 0.0445443 Complement component C8 alpha chain
Q8TBP6 -1.527281 0.3500100 8.851865 -4.363535 0.0018871 0.0445443 Solute carrier family 25 member 40
P04003 -1.392094 0.3246379 9.090898 -4.288144 0.0019793 0.0459247 C4b-binding protein alpha chain
Q6UWS5 1.776260 0.3726694 7.068224 4.766316 0.0019908 0.0459247 Protein PET117 homolog, mitochondrial
O15230 -1.351267 0.3157713 9.044210 -4.279259 0.0020293 0.0462856 Laminin subunit alpha-5
O14980 -1.048446 0.2497751 9.382448 -4.197561 0.0021118 0.0476331 Exportin-1
O94875-10 1.381826 0.3251982 8.958355 4.249182 0.0021677 0.0483561 Sorbin and SH3 domain-containing protein 2
P12814 -2.192490 0.5008954 8.144626 -4.377140 0.0022587 0.0493912 Alpha-actinin-1
P02743 -1.660711 0.3999916 9.385413 -4.151865 0.0022628 0.0493912 Serum amyloid P-component;Serum amyloid P-component(1-203)
Q9HAT2 1.866882 0.4480930 9.216677 4.166282 0.0023025 0.0497243 Sialate O-acetylesterase

4.5 Evaluate results average contrast \(\log_2 FC_{V-A}\)

4.5.1 Volcano-plot

volcanoAvg <- ggplot(rowData(pe[["proteinRobust"]])$"tissueV + 0.5 * locationR:tissueV",
                 aes(x = logFC, y = -log10(pval), color = adjPval < 0.05)) +
 geom_point(cex = 2.5) +
 scale_color_manual(values = alpha(c("black", "red"), 0.5)) + theme_minimal()
volcanoAvg

4.5.2 Heatmap

We first select the names of the proteins that were declared signficant.

sigNamesAvg <- rowData(pe[["proteinRobust"]])$"tissueV + 0.5 * locationR:tissueV" %>%
 rownames_to_column("proteinRobust") %>%
 filter(adjPval<0.05) %>%
 pull(proteinRobust)
heatmap(assay(pe[["proteinRobust"]])[sigNamesAvg, ])

There are 461 proteins significantly differentially expressed at the 5% FDR level.

rowData(pe[["proteinRobust"]])$"tissueV + 0.5 * locationR:tissueV" %>%
  cbind(.,rowData(pe[["proteinRobust"]])$Protein.names) %>%
  na.exclude %>%
  filter(adjPval<0.05) %>%
  arrange(pval) %>%
  knitr::kable(.)
logFC se df t pval adjPval rowData(pe[[“proteinRobust”]])$Protein.names
P08590 6.4625112 0.2976280 9.117912 21.713386 0.0000000 0.0000074 Myosin light chain 3
P12883 3.0427569 0.2557724 9.255194 11.896344 0.0000006 0.0006551 Myosin-7
O75368 -2.0672256 0.1911057 9.251939 -10.817185 0.0000015 0.0007617 SH3 domain-binding glutamic acid-rich-like protein
P10916 4.9061329 0.3591470 7.385413 13.660515 0.0000017 0.0007617 Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
Q6UWY5 -2.8614477 0.2723232 9.170135 -10.507543 0.0000020 0.0007617 Olfactomedin-like protein 1
P46821 -1.9028923 0.1876947 9.385413 -10.138230 0.0000023 0.0007617 Microtubule-associated protein 1B;MAP1B heavy chain;MAP1 light chain LC1
P06858 2.5622451 0.2524054 9.218266 10.151307 0.0000026 0.0007617 Lipoprotein lipase
P29622 -1.9885126 0.2115311 9.385413 -9.400570 0.0000044 0.0010675 Kallistatin
P05546 -1.8329275 0.1931907 9.198639 -9.487658 0.0000047 0.0010675 Heparin cofactor 2
P21810 -3.1872304 0.3151219 8.304055 -10.114278 0.0000059 0.0011366 Biglycan
P35442 -2.7706752 0.2792024 8.385413 -9.923538 0.0000064 0.0011366 Thrombospondin-2
P13533 -4.1989377 0.4579673 9.115028 -9.168640 0.0000067 0.0011366 Myosin-6
Q06828 -4.1723327 0.4703068 9.003303 -8.871513 0.0000096 0.0014958 Fibromodulin
Q8N474 -2.7331853 0.2795787 7.847514 -9.776084 0.0000115 0.0016658 Secreted frizzled-related protein 1
P02452 -2.6166150 0.2921724 8.367424 -8.955722 0.0000144 0.0018663 Collagen alpha-1(I) chain
Q9UGT4 -2.3750749 0.2867846 9.193722 -8.281739 0.0000147 0.0018663 Sushi domain-containing protein 2
O94875-10 1.8515322 0.2254187 8.958355 8.213746 0.0000184 0.0019441 Sorbin and SH3 domain-containing protein 2
Q16647 -2.1609826 0.2677306 9.156725 -8.071483 0.0000186 0.0019441 Prostacyclin synthase
Q14764 -1.6211158 0.2051612 9.385413 -7.901669 0.0000191 0.0019441 Major vault protein
A6NMZ7 -2.6666436 0.3375438 9.385413 -7.900140 0.0000192 0.0019441 Collagen alpha-6(VI) chain
O95865 -1.5774343 0.2030636 9.385413 -7.768178 0.0000220 0.0020570 N(G),N(G)-dimethylarginine dimethylaminohydrolase 2
Q9P2B2 -2.0463902 0.2638435 9.385413 -7.756076 0.0000223 0.0020570 Prostaglandin F2 receptor negative regulator
Q15113 -2.3717647 0.3035044 9.188121 -7.814597 0.0000237 0.0020912 Procollagen C-endopeptidase enhancer 1
P18428 -1.8519938 0.2405365 9.013977 -7.699428 0.0000298 0.0025169 Lipopolysaccharide-binding protein
P02776 -2.2952145 0.2665516 7.718405 -8.610771 0.0000319 0.0025481 Platelet factor 4;Platelet factor 4, short form
P24844 -2.1677081 0.2920895 9.330669 -7.421383 0.0000330 0.0025481 Myosin regulatory light polypeptide 9
Q9BW30 -2.5325002 0.3361911 9.049210 -7.532919 0.0000346 0.0025481 Tubulin polymerization-promoting protein family member 3
P54652 -2.1555836 0.2857710 9.007166 -7.543045 0.0000351 0.0025481 Heat shock-related 70 kDa protein 2
P00748 -1.9760261 0.2655421 9.091376 -7.441479 0.0000372 0.0025980 Coagulation factor XII;Coagulation factor XIIa heavy chain;Beta-factor XIIa part 1;Coagulation factor XIIa light chain
O43677 -2.8617874 0.3490622 7.933870 -8.198503 0.0000384 0.0025980 NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial
P48681 -1.4117043 0.1954445 9.321612 -7.223044 0.0000413 0.0026554 Nestin
P51888 -2.5731928 0.2835498 6.959924 -9.074923 0.0000419 0.0026554 Prolargin
P02775 -2.0605776 0.2881496 9.385413 -7.151070 0.0000432 0.0026568 Platelet basic protein;Connective tissue-activating peptide III;TC-2;Connective tissue-activating peptide III(1-81);Beta-thromboglobulin;Neutrophil-activating peptide 2(74);Neutrophil-activating peptide 2(73);Neutrophil-activating peptide 2;TC-1;Neutrophil-activating peptide 2(1-66);Neutrophil-activating peptide 2(1-63)
P08294 -2.3273246 0.2968595 7.979491 -7.839819 0.0000512 0.0030425 Extracellular superoxide dismutase [Cu-Zn]
O00180 -4.4260339 0.5900034 8.385413 -7.501710 0.0000539 0.0030425 Potassium channel subfamily K member 1
P02743 -1.9672445 0.2828368 9.385413 -6.955406 0.0000540 0.0030425 Serum amyloid P-component;Serum amyloid P-component(1-203)
P14854 1.6832743 0.2271074 8.346841 7.411798 0.0000604 0.0031941 Cytochrome c oxidase subunit 6B1
Q5NDL2 -2.5211042 0.3501742 8.686198 -7.199572 0.0000610 0.0031941 EGF domain-specific O-linked N-acetylglucosamine transferase
Q92604 -2.0980384 0.3057458 9.345516 -6.862036 0.0000614 0.0031941 Acyl-CoA:lysophosphatidylglycerol acyltransferase 1
P60468 -1.9885569 0.2703727 8.241407 -7.354874 0.0000683 0.0034653 Protein transport protein Sec61 subunit beta
P23083 -3.2749341 0.4122019 7.385413 -7.944976 0.0000714 0.0035334 Ig heavy chain V-I region V35
P30405 -1.6842375 0.2536837 9.385413 -6.639124 0.0000781 0.0037005 Peptidyl-prolyl cis-trans isomerase F, mitochondrial
P51884 -1.9277723 0.2600484 7.936878 -7.413128 0.0000784 0.0037005 Lumican
Q9ULL5-3 -2.2984552 0.3119661 7.893242 -7.367645 0.0000842 0.0037660 Proline-rich protein 12
P01031 -1.4875185 0.2092918 8.183937 -7.107390 0.0000905 0.0037660 Complement C5;Complement C5 beta chain;Complement C5 alpha chain;C5a anaphylatoxin;Complement C5 alpha chain
Q6PCB0 -1.8152862 0.2753405 9.198450 -6.592879 0.0000905 0.0037660 von Willebrand factor A domain-containing protein 1
Q8TBP6 -1.7102618 0.2536922 8.851865 -6.741483 0.0000914 0.0037660 Solute carrier family 25 member 40
Q53GQ0 -1.8232291 0.2797866 9.334954 -6.516498 0.0000926 0.0037660 Very-long-chain 3-oxoacyl-CoA reductase
P36955 -1.6946775 0.2459657 8.456893 -6.889895 0.0000966 0.0037660 Pigment epithelium-derived factor
O14980 -1.1393991 0.1766395 9.382448 -6.450420 0.0000980 0.0037660 Exportin-1
Q92508 3.5066909 0.4088131 6.385413 8.577735 0.0000980 0.0037660 Piezo-type mechanosensitive ion channel component 1
Q14195-2 -2.2588828 0.3476626 9.262403 -6.497341 0.0000982 0.0037660 Dihydropyrimidinase-related protein 3
P05997 -2.5339895 0.3799038 8.864434 -6.670083 0.0000983 0.0037660 Collagen alpha-2(V) chain
Q15327 -1.7881570 0.2788386 9.280457 -6.412874 0.0001077 0.0039884 Ankyrin repeat domain-containing protein 1
P00325 -1.5039787 0.2325735 9.141096 -6.466682 0.0001081 0.0039884 Alcohol dehydrogenase 1B
P35625 -2.9820031 0.4278849 7.962134 -6.969171 0.0001188 0.0043077 Metalloproteinase inhibitor 3
P07451 -1.2910732 0.2057778 9.385413 -6.274113 0.0001214 0.0043228 Carbonic anhydrase 3
P04004 -1.7834542 0.2780483 8.981078 -6.414189 0.0001244 0.0043267 Vitronectin;Vitronectin V65 subunit;Vitronectin V10 subunit;Somatomedin-B
P41240 -1.3613815 0.2127198 8.922337 -6.399880 0.0001302 0.0043267 Tyrosine-protein kinase CSK
Q69YU5 2.4923143 0.3874663 8.841525 6.432339 0.0001305 0.0043267 Uncharacterized protein C12orf73
Q8WWA0 -4.4480904 0.6626292 8.244689 -6.712790 0.0001313 0.0043267 Intelectin-1
P46060 -1.7409587 0.2624323 8.385413 -6.633934 0.0001321 0.0043267 Ran GTPase-activating protein 1
P28066 -1.6401936 0.2502063 8.500773 -6.555364 0.0001353 0.0043611 Proteasome subunit alpha type-5
O15230 -1.3831391 0.2198154 9.044210 -6.292275 0.0001393 0.0044015 Laminin subunit alpha-5
O95980 -1.9680314 0.2898803 7.980660 -6.789117 0.0001409 0.0044015 Reversion-inducing cysteine-rich protein with Kazal motifs
Q6YN16 1.5369703 0.2490340 9.222955 6.171729 0.0001483 0.0045619 Hydroxysteroid dehydrogenase-like protein 2
Q7L4S7 -2.1476054 0.2976126 7.157555 -7.216110 0.0001572 0.0046901 Protein ARMCX6
P04003 -1.4355734 0.2328336 9.090898 -6.165662 0.0001587 0.0046901 C4b-binding protein alpha chain
Q15274 -2.0534369 0.3025225 7.757883 -6.787717 0.0001608 0.0046901 Nicotinate-nucleotide pyrophosphorylase [carboxylating]
P04083 -1.3497192 0.2233143 9.385413 -6.044035 0.0001617 0.0046901 Annexin A1
P36021 -2.5372663 0.3952239 8.385413 -6.419821 0.0001670 0.0047747 Monocarboxylate transporter 8
Q9BXN1 -2.2900275 0.3712225 8.937487 -6.168882 0.0001698 0.0047874 Asporin
Q9Y6X5 -1.4781975 0.2387999 8.750753 -6.190111 0.0001809 0.0050078 Bis(5-adenosyl)-triphosphatase ENPP4
Q07954 -1.3233833 0.2224711 9.385413 -5.948564 0.0001826 0.0050078 Prolow-density lipoprotein receptor-related protein 1;Low-density lipoprotein receptor-related protein 1 85 kDa subunit;Low-density lipoprotein receptor-related protein 1 515 kDa subunit;Low-density lipoprotein receptor-related protein 1 intracellular domain
O75828 -1.5053475 0.2540246 9.385413 -5.925992 0.0001879 0.0050083 Carbonyl reductase [NADPH] 3
P12110 -1.6865779 0.2700881 8.535409 -6.244548 0.0001885 0.0050083 Collagen alpha-2(VI) chain
Q9UBG0 -1.6619433 0.2773921 9.131671 -5.991314 0.0001931 0.0050083 C-type mannose receptor 2
P04196 -1.6884017 0.2542452 7.683140 -6.640839 0.0001946 0.0050083 Histidine-rich glycoprotein
Q9NZ01 -1.8500678 0.3007922 8.691035 -6.150652 0.0001949 0.0050083 Very-long-chain enoyl-CoA reductase
P23434 1.2703798 0.2165638 9.385413 5.866076 0.0002029 0.0051267 Glycine cleavage system H protein, mitochondrial
P23142 -2.3359021 0.3515315 7.590129 -6.644929 0.0002046 0.0051267 Fibulin-1
Q92681 -1.8263794 0.2904491 8.133279 -6.288122 0.0002200 0.0054460 Regulatory solute carrier protein family 1 member 1
P07357 -1.2056635 0.2077663 9.290174 -5.802980 0.0002289 0.0055985 Complement component C8 alpha chain
P04275 -1.2082122 0.2055449 8.991784 -5.878095 0.0002362 0.0057087 von Willebrand factor;von Willebrand antigen 2
P49207 -1.3752484 0.2347644 8.970773 -5.857995 0.0002444 0.0058016 60S ribosomal protein L34
Q8TBQ9 -1.7430434 0.2824761 8.170120 -6.170588 0.0002458 0.0058016 Protein kish-A
Q9BUF5 -1.7774391 0.3096233 9.217423 -5.740650 0.0002555 0.0059622 Tubulin beta-6 chain
P50453 -1.2397969 0.2150088 9.052869 -5.766260 0.0002648 0.0060077 Serpin B9
Q5JPH6 3.3748852 0.4562924 6.212234 7.396321 0.0002665 0.0060077 Probable glutamate–tRNA ligase, mitochondrial
Q9BZH6 2.6758207 0.4457948 8.367230 6.002360 0.0002702 0.0060077 WD repeat-containing protein 11
P01024 -1.1496569 0.2015704 9.197920 -5.703501 0.0002702 0.0060077 Complement C3;Complement C3 beta chain;C3-beta-c;Complement C3 alpha chain;C3a anaphylatoxin;Acylation stimulating protein;Complement C3b alpha chain;Complement C3c alpha chain fragment 1;Complement C3dg fragment;Complement C3g fragment;Complement C3d fragment;Complement C3f fragment;Complement C3c alpha chain fragment 2
Q9HCB6 -2.1126269 0.3589347 8.648303 -5.885825 0.0002723 0.0060077 Spondin-1
Q86WV6 -1.2006082 0.2120678 9.239827 -5.661436 0.0002805 0.0061226 Stimulator of interferon genes protein
P30711 -1.7885395 0.3126012 9.018645 -5.721474 0.0002842 0.0061378 Glutathione S-transferase theta-1
Q9NRG4 2.3553762 0.3989134 8.385413 5.904480 0.0003002 0.0063497 N-lysine methyltransferase SMYD2
O60760 -2.2815940 0.3864378 8.385413 -5.904169 0.0003003 0.0063497 Hematopoietic prostaglandin D synthase
P62760 -1.8910941 0.3355983 9.120970 -5.634992 0.0003044 0.0063707 Visinin-like protein 1
P12814 -1.9593420 0.3281249 8.144626 -5.971329 0.0003113 0.0064488 Alpha-actinin-1
P24298 1.6321192 0.2831640 8.623072 5.763865 0.0003191 0.0065425 Alanine aminotransferase 1
Q9UQ35 -1.2479485 0.2265532 9.385413 -5.508412 0.0003242 0.0065816 Serine/arginine repetitive matrix protein 2
P14550 -1.3044364 0.2225655 8.301450 -5.860910 0.0003283 0.0065991 Alcohol dehydrogenase [NADP(+)]
O94919 -1.1546247 0.2088661 9.248102 -5.528061 0.0003329 0.0066246 Endonuclease domain-containing 1 protein
Q9Y3B4 -1.2989386 0.2361784 9.218746 -5.499820 0.0003494 0.0068655 Splicing factor 3B subunit 6
P49458 -1.9200693 0.3013686 7.120983 -6.371165 0.0003517 0.0068655 Signal recognition particle 9 kDa protein
Q9UNW9 3.3281626 0.6111632 9.054127 5.445620 0.0003996 0.0076489 RNA-binding protein Nova-2
P48163 -1.9140897 0.3290692 7.960353 -5.816679 0.0004050 0.0076489 NADP-dependent malic enzyme
Q5M9N0 -2.7847331 0.4916908 8.350040 -5.663586 0.0004057 0.0076489 Coiled-coil domain-containing protein 158
P02747 -1.8649499 0.3002262 7.138784 -6.211815 0.0004069 0.0076489 Complement C1q subcomponent subunit C
Q00G26 1.4536200 0.2477814 7.788675 5.866543 0.0004159 0.0077448 Perilipin-5
Q8WY22 -1.5477211 0.2756010 8.385413 -5.615805 0.0004231 0.0077538 BRI3-binding protein
Q9UHG2 -2.4417072 0.4457629 8.796297 -5.477592 0.0004240 0.0077538 ProSAAS;KEP;Big SAAS;Little SAAS;Big PEN-LEN;PEN;Little LEN;Big LEN
Q9ULC3 -1.4634583 0.2660801 8.669265 -5.500068 0.0004336 0.0078588 Ras-related protein Rab-23
P25940 -1.6268129 0.3026580 9.043783 -5.375087 0.0004401 0.0079054 Collagen alpha-3(V) chain
Q53GG5-2 -2.4390475 0.4404803 8.429675 -5.537246 0.0004569 0.0080899 PDZ and LIM domain protein 3
Q8WZA9 -1.1072814 0.2082637 9.101344 -5.316729 0.0004653 0.0080899 Immunity-related GTPase family Q protein
P07585 -2.1345776 0.4031029 9.163968 -5.295366 0.0004680 0.0080899 Decorin
O00264 -1.4169853 0.2667510 9.079390 -5.312014 0.0004721 0.0080899 Membrane-associated progesterone receptor component 1
Q53T59 -1.8337712 0.3208050 7.876061 -5.716155 0.0004722 0.0080899 HCLS1-binding protein 3
Q6SZW1 -2.0501728 0.3456301 7.385413 -5.931696 0.0004742 0.0080899 Sterile alpha and TIR motif-containing protein 1
Q9BS26 -1.1652487 0.2228454 9.249914 -5.228955 0.0004964 0.0083980 Endoplasmic reticulum resident protein 44
P01008 -1.5396740 0.2964219 9.310907 -5.194199 0.0005096 0.0085495 Antithrombin-III
Q9UKR5 -3.7435260 0.6964057 8.595465 -5.375496 0.0005225 0.0086032 Probable ergosterol biosynthetic protein 28
P14543 -1.3422700 0.2580050 9.204669 -5.202496 0.0005229 0.0086032 Nidogen-1
P08603 -1.1544473 0.2240173 9.385413 -5.153386 0.0005255 0.0086032 Complement factor H
Q92621 -1.2423196 0.2415233 9.385413 -5.143684 0.0005326 0.0086499 Nuclear pore complex protein Nup205
Q9BTV4 -1.6057405 0.3110895 9.284468 -5.161667 0.0005377 0.0086637 Transmembrane protein 43
P13671 -1.3648753 0.2664751 9.385413 -5.121963 0.0005489 0.0087744 Complement component C6
Q2TAA5 -1.1443503 0.2235983 9.249693 -5.117885 0.0005779 0.0091655 GDP-Man:Man(3)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase
Q12996 -1.4804805 0.2552304 7.207709 -5.800565 0.0005960 0.0093205 Cleavage stimulation factor subunit 3
P20774 -2.1010556 0.3896021 8.210882 -5.392824 0.0005969 0.0093205 Mimecan
Q9UJC5 -1.2259781 0.2425389 9.326832 -5.054769 0.0006146 0.0094299 SH3 domain-binding glutamic acid-rich-like protein 2
P01042 -2.0066697 0.3480072 7.210294 -5.766173 0.0006170 0.0094299 Kininogen-1;Kininogen-1 heavy chain;T-kinin;Bradykinin;Lysyl-bradykinin;Kininogen-1 light chain;Low molecular weight growth-promoting factor
O14967 -1.6369952 0.3092277 8.430438 -5.293818 0.0006179 0.0094299 Calmegin
Q16082 -1.3233427 0.2607936 9.207589 -5.074291 0.0006225 0.0094299 Heat shock protein beta-2
Q6PI78 1.5357334 0.3017719 9.040261 5.089054 0.0006457 0.0097101 Transmembrane protein 65
Q8TDB4 -2.3494772 0.3787763 6.330306 -6.202809 0.0006590 0.0097915 Protein MGARP
Q9HAT2 1.6055669 0.3192733 9.216677 5.028817 0.0006608 0.0097915 Sialate O-acetylesterase
Q9BUH6 -1.1106212 0.2210609 9.115985 -5.024051 0.0006878 0.0100890 Protein PAXX
Q9ULD0 -2.0151143 0.3202146 6.128068 -6.293011 0.0006908 0.0100890 2-oxoglutarate dehydrogenase-like, mitochondrial
Q14314 -1.9322639 0.3920483 9.382448 -4.928637 0.0007208 0.0104515 Fibroleukin
P45877 -0.9996304 0.2027328 9.343571 -4.930777 0.0007275 0.0104735 Peptidyl-prolyl cis-trans isomerase C
Q96H79 -2.1774013 0.3587038 6.334231 -6.070192 0.0007408 0.0105623 Zinc finger CCCH-type antiviral protein 1-like
P35052 -1.2875376 0.2389775 7.703314 -5.387694 0.0007440 0.0105623 Glypican-1;Secreted glypican-1
P11586 1.2680380 0.2388823 7.881516 5.308212 0.0007574 0.0106771 C-1-tetrahydrofolate synthase, cytoplasmic;Methylenetetrahydrofolate dehydrogenase;Methenyltetrahydrofolate cyclohydrolase;Formyltetrahydrofolate synthetase;C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed
Q9HAV4 -1.6824690 0.3206960 7.987893 -5.246305 0.0007811 0.0109357 Exportin-5
P40261 -1.4339415 0.2942762 9.340024 -4.872774 0.0007907 0.0109462 Nicotinamide N-methyltransferase
P02790 -1.3244981 0.2724643 9.385413 -4.861179 0.0007927 0.0109462 Hemopexin
P19429 2.0691315 0.3954475 7.976624 5.232379 0.0007980 0.0109462 Troponin I, cardiac muscle
P34932 -0.8925962 0.1844794 9.385413 -4.838461 0.0008188 0.0111559 Heat shock 70 kDa protein 4
Q09161 2.0115745 0.3402010 6.358037 5.912900 0.0008442 0.0114245 Nuclear cap-binding protein subunit 1
Q15126 -1.0103044 0.2097310 9.342811 -4.817144 0.0008552 0.0114968 Phosphomevalonate kinase
P50479 -2.1200408 0.4140571 8.131897 -5.120165 0.0008621 0.0115130 PDZ and LIM domain protein 4
Q9NY15 -1.4835786 0.3089047 9.336638 -4.802707 0.0008747 0.0116049 Stabilin-1
Q86VP6 -1.3548284 0.2717978 8.542953 -4.984693 0.0008822 0.0116274 Cullin-associated NEDD8-dissociated protein 1
Q07507 -1.3153838 0.2587790 8.160106 -5.083039 0.0008935 0.0116274 Dermatopontin
O43175 -2.0775407 0.4307821 9.173117 -4.822719 0.0008937 0.0116274 D-3-phosphoglycerate dehydrogenase
P02461 -2.9357775 0.5844720 8.323445 -5.022957 0.0009077 0.0116274 Collagen alpha-1(III) chain
P01034 -1.4660858 0.3001221 8.837162 -4.884964 0.0009125 0.0116274 Cystatin-C
P28300 -1.4793279 0.2827310 7.649016 -5.232280 0.0009129 0.0116274 Protein-lysine 6-oxidase
P13667 -1.1046003 0.2299757 9.181460 -4.803117 0.0009164 0.0116274 Protein disulfide-isomerase A4
Q86VU5 1.3820110 0.2907797 9.385413 4.752776 0.0009261 0.0116774 Catechol O-methyltransferase domain-containing protein 1
O43143 -0.8972350 0.1881734 9.289616 -4.768130 0.0009321 0.0116801 Pre-mRNA-splicing factor ATP-dependent RNA helicase DHX15
O95183 -1.4595318 0.3089309 9.371170 -4.724460 0.0009689 0.0120661 Vesicle-associated membrane protein 5
Q96CS3 -1.1904104 0.2496881 9.119924 -4.767590 0.0009819 0.0121212 FAS-associated factor 2
P06727 -1.0625381 0.2206360 8.884167 -4.815797 0.0009881 0.0121212 Apolipoprotein A-IV
P09619 -1.2925211 0.2721302 9.154490 -4.749643 0.0009967 0.0121212 Platelet-derived growth factor receptor beta
P26447 -1.5232285 0.3150582 8.774968 -4.834753 0.0009972 0.0121212 Protein S100-A4
P46940 -1.1176083 0.2393244 9.306592 -4.669847 0.0010683 0.0129091 Ras GTPase-activating-like protein IQGAP1
Q15582 -2.2755713 0.4543685 7.899813 -5.008206 0.0010822 0.0129993 Transforming growth factor-beta-induced protein ig-h3
Q96JB2 -1.9983947 0.4070184 8.142504 -4.909838 0.0011200 0.0133746 Conserved oligomeric Golgi complex subunit 3
P01019 -1.0245069 0.2195559 9.093510 -4.666269 0.0011427 0.0135650 Angiotensinogen;Angiotensin-1;Angiotensin-2;Angiotensin-3;Angiotensin-4;Angiotensin 1-9;Angiotensin 1-7;Angiotensin 1-5;Angiotensin 1-4
Q99983 -3.0353776 0.5731048 6.904704 -5.296374 0.0011784 0.0139082 Osteomodulin
Q96LL9 -1.2761049 0.2726611 8.842792 -4.680187 0.0012079 0.0140956 DnaJ homolog subfamily C member 30
Q9NRX4 1.3837621 0.3021988 9.339127 4.578979 0.0012082 0.0140956 14 kDa phosphohistidine phosphatase
O95486 -1.3108014 0.2851357 9.187800 -4.597114 0.0012278 0.0142428 Protein transport protein Sec24A
P62328 -1.4789049 0.2892444 7.220282 -5.112994 0.0012549 0.0144745 Thymosin beta-4;Hematopoietic system regulatory peptide
P02748 -1.2312031 0.2668957 8.865762 -4.613050 0.0013178 0.0151138 Complement component C9;Complement component C9a;Complement component C9b
P83916 -1.6679489 0.3077674 6.385413 -5.419511 0.0013357 0.0152331 Chromobox protein homolog 1
Q8WWQ0 -1.2921726 0.2873956 9.385413 -4.496147 0.0013478 0.0152848 PH-interacting protein
P00747 -0.8346905 0.1843299 9.172800 -4.528243 0.0013623 0.0153642 Plasminogen;Plasmin heavy chain A;Activation peptide;Angiostatin;Plasmin heavy chain A, short form;Plasmin light chain B
P27658 -1.6429540 0.3664317 9.385413 -4.483656 0.0013729 0.0153982 Collagen alpha-1(VIII) chain;Vastatin
O95445 -2.5390830 0.5603209 9.052359 -4.531480 0.0014023 0.0154891 Apolipoprotein M
Q9UBV8 -1.1721927 0.2568550 8.885488 -4.563635 0.0014048 0.0154891 Peflin
Q92930 -1.4926298 0.3053336 7.597170 -4.888521 0.0014055 0.0154891 Ras-related protein Rab-8B
O15118 -2.1251890 0.3964131 6.385413 -5.361047 0.0014158 0.0154891 Niemann-Pick C1 protein
P03950 -1.7958993 0.3814592 8.216113 -4.707972 0.0014192 0.0154891 Angiogenin
Q8NAT1 -0.8669596 0.1945741 9.385413 -4.455677 0.0014312 0.0155361 Protein O-linked-mannose beta-1,4-N-acetylglucosaminyltransferase 2
Q9Y287 -1.6263595 0.3659544 9.385413 -4.444159 0.0014559 0.0157204 Integral membrane protein 2B;BRI2, membrane form;BRI2 intracellular domain;BRI2C, soluble form;Bri23 peptide
Q7Z3T8 -1.3963655 0.3020251 8.413206 -4.623343 0.0014913 0.0159618 Zinc finger FYVE domain-containing protein 16
P62857 -1.3918700 0.2939084 7.956911 -4.735728 0.0014940 0.0159618 40S ribosomal protein S28
Q08945 -1.4241196 0.3089376 8.385413 -4.609731 0.0015322 0.0162239 FACT complex subunit SSRP1
P82663 -1.3644647 0.3087747 9.302714 -4.418965 0.0015444 0.0162239 28S ribosomal protein S25, mitochondrial
Q9BYN0 -1.2858687 0.2896091 9.180640 -4.440015 0.0015462 0.0162239 Sulfiredoxin-1
Q6UWS5 1.3552496 0.2719635 7.068224 4.983204 0.0015505 0.0162239 Protein PET117 homolog, mitochondrial
P54577 -1.0275324 0.2300731 8.964139 -4.466112 0.0015790 0.0163449 Tyrosine–tRNA ligase, cytoplasmic;Tyrosine–tRNA ligase, cytoplasmic, N-terminally processed
P00352 -1.1336794 0.2474061 8.402816 -4.582262 0.0015817 0.0163449 Retinal dehydrogenase 1
Q96FN9 -1.6915779 0.3690046 8.385413 -4.584165 0.0015862 0.0163449 Probable D-tyrosyl-tRNA(Tyr) deacylase 2
Q9UKX3 1.6936818 0.3854938 9.208912 4.393538 0.0016433 0.0168485 Myosin-13
Q9H1E5 -1.0100442 0.2319493 9.385413 -4.354590 0.0016644 0.0169760 Thioredoxin-related transmembrane protein 4
Q9BXV9 1.4127212 0.3218254 9.163202 4.389714 0.0016725 0.0169760 Uncharacterized protein C14orf142
P80723 -1.5225978 0.3278699 7.910668 -4.643908 0.0017078 0.0172483 Brain acid soluble protein 1
A5D6W6 -2.1874865 0.4705266 7.868778 -4.649017 0.0017207 0.0172842 Fat storage-inducing transmembrane protein 1
Q8IYI6 -0.9655844 0.2230263 9.385413 -4.329463 0.0017284 0.0172842 Exocyst complex component 8
P15924 0.9305974 0.2148943 9.350459 4.330490 0.0017409 0.0173234 Desmoplakin
O15061 -1.0942259 0.2546655 9.385413 -4.296719 0.0018158 0.0178238 Synemin
Q9UK22 -1.4762619 0.2882849 6.372396 -5.120844 0.0018178 0.0178238 F-box only protein 2
P07384 -0.8789740 0.2042255 9.333139 -4.303938 0.0018195 0.0178238 Calpain-1 catalytic subunit
P52907 -0.8481991 0.1972352 9.339311 -4.300445 0.0018263 0.0178238 F-actin-capping protein subunit alpha-1
Q04721 1.1127233 0.2577419 9.201253 4.317199 0.0018437 0.0178982 Neurogenic locus notch homolog protein 2;Notch 2 extracellular truncation;Notch 2 intracellular domain
Q8N142 1.0825486 0.2509220 9.201572 4.314284 0.0018515 0.0178982 Adenylosuccinate synthetase isozyme 1
O60262 -1.2355761 0.2771111 8.388576 -4.458775 0.0018804 0.0180907 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7
Q96A65 -0.8662506 0.2035141 9.382448 -4.256465 0.0019311 0.0184915 Exocyst complex component 4
Q9NS69 -1.0714067 0.2476392 8.946979 -4.326483 0.0019416 0.0185043 Mitochondrial import receptor subunit TOM22 homolog
Q96CX2 -0.9012081 0.2113310 9.290787 -4.264439 0.0019510 0.0185072 BTB/POZ domain-containing protein KCTD12
Q6IC98 -0.9007405 0.2081057 8.888308 -4.328283 0.0019666 0.0185681 GRAM domain-containing protein 4
P62745 -1.2315256 0.2839409 8.788016 -4.337261 0.0019937 0.0186338 Rho-related GTP-binding protein RhoB
O00625 -1.1467230 0.2709208 9.385413 -4.232687 0.0020006 0.0186338 Pirin
P31323 -0.9308385 0.2186352 9.229929 -4.257496 0.0020011 0.0186338 cAMP-dependent protein kinase type II-beta regulatory subunit
P05455 -0.8673708 0.2037435 9.178555 -4.257171 0.0020275 0.0187940 Lupus La protein
P61009 -0.8913019 0.2048775 8.621704 -4.350413 0.0020468 0.0188867 Signal peptidase complex subunit 3
P62277 -1.3147062 0.3106711 9.269754 -4.231827 0.0020596 0.0189187 40S ribosomal protein S13
P19447 -1.6209348 0.3503038 7.385413 -4.627226 0.0020905 0.0191159 TFIIH basal transcription factor complex helicase XPB subunit
P13796 -0.8965848 0.2123820 9.058132 -4.221566 0.0022024 0.0198918 Plastin-2
P50991 -1.4847501 0.3465048 8.685140 -4.284934 0.0022089 0.0198918 T-complex protein 1 subunit delta
Q9H1K0 -1.6569316 0.3616836 7.385413 -4.581164 0.0022125 0.0198918 Rabenosyn-5
Q9UL18 -1.3355815 0.3024699 8.037138 -4.415585 0.0022146 0.0198918 Protein argonaute-1
O75489 0.9821574 0.2367724 9.385413 4.148107 0.0022758 0.0202641 NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial
Q96C86 -0.8840200 0.2112887 9.145534 -4.183943 0.0022805 0.0202641 m7GpppX diphosphatase
Q9UBB5 1.4054756 0.2873545 6.385413 4.891086 0.0022976 0.0202641 Methyl-CpG-binding domain protein 2
Q04760 1.3888487 0.3250035 8.599181 4.273334 0.0022977 0.0202641 Lactoylglutathione lyase
Q12988 -1.0008329 0.2396145 9.134204 -4.176846 0.0023111 0.0202641 Heat shock protein beta-3
Q8N5M1 -1.3322320 0.3166085 8.937206 -4.207821 0.0023159 0.0202641 ATP synthase mitochondrial F1 complex assembly factor 2
Q6P1N0 -1.6664832 0.3563734 6.936107 -4.676227 0.0023268 0.0202725 Coiled-coil and C2 domain-containing protein 1A
Q96AG4 -1.0700845 0.2592741 9.385413 -4.127233 0.0023497 0.0203023 Leucine-rich repeat-containing protein 59
Q07065 -0.9428402 0.2242953 8.903162 -4.203566 0.0023503 0.0203023 Cytoskeleton-associated protein 4
Q9Y4W6 0.9288317 0.2250637 9.237547 4.126973 0.0024317 0.0209168 AFG3-like protein 2
P00492 -0.9748591 0.2342661 8.867949 -4.161333 0.0025227 0.0215202 Hypoxanthine-guanine phosphoribosyltransferase
Q8IYU8 -3.0517638 0.6353282 6.385413 -4.803445 0.0025231 0.0215202 Calcium uptake protein 2, mitochondrial
O75348 -1.2953207 0.3178560 9.377764 -4.075181 0.0025496 0.0216557 V-type proton ATPase subunit G 1
Q9UKS6 0.9838252 0.2380314 8.943424 4.133174 0.0025822 0.0218407 Protein kinase C and casein kinase substrate in neurons protein 3
P50238 -1.7738249 0.4308810 8.850185 -4.116739 0.0027058 0.0227914 Cysteine-rich protein 1
P04843 -1.5463708 0.3734394 8.660976 -4.140889 0.0027359 0.0228771 Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit 1
P05543 -1.2021068 0.2678425 7.101585 -4.488111 0.0027385 0.0228771 Thyroxine-binding globulin
Q96GK7 -1.2685155 0.2966639 7.917392 -4.275936 0.0027676 0.0230170 Fumarylacetoacetate hydrolase domain-containing protein 2A
P25311 -1.0760599 0.2606542 8.673237 -4.128305 0.0027779 0.0230170 Zinc-alpha-2-glycoprotein
Q9Y490 -0.8565056 0.2115741 9.149741 -4.048254 0.0027957 0.0230644 Talin-1
P58546 -1.2877434 0.3138586 8.783206 -4.102941 0.0028064 0.0230644 Myotrophin
P53618 -0.9257503 0.2314827 9.385413 -3.999220 0.0028622 0.0234285 Coatomer subunit beta
P28070 -0.9313857 0.2219436 8.111747 -4.196497 0.0029195 0.0237512 Proteasome subunit beta type-4
Q9NNX1 3.4364699 0.7363292 6.385413 4.667030 0.0029250 0.0237512 Tuftelin
Q9BXF6 -0.9435750 0.2370306 9.385413 -3.980816 0.0029451 0.0238189 Rab11 family-interacting protein 5
Q14118 -0.8636209 0.2063191 8.111452 -4.185849 0.0029629 0.0238356 Dystroglycan;Alpha-dystroglycan;Beta-dystroglycan
P21980 -0.9931919 0.2428774 8.618924 -4.089273 0.0029798 0.0238356 Protein-glutamine gamma-glutamyltransferase 2
P50552 -0.9356255 0.2329598 9.074476 -4.016253 0.0029847 0.0238356 Vasodilator-stimulated phosphoprotein
Q92575 -1.0319247 0.2532376 8.685218 -4.074927 0.0029941 0.0238356 UBX domain-containing protein 4
Q01581 -1.6309708 0.3718001 7.186730 -4.386687 0.0030119 0.0238838 Hydroxymethylglutaryl-CoA synthase, cytoplasmic
P31994-2 -0.8401092 0.2094556 8.992524 -4.010918 0.0030648 0.0242083 Low affinity immunoglobulin gamma Fc region receptor II-b
O75165 -0.7960642 0.1998267 9.132663 -3.983773 0.0030957 0.0242617 DnaJ homolog subfamily C member 13
Q9HB40 -1.4975944 0.3192059 6.179009 -4.691625 0.0031056 0.0242617 Retinoid-inducible serine carboxypeptidase
Q00577 -1.0160743 0.2542684 9.027366 -3.996069 0.0031099 0.0242617 Transcriptional activator protein Pur-alpha
O15031 -0.9218013 0.2310329 9.055589 -3.989914 0.0031194 0.0242617 Plexin-B2
P14625 -0.9806254 0.2486476 9.333808 -3.943837 0.0031532 0.0244236 Endoplasmin
Q7L4E1 -1.9857976 0.4950092 8.847472 -4.011637 0.0031642 0.0244236 Protein FAM73B
A6NDG6 1.0861342 0.2722626 8.937374 3.989289 0.0032057 0.0246261 Phosphoglycolate phosphatase
Q15125 -1.5304848 0.3855947 9.041599 -3.969154 0.0032291 0.0246261 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase
Q2TAY7 -1.0799883 0.2732212 9.123335 -3.952799 0.0032522 0.0246261 WD40 repeat-containing protein SMU1;WD40 repeat-containing protein SMU1, N-terminally processed
E5RK69 -1.1331593 0.2897068 9.385413 -3.911400 0.0032812 0.0246261 Annexin
Q14258 -1.0273754 0.2506553 8.157903 -4.098758 0.0033032 0.0246261 E3 ubiquitin/ISG15 ligase TRIM25
Q9NS86 -1.0079781 0.2479673 8.316103 -4.064963 0.0033269 0.0246261 LanC-like protein 2
Q02818 -1.1109599 0.2603296 7.340441 -4.267513 0.0033293 0.0246261 Nucleobindin-1
P43121 -1.0927918 0.2720489 8.594930 -4.016894 0.0033306 0.0246261 Cell surface glycoprotein MUC18
Q7KZF4 -0.8983119 0.2302334 9.385413 -3.901744 0.0033311 0.0246261 Staphylococcal nuclease domain-containing protein 1
Q9Y2D4 -1.5301277 0.3819079 8.653139 -4.006536 0.0033354 0.0246261 Exocyst complex component 6B
P01303 -1.4085709 0.3549264 8.890312 -3.968628 0.0033419 0.0246261 Pro-neuropeptide Y;Neuropeptide Y;C-flanking peptide of NPY
Q9BWJ5 -1.1951212 0.3064683 9.385413 -3.899657 0.0033420 0.0246261 Splicing factor 3B subunit 5
P49773 -0.9630558 0.2471701 9.385413 -3.896327 0.0033594 0.0246261 Histidine triad nucleotide-binding protein 1
Q15738 -1.1253828 0.2888439 9.385413 -3.896163 0.0033603 0.0246261 Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating
P46063 -0.8051976 0.2054091 9.154885 -3.919971 0.0033970 0.0248052 ATP-dependent DNA helicase Q1
Q9HBL0 1.0970067 0.2708307 8.290796 4.050526 0.0034176 0.0248666 Tensin-1
O95810 -0.7367195 0.1898992 9.385413 -3.879528 0.0034489 0.0250047 Serum deprivation-response protein
Q8IUX7 -2.4425715 0.5075886 5.640778 -4.812108 0.0035035 0.0253101 Adipocyte enhancer-binding protein 1
Q9Y5U8 -2.4377353 0.6307150 9.327097 -3.865035 0.0035696 0.0256674 Mitochondrial pyruvate carrier 1
P14555 -3.1537863 0.7281822 6.867951 -4.331040 0.0035904 0.0256674 Phospholipase A2, membrane associated
Q96PK6 -0.9222337 0.2373986 9.148490 -3.884749 0.0035909 0.0256674 RNA-binding protein 14
Q9UHD9 -0.9017767 0.2318045 9.043824 -3.890247 0.0036397 0.0257977 Ubiquilin-2
Q96EM0 -1.2584685 0.3144044 8.309610 -4.002706 0.0036419 0.0257977 Trans-3-hydroxy-L-proline dehydratase
Q9HCN8 -0.8835166 0.2288465 9.253672 -3.860738 0.0036473 0.0257977 Stromal cell-derived factor 2-like protein 1
P07360 -0.9669760 0.2462742 8.752393 -3.926420 0.0036711 0.0258764 Complement component C8 gamma chain
P10109 0.8561493 0.2221550 9.243225 3.853837 0.0036944 0.0259004 Adrenodoxin, mitochondrial
Q9H4A6 -1.0469452 0.2719485 9.266844 -3.849793 0.0037001 0.0259004 Golgi phosphoprotein 3
P27695 -1.4992289 0.3923412 9.385413 -3.821237 0.0037793 0.0263153 DNA-(apurinic or apyrimidinic site) lyase;DNA-(apurinic or apyrimidinic site) lyase, mitochondrial
Q53FA7 1.3792842 0.3581051 9.140607 3.851619 0.0037853 0.0263153 Quinone oxidoreductase PIG3
Q9NQZ5 1.3063706 0.3399333 9.137333 3.843021 0.0038384 0.0265728 StAR-related lipid transfer protein 7, mitochondrial
Q9UQR1 -1.5901460 0.3824514 7.327082 -4.157773 0.0038485 0.0265728 Zinc finger protein 148
Q68DH5 -1.0294876 0.2612363 8.365194 -3.940828 0.0039282 0.0270311 LMBR1 domain-containing protein 2
P78406 -1.7207435 0.3887386 6.279703 -4.426479 0.0039782 0.0270918 mRNA export factor
P62312 -1.5890450 0.4091948 8.671810 -3.883346 0.0039851 0.0270918 U6 snRNA-associated Sm-like protein LSm6
P10643 -1.1553612 0.3037929 9.241403 -3.803121 0.0039995 0.0270918 Complement component C7
Q9BT09 -1.2257851 0.3203966 9.058668 -3.825837 0.0040051 0.0270918 Protein canopy homolog 3
Q6PCE3 -1.3823379 0.3363631 7.385413 -4.109659 0.0040266 0.0270918 Glucose 1,6-bisphosphate synthase
Q9BVC6 -1.1861599 0.3132913 9.341936 -3.786124 0.0040278 0.0270918 Transmembrane protein 109
P00488 -1.1640817 0.3067565 9.268393 -3.794807 0.0040304 0.0270918 Coagulation factor XIII A chain
Q3ZCW2 -1.4639580 0.3351832 6.410138 -4.367635 0.0040470 0.0271133 Galectin-related protein
Q96KP1 -1.0715375 0.2583008 7.188491 -4.148409 0.0040611 0.0271186 Exocyst complex component 2
P61925 1.3829061 0.3292482 6.953044 4.200194 0.0040956 0.0271960 cAMP-dependent protein kinase inhibitor alpha
Q9UNN8 -1.2626877 0.3237195 8.433185 -3.900561 0.0040995 0.0271960 Endothelial protein C receptor
O00299 -0.9207980 0.2441733 9.349959 -3.771084 0.0041180 0.0272298 Chloride intracellular channel protein 1
Q8IVD9 -0.9866036 0.2486289 7.962021 -3.968177 0.0041691 0.0274783 NudC domain-containing protein 3
O15121 -1.4079273 0.3728328 9.216343 -3.776297 0.0041910 0.0275334 Sphingolipid delta(4)-desaturase DES1
P04207 -1.4228021 0.3725405 8.861844 -3.819188 0.0042135 0.0275916 Ig kappa chain V-III region CLL
P24311 1.0701358 0.2851747 9.295713 3.752563 0.0042839 0.0279625 Cytochrome c oxidase subunit 7B, mitochondrial
O75663 -1.7379175 0.4581589 8.939622 -3.793263 0.0043137 0.0280667 TIP41-like protein
Q8NBF2 -0.8250417 0.2215677 9.379760 -3.723655 0.0044137 0.0285351 NHL repeat-containing protein 2
P61020 -0.8382949 0.2205335 8.768454 -3.801213 0.0044149 0.0285351 Ras-related protein Rab-5B
P60903 -0.8876449 0.2381638 9.333841 -3.727035 0.0044279 0.0285351 Protein S100-A10
P41208 -1.1263858 0.2999947 9.075440 -3.754686 0.0044552 0.0286207 Centrin-2
P20042 -0.8887367 0.2370873 9.065935 -3.748564 0.0045061 0.0287075 Eukaryotic translation initiation factor 2 subunit 2
P27169 -1.0504292 0.2769234 8.718029 -3.793212 0.0045159 0.0287075 Serum paraoxonase/arylesterase 1
Q08357 -1.2684736 0.3315172 8.463053 -3.826267 0.0045409 0.0287075 Sodium-dependent phosphate transporter 2
Q16204 -0.8049274 0.2138365 8.902922 -3.764218 0.0045433 0.0287075 Coiled-coil domain-containing protein 6
Q8WUM0 -0.7917468 0.2110572 8.990261 -3.751338 0.0045540 0.0287075 Nuclear pore complex protein Nup133
P00918 -0.9510512 0.2547612 9.125781 -3.733109 0.0045623 0.0287075 Carbonic anhydrase 2
Q96MM6 1.7864789 0.4212053 6.459250 4.241349 0.0045992 0.0287075 Heat shock 70 kDa protein 12B
P31689 -1.4924000 0.3848993 8.072563 -3.877378 0.0046114 0.0287075 DnaJ homolog subfamily A member 1
P49756 -0.8931713 0.2418433 9.385413 -3.693182 0.0046276 0.0287075 RNA-binding protein 25
Q5JUQ0 2.7926112 0.6712936 6.726504 4.160044 0.0046289 0.0287075 Protein FAM78A
P01611 -1.3131481 0.3557280 9.385413 -3.691439 0.0046405 0.0287075 Ig kappa chain V-I region Wes
P32119 -0.9674030 0.2451869 7.636769 -3.945574 0.0046754 0.0287075 Peroxiredoxin-2
P62330 -0.8152583 0.2199163 9.196457 -3.707130 0.0046879 0.0287075 ADP-ribosylation factor 6
O75643 -0.7616501 0.2067379 9.385413 -3.684133 0.0046947 0.0287075 U5 small nuclear ribonucleoprotein 200 kDa helicase
P17050 -0.9853240 0.2652090 9.121362 -3.715273 0.0046949 0.0287075 Alpha-N-acetylgalactosaminidase
P31949 -0.9787100 0.2647594 9.277157 -3.696602 0.0046950 0.0287075 Protein S100-A11;Protein S100-A11, N-terminally processed
Q9Y646 -0.7162308 0.1940218 9.210822 -3.691497 0.0047915 0.0291484 Carboxypeptidase Q
Q1KMD3 -0.9795111 0.2640085 9.051770 -3.710149 0.0047958 0.0291484 Heterogeneous nuclear ribonucleoprotein U-like protein 2
Q6ZVF9 -1.5028535 0.3517719 6.221356 -4.272239 0.0048341 0.0292737 G protein-regulated inducer of neurite outgrowth 3
Q9BU61 -1.2998963 0.3549162 9.385413 -3.662545 0.0048588 0.0292737 NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3
Q9Y5U9 -0.9729708 0.2545202 8.183105 -3.822764 0.0048597 0.0292737 Immediate early response 3-interacting protein 1
Q8TCJ2 -0.9004011 0.2429306 8.907652 -3.706413 0.0049600 0.0297891 Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit STT3B
Q15493 -1.6077032 0.4360378 9.046599 -3.687073 0.0049758 0.0297963 Regucalcin
Q9UBS4 -1.7446965 0.4698184 8.803956 -3.713555 0.0050071 0.0298953 DnaJ homolog subfamily B member 11
Q9BVG4 -1.4704698 0.4039345 9.385413 -3.640367 0.0050337 0.0299660 Protein PBDC1
O15144 -1.0444705 0.2843210 9.070426 -3.673560 0.0050589 0.0299983 Actin-related protein 2/3 complex subunit 2
Q9BXR6 -1.3501527 0.3714481 9.382448 -3.634835 0.0050810 0.0299983 Complement factor H-related protein 5
O43290 -0.7923809 0.2180343 9.385413 -3.634203 0.0050835 0.0299983 U4/U6.U5 tri-snRNP-associated protein 1
Q04837 -1.2562850 0.3379135 8.636848 -3.717771 0.0051451 0.0302738 Single-stranded DNA-binding protein, mitochondrial
O00567 -1.5854812 0.4377198 9.376799 -3.622138 0.0051902 0.0304511 Nucleolar protein 56
Q04941 -1.3384979 0.3673776 9.127049 -3.643385 0.0052480 0.0307016 Proteolipid protein 2
Q6P1L8 0.6869586 0.1895585 9.186165 3.623993 0.0053529 0.0312208 39S ribosomal protein L14, mitochondrial
P21281 -1.3587904 0.3769568 9.344431 -3.604631 0.0053675 0.0312208 V-type proton ATPase subunit B, brain isoform
Q8TDB6 -0.9160565 0.2529440 9.153547 -3.621578 0.0054049 0.0312627 E3 ubiquitin-protein ligase DTX3L
P56199 -0.9018380 0.2448251 8.647866 -3.683600 0.0054055 0.0312627 Integrin alpha-1
Q8IWU2 -0.7746135 0.2080306 8.224391 -3.723556 0.0055613 0.0319924 Serine/threonine-protein kinase LMTK2
Q9Y623 -2.1252883 0.5700777 8.189261 -3.728068 0.0055670 0.0319924 Myosin-4
P46777 -1.0470686 0.2879004 8.852405 -3.636912 0.0055790 0.0319924 60S ribosomal protein L5
Q96PE7 -1.1531979 0.3230087 9.385413 -3.570176 0.0056319 0.0321622 Methylmalonyl-CoA epimerase, mitochondrial
Q6ICB0 -2.0977670 0.5236139 6.696096 -4.006324 0.0056403 0.0321622 Desumoylating isopeptidase 1
P30050 -1.1234823 0.3143996 9.261423 -3.573421 0.0057230 0.0325424 60S ribosomal protein L12
P08754 -1.0611744 0.2984515 9.385413 -3.555601 0.0057651 0.0326906 Guanine nucleotide-binding protein G(k) subunit alpha
P11021 -0.7515167 0.2089700 8.970360 -3.596290 0.0058129 0.0328607 78 kDa glucose-regulated protein
P56192 -1.0557634 0.2923102 8.813819 -3.611792 0.0058414 0.0328607 Methionine–tRNA ligase, cytoplasmic
Q53GG5 1.0003784 0.2774742 8.865410 3.605302 0.0058437 0.0328607 PDZ and LIM domain protein 3
Q8NDY3 1.2195639 0.3410277 9.101142 3.576143 0.0058602 0.0328626 [Protein ADP-ribosylarginine] hydrolase-like protein 1
O75533 -0.7695176 0.2164213 9.256606 -3.555646 0.0058921 0.0329503 Splicing factor 3B subunit 1
P01699 -1.8429363 0.4533786 6.314916 -4.064895 0.0059388 0.0331204 Ig lambda chain V-I region VOR
Q14019 -2.4182957 0.5985491 6.385413 -4.040263 0.0059733 0.0331901 Coactosin-like protein
Q9Y5J7 -1.4119681 0.3997182 9.385413 -3.532409 0.0059840 0.0331901 Mitochondrial import inner membrane translocase subunit Tim9
P23284 -0.7777143 0.2189746 9.127890 -3.551619 0.0060629 0.0335357 Peptidyl-prolyl cis-trans isomerase B
Q9Y5Z7 -1.8906077 0.4616964 6.110612 -4.094916 0.0061500 0.0339251 Host cell factor 2
Q9HAV7 0.8784715 0.2455573 8.806708 3.577460 0.0061670 0.0339271 GrpE protein homolog 1, mitochondrial
P08670 -1.0385574 0.2890644 8.643328 -3.592824 0.0062100 0.0340714 Vimentin
Q9H9B4 -0.7835938 0.2188802 8.717170 -3.580012 0.0062456 0.0341738 Sideroflexin-1
Q5T447 -1.0539901 0.2946359 8.718056 -3.577263 0.0062709 0.0342204 E3 ubiquitin-protein ligase HECTD3
P05060 -2.3172970 0.6115268 7.305570 -3.789363 0.0062887 0.0342252 Secretogranin-1;PE-11;GAWK peptide;CCB peptide
P14174 -0.9252890 0.2597430 8.795118 -3.562324 0.0063263 0.0343378 Macrophage migration inhibitory factor
P00742 -1.3823666 0.3377126 6.021781 -4.093323 0.0063561 0.0343429 Coagulation factor X;Factor X light chain;Factor X heavy chain;Activated factor Xa heavy chain
P05062 -2.0691367 0.5491873 7.376614 -3.767634 0.0063611 0.0343429 Fructose-bisphosphate aldolase B
P01597 -2.2245190 0.6295868 8.995469 -3.533300 0.0063859 0.0343855 Ig kappa chain V-I region DEE
Q9UK41 -1.5840168 0.4525342 9.249370 -3.500325 0.0064436 0.0346045 Vacuolar protein sorting-associated protein 28 homolog
O14807 -1.0071551 0.2870529 9.142433 -3.508604 0.0064740 0.0346760 Ras-related protein M-Ras
Q9GZY4 -1.6315958 0.4423737 7.703311 -3.688275 0.0065660 0.0349087 Cytochrome c oxidase assembly factor 1 homolog
Q13011 0.8125674 0.2281934 8.603557 3.560872 0.0065690 0.0349087 Delta(3,5)-Delta(2,4)-dienoyl-CoA isomerase, mitochondrial
A4D2B0 -1.7771506 0.4954576 8.385413 -3.586888 0.0065854 0.0349087 Metallo-beta-lactamase domain-containing protein 1
P27797 -0.8785716 0.2529576 9.382448 -3.473197 0.0065862 0.0349087 Calreticulin
Q9HAN9 1.2290381 0.3277463 7.306422 3.749968 0.0066297 0.0350474 Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1
P02749 -1.0092251 0.2887067 9.025558 -3.495676 0.0067400 0.0355380 Beta-2-glycoprotein 1
Q14011 -1.6557884 0.4613486 8.231467 -3.589018 0.0067678 0.0355925 Cold-inducible RNA-binding protein
P62191 -0.9985121 0.2875705 9.176854 -3.472234 0.0068202 0.0357754 26S protease regulatory subunit 4
Q8NBJ5 -1.0369389 0.2922708 8.473099 -3.547871 0.0068666 0.0357787 Procollagen galactosyltransferase 1
P16455 -0.8416366 0.2363383 8.365652 -3.561152 0.0068706 0.0357787 Methylated-DNA–protein-cysteine methyltransferase
Q12907 -1.6608858 0.4654093 8.305704 -3.568657 0.0068737 0.0357787 Vesicular integral-membrane protein VIP36
Q9UMR3 -1.7064633 0.4609378 7.385413 -3.702155 0.0069386 0.0360239 T-box transcription factor TBX20
Q5VIR6-4 -0.9082357 0.2626254 9.130015 -3.458294 0.0070272 0.0363239 Vacuolar protein sorting-associated protein 53 homolog
P06396 -1.1602520 0.3284971 8.474042 -3.532001 0.0070322 0.0363239 Gelsolin
Q6Y288 -1.0921514 0.3170900 9.229532 -3.444295 0.0070709 0.0364313 Beta-1,3-glucosyltransferase
P98160 -0.7123685 0.2057393 9.004949 -3.462481 0.0071269 0.0366270 Basement membrane-specific heparan sulfate proteoglycan core protein;Endorepellin;LG3 peptide
Q9HCJ6 -0.9011150 0.2633086 9.382448 -3.422277 0.0071515 0.0366605 Synaptic vesicle membrane protein VAT-1 homolog-like
O43707 -1.3824302 0.3940398 8.555847 -3.508352 0.0071799 0.0367132 Alpha-actinin-4
Q13425 -0.7846763 0.2289447 9.241730 -3.427362 0.0072514 0.0369860 Beta-2-syntrophin
Q9UBI9 -1.9787149 0.5456575 7.613412 -3.626295 0.0073101 0.0371672 Headcase protein homolog
Q13636 -1.9278246 0.4828349 5.941397 -3.992720 0.0073236 0.0371672 Ras-related protein Rab-31
O43592 -0.8599780 0.2513274 9.208263 -3.421744 0.0073560 0.0372388 Exportin-T
P43686 -1.3071386 0.3842049 9.385413 -3.402192 0.0073848 0.0372913 26S protease regulatory subunit 6B
O75190-3 1.2139008 0.3579316 9.385413 3.391433 0.0075148 0.0378540 DnaJ homolog subfamily B member 6
Q9NX08 -0.7560262 0.2199925 8.886277 -3.436601 0.0075720 0.0379630 COMM domain-containing protein 8
Q96CN7 -1.0345528 0.3035605 9.151255 -3.408061 0.0075873 0.0379630 Isochorismatase domain-containing protein 1
O60568 -1.0499114 0.3101574 9.385413 -3.385092 0.0075926 0.0379630 Procollagen-lysine,2-oxoglutarate 5-dioxygenase 3
O60927 -0.9982244 0.2669526 6.797580 -3.739332 0.0076677 0.0381466 Protein phosphatase 1 regulatory subunit 11
Q9H2J4 -0.8634690 0.2556745 9.385413 -3.377220 0.0076903 0.0381466 Phosducin-like protein 3
Q8NFQ8 -0.7967626 0.2241386 7.843418 -3.554776 0.0077012 0.0381466 Torsin-1A-interacting protein 2
P15848 0.9063750 0.2622189 8.604816 3.456558 0.0077045 0.0381466 Arylsulfatase B
P30101 -0.7466004 0.2200397 9.129332 -3.393025 0.0077988 0.0385196 Protein disulfide-isomerase A3
P51692 -1.7183021 0.5058169 9.071768 -3.397083 0.0078195 0.0385280 Signal transducer and activator of transcription 5B
Q96LD4 -2.0992980 0.5326176 5.906119 -3.941473 0.0078555 0.0386116 Tripartite motif-containing protein 47
Q96G03 -0.8867606 0.2633690 9.330409 -3.366989 0.0078842 0.0386591 Phosphoglucomutase-2
P05387 -0.7376313 0.2197628 9.385413 -3.356488 0.0079539 0.0389072 60S acidic ribosomal protein P2
Q08AG7 -1.2342110 0.3426996 7.362325 -3.601437 0.0080096 0.0390851 Mitotic-spindle organizing protein 1
Q9Y678 -0.6484637 0.1937556 9.385413 -3.346813 0.0080802 0.0393350 Coatomer subunit gamma-1
P29992 -1.0188326 0.2947365 8.303781 -3.456757 0.0081310 0.0394877 Guanine nucleotide-binding protein subunit alpha-11
Q9BX97 -1.3844164 0.3942853 7.837641 -3.511205 0.0082107 0.0397799 Plasmalemma vesicle-associated protein
P16083 -1.0262131 0.3000391 8.385413 -3.420264 0.0084662 0.0409198 Ribosyldihydronicotinamide dehydrogenase [quinone]
P03915 -1.1707120 0.3448778 8.492156 -3.394570 0.0086415 0.0416682 NADH-ubiquinone oxidoreductase chain 5
Q13825 1.4155209 0.4286271 9.385413 3.302453 0.0086860 0.0417125 Methylglutaconyl-CoA hydratase, mitochondrial
P55735 -0.8920338 0.2672114 8.993847 -3.338307 0.0086918 0.0417125 Protein SEC13 homolog
Q13541 0.9219952 0.2801292 9.385413 3.291322 0.0088453 0.0423489 Eukaryotic translation initiation factor 4E-binding protein 1
Q9BSH5 -0.8053114 0.2432271 9.081702 -3.310944 0.0089588 0.0427913 Haloacid dehalogenase-like hydrolase domain-containing protein 3
O95159 -1.8090106 0.5289166 8.060595 -3.420219 0.0089825 0.0428040 Zinc finger protein-like 1
P61225 -0.7353323 0.2254094 9.385413 -3.262208 0.0092764 0.0440350 Ras-related protein Rap-2b
O75436 -1.0001875 0.2995476 8.574417 -3.338993 0.0092842 0.0440350 Vacuolar protein sorting-associated protein 26A
P22748 1.3439356 0.3988665 8.227398 3.369388 0.0094030 0.0444942 Carbonic anhydrase 4
O43920 0.7871398 0.2413857 9.266721 3.260921 0.0094526 0.0446249 NADH dehydrogenase [ubiquinone] iron-sulfur protein 5
B0YJ81 -0.8197164 0.2437757 8.223227 -3.362585 0.0095069 0.0447771 Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase 1
P61026 -0.8525514 0.2469341 7.519029 -3.452546 0.0095312 0.0447877 Ras-related protein Rab-10
Q5VUM1 0.7593853 0.2321285 9.045228 3.271401 0.0095967 0.0449156 Succinate dehydrogenase assembly factor 4, mitochondrial
Q8N392 2.3525552 0.6309863 6.037587 3.728378 0.0096451 0.0449156 Rho GTPase-activating protein 18
Q8N129 -0.9589743 0.2874231 8.368916 -3.336456 0.0096458 0.0449156 Protein canopy homolog 4
P22897 -1.2570252 0.3866597 9.236964 -3.250986 0.0096469 0.0449156 Macrophage mannose receptor 1
I3L505 1.1736484 0.3548842 8.571534 3.307130 0.0097586 0.0453318 Acyl carrier protein
Q99459 -0.8211683 0.2419414 7.796908 -3.394079 0.0098104 0.0454681 Cell division cycle 5-like protein
Q13061 -2.4676439 0.7427573 8.281135 -3.322275 0.0100042 0.0462607 Triadin
Q9UBQ0 -1.1062507 0.3422745 9.158961 -3.232057 0.0100576 0.0464023 Vacuolar protein sorting-associated protein 29
P01621 -1.2058630 0.3710231 8.927861 -3.250102 0.0101023 0.0465026 Ig kappa chain V-III region NG9
O14656 -1.8276459 0.5541078 8.385413 -3.298358 0.0101964 0.0468296 Torsin-1A
P41743 -1.1383453 0.3178404 6.465679 -3.581500 0.0102399 0.0469233 Protein kinase C iota type
P09467 -1.3548161 0.3766861 6.379503 -3.596671 0.0102775 0.0469893 Fructose-1,6-bisphosphatase 1
P04430 -1.0635292 0.3314758 9.250027 -3.208467 0.0103183 0.0470701 Ig kappa chain V-I region BAN
Q9H4G4 -1.8410577 0.5694674 8.904758 -3.232947 0.0104175 0.0474158 Golgi-associated plant pathogenesis-related protein 1
P35754 0.7959584 0.2488883 9.268764 3.198055 0.0104680 0.0475244 Glutaredoxin-1
Q08211 -0.7008973 0.2199769 9.382448 -3.186232 0.0105108 0.0475244 ATP-dependent RNA helicase A
Q6UXG3 1.6056385 0.5021363 9.243547 3.197615 0.0105116 0.0475244 CMRF35-like molecule 9
Q9HD45 -0.9322808 0.2920818 9.281520 -3.191848 0.0105563 0.0476206 Transmembrane 9 superfamily member 3
O00487 -0.7979909 0.2500603 9.242344 -3.191194 0.0106238 0.0478188 26S proteasome non-ATPase regulatory subunit 14
Q86WH2 -1.4748731 0.3898450 5.524605 -3.783230 0.0106687 0.0479148 Ras association domain-containing protein 3
P08648 -0.9830382 0.3010637 8.373691 -3.265216 0.0107486 0.0481672 Integrin alpha-5;Integrin alpha-5 heavy chain;Integrin alpha-5 light chain
P07196 -3.1755881 0.8558310 5.733074 -3.710532 0.0108167 0.0483656 Neurofilament light polypeptide
P00156 -1.7108654 0.5393991 9.325104 -3.171799 0.0108447 0.0483803 Cytochrome b
P34947 -1.4297892 0.4514007 9.363114 -3.167450 0.0108677 0.0483803 G protein-coupled receptor kinase 5
Q6B0K9 -1.3489774 0.4080821 7.853752 -3.305652 0.0110508 0.0490876 Hemoglobin subunit mu
Q92616 -0.5950798 0.1874991 9.031070 -3.173775 0.0112487 0.0498578 Translational activator GCN1
Q92805 1.3236880 0.4166069 8.947665 3.177307 0.0113157 0.0499740 Golgin subfamily A member 1
Q14165 -1.0392026 0.3299855 9.277055 -3.149237 0.0113242 0.0499740 Malectin
P51665 -0.7776248 0.2465259 9.194991 -3.154333 0.0113529 0.0499924 26S proteasome non-ATPase regulatory subunit 7

4.6 Interaction

4.6.1 Volcano-plot

volcanoInt <- ggplot(rowData(pe[["proteinRobust"]])$"locationR:tissueV",
                 aes(x = logFC, y = -log10(pval), color = adjPval < 0.05)) +
 geom_point(cex = 2.5) +
 scale_color_manual(values = alpha(c("black", "red"), 0.5)) + theme_minimal()
volcanoInt

4.6.2 Heatmap

There were no genes significant at the 5% FDR level. We return the top 25 genes.

sigNamesInt <- rowData(pe[["proteinRobust"]])$"locationR:tissueV" %>%
 rownames_to_column("proteinRobust") %>%
 filter(adjPval<0.05) %>%
 pull(proteinRobust)
hlp <- order((rowData(pe[["proteinRobust"]])$"locationR:tissueV")[,"adjPval"])[1:25]
heatmap(assay(pe[["proteinRobust"]])[hlp, ])

There are 0 proteins significantly differentially expressed at the 5% FDR level.

rowData(pe[["proteinRobust"]])$"locationR:tissueV" %>%
  cbind(.,rowData(pe[["proteinRobust"]])$Protein.names) %>%
  na.exclude %>%
  filter(adjPval<0.05) %>%
  arrange(pval)

5 Large difference in number of proteins that are returned

Note, that much more proteins are returned significant for average contrast (\(\log_2 FC_{V-A}\)) as compared to contrast for assessing the fold change between ventriculum and atrium left and right. The power for the average contrast is larger than for the contrast left or right because the log2 FC can be estimated with higher precision.

For none of the proteins the interaction was significant (change in log2 FC between ventriculum and atrium in the right vs the left heart region). The power for the interaction is typically low.

5.1 Reason

Part of variance covariance matrix of model parameters due to design:

X <- model.matrix(~ location*tissue + patient, colData(pe))
covarUnscaled <- solve(t(X) %*% X)

Variance of contrasts (diagonal elements) due to design

varContrasts <- t(L)%*%covarUnscaled%*%L %>%
  diag
varContrasts
##                           tissueV       tissueV + locationR:tissueV 
##                         0.6666667                         0.6666667 
## tissueV + 0.5 * locationR:tissueV                 locationR:tissueV 
##                         0.3333333                         1.3333333
sqrt(varContrasts)
##                           tissueV       tissueV + locationR:tissueV 
##                         0.8164966                         0.8164966 
## tissueV + 0.5 * locationR:tissueV                 locationR:tissueV 
##                         0.5773503                         1.1547005

So it is clear that the standard error of the log2 FC left and right is the same. That of the average contrast is a factor \(\sqrt{2}\) smaller! Indeed, we use double the number of samples to estimate it!

varContrasts[3]/varContrasts[2]
## tissueV + 0.5 * locationR:tissueV 
##                               0.5
sqrt(varContrasts)[3]/sqrt(varContrasts)[2]
## tissueV + 0.5 * locationR:tissueV 
##                         0.7071068
1/sqrt(2)
## [1] 0.7071068

The standard error of the interaction is a factor \(\sqrt{2}\) larger than that of the main effects!

varContrasts[4]/varContrasts[2]
## locationR:tissueV 
##                 2
sqrt(varContrasts)[4]/sqrt(varContrasts)[2]
## locationR:tissueV 
##          1.414214
sqrt(2)
## [1] 1.414214

5.2 Msqrob

This is not the case for the standard errors of protein 2???

rowData(pe[["proteinRobust"]])$"tissueV"[2,]
rowData(pe[["proteinRobust"]])$"tissueV + locationR:tissueV"[2,]
rowData(pe[["proteinRobust"]])$"tissueV + 0.5 * locationR:tissueV"[2,]
rowData(pe[["proteinRobust"]])$"locationR:tissueV"[2,]

Because msqrob is using robust regression to assess DE!

pe %>%
  colData %>%
  as_tibble %>%
  mutate(w=getModel(rowData(pe[["proteinRobust"]])$msqrobModels[[2]])$w)

For protein 2 the samples at the left and right side have different weights!

5.2.1 Part of standard error due to design:

covUnscaledRobust <- solve(
  t(X) %*%
  diag(
    getModel(rowData(pe[["proteinRobust"]])$msqrobModels[[2]])$w) %*% X)

varContrastsRobust <- t(L)%*%covUnscaledRobust%*%L %>%
  diag
varContrastsRobust
##                           tissueV       tissueV + locationR:tissueV 
##                         0.7187863                         0.8704210 
## tissueV + 0.5 * locationR:tissueV                 locationR:tissueV 
##                         0.3950893                         1.5980575
sqrt(varContrastsRobust)
##                           tissueV       tissueV + locationR:tissueV 
##                         0.8478127                         0.9329636 
## tissueV + 0.5 * locationR:tissueV                 locationR:tissueV 
##                         0.6285613                         1.2641430

5.2.2 Standard errors Contrasts

sqrt(varContrastsRobust) * getSigmaPosterior(rowData(pe[["proteinRobust"]])$msqrobModels[[2]])
##                           tissueV       tissueV + locationR:tissueV 
##                         0.5601628                         0.6164233 
## tissueV + 0.5 * locationR:tissueV                 locationR:tissueV 
##                         0.4153001                         0.8352387
rowData(pe[["proteinRobust"]])$"tissueV"[2,]
rowData(pe[["proteinRobust"]])$"tissueV + locationR:tissueV"[2,]
rowData(pe[["proteinRobust"]])$"tissueV + 0.5 * locationR:tissueV"[2,]
rowData(pe[["proteinRobust"]])$"locationR:tissueV"[2,]

5.3 Stagewise testing

5.3.1 Omnibus test

source("https://raw.githubusercontent.com/statOmics/SGA2020/gh-pages/assets/topFeaturesOmnibus.R")
pe <- omnibusTest(pe, "proteinRobust", L)

5.3.2 Heatmap significant proteins Omnibus test

We first select the names of the proteins that were declared signficant.

sigNamesOmnibus <- rowData(pe[["proteinRobust"]])$omnibusTest %>%
 rownames_to_column("proteinRobust") %>%
 filter(adjPval<0.05) %>%
 pull(proteinRobust)
heatmap(assay(pe[["proteinRobust"]])[sigNamesOmnibus, ])

There are 262 proteins significantly differentially expressed at the 5% FDR level.

rowData(pe[["proteinRobust"]])$omnibusTest  %>%
  cbind(.,rowData(pe[["proteinRobust"]])$Protein.names) %>%
  na.exclude %>%
  filter(adjPval<0.05) %>%
  arrange(pval) %>%
  knitr::kable(.)
tissueV tissueV…locationR.tissueV tissueV…0.5…locationR.tissueV locationR.tissueV df1 df2 Fstat pval adjPval rowData(pe[[“proteinRobust”]])$Protein.names
P08590 7.5669453 5.3580772 6.4625112 -2.2088680 2 9.117912 241.941690 0.0000000 0.0000255 Myosin light chain 3
P12883 4.3331248 1.7523890 3.0427569 -2.5807358 2 9.255194 82.809688 0.0000012 0.0012591 Myosin-7
P10916 6.9086744 2.9035913 4.9061329 -4.0050831 2 7.385413 107.580783 0.0000035 0.0023247 Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
O75368 -2.2903758 -1.8440754 -2.0672256 0.4463004 2 9.251939 59.046905 0.0000054 0.0023247 SH3 domain-binding glutamic acid-rich-like protein
P06858 1.7952437 3.3292464 2.5622451 1.5340027 2 9.218266 56.616101 0.0000066 0.0023247 Lipoprotein lipase
Q6UWY5 -3.2532286 -2.4696667 -2.8614477 0.7835619 2 9.170135 55.962919 0.0000073 0.0023247 Olfactomedin-like protein 1
P46821 -2.1828217 -1.6229630 -1.9028923 0.5598587 2 9.385413 52.504004 0.0000080 0.0023247 Microtubule-associated protein 1B;MAP1B heavy chain;MAP1 light chain LC1
P29622 -2.1148699 -1.8621552 -1.9885126 0.2527147 2 9.385413 44.363771 0.0000165 0.0039435 Kallistatin
P05546 -1.9156713 -1.7501838 -1.8329275 0.1654876 2 9.198639 45.181005 0.0000175 0.0039435 Heparin cofactor 2
P21810 -3.3802538 -2.9942069 -3.1872304 0.3860470 2 8.304055 51.174076 0.0000214 0.0042345 Biglycan
P35442 -2.3342598 -3.2070907 -2.7706752 -0.8728309 2 8.385413 49.249094 0.0000232 0.0042345 Thrombospondin-2
P13533 -4.3139246 -4.0839508 -4.1989377 0.2299738 2 9.115028 42.042011 0.0000250 0.0042345 Myosin-6
Q8N474 -3.3046470 -2.1617235 -2.7331853 1.1429234 2 7.847514 52.144823 0.0000294 0.0045872 Secreted frizzled-related protein 1
Q06828 -4.2091891 -4.1354763 -4.1723327 0.0737128 2 9.003303 39.385102 0.0000353 0.0051216 Fibromodulin
P02452 -3.2261931 -2.0070368 -2.6166150 1.2191563 2 8.367424 42.481732 0.0000415 0.0056136 Collagen alpha-1(I) chain
O95865 -2.1589316 -0.9959370 -1.5774343 1.1629946 2 9.385413 34.272459 0.0000486 0.0057994 N(G),N(G)-dimethylarginine dimethylaminohydrolase 2
O94875-10 2.3212380 1.3818264 1.8515322 -0.9394116 2 8.958355 36.659139 0.0000486 0.0057994 Sorbin and SH3 domain-containing protein 2
Q16647 -2.7876976 -1.5342676 -2.1609826 1.2534300 2 9.156725 34.947347 0.0000517 0.0058198 Prostacyclin synthase
Q9UGT4 -2.2836150 -2.4665348 -2.3750749 -0.1829198 2 9.193722 34.308942 0.0000545 0.0058198 Sushi domain-containing protein 2
P02776 -1.7487175 -2.8417114 -2.2952145 -1.0929939 2 7.718405 43.279869 0.0000639 0.0062978 Platelet factor 4;Platelet factor 4, short form
A6NMZ7 -2.2673287 -3.0659585 -2.6666436 -0.7986298 2 9.385413 31.905851 0.0000652 0.0062978 Collagen alpha-6(VI) chain
Q14764 -1.6259758 -1.6162557 -1.6211158 0.0097201 2 9.385413 31.218467 0.0000712 0.0065710 Major vault protein
Q15113 -2.7550209 -1.9885085 -2.3717647 0.7665124 2 9.188121 31.518143 0.0000770 0.0067277 Procollagen C-endopeptidase enhancer 1
Q9ULL5-3 -3.3863077 -1.2106027 -2.2984552 2.1757051 2 7.893242 39.193814 0.0000796 0.0067277 Proline-rich protein 12
Q9P2B2 -2.0475095 -2.0452709 -2.0463902 0.0022386 2 9.385413 30.078364 0.0000829 0.0067277 Prostaglandin F2 receptor negative regulator
P14854 2.3006633 1.0658853 1.6832743 -1.2347780 2 8.346841 33.671446 0.0001009 0.0075831 Cytochrome c oxidase subunit 6B1
P18428 -2.0025775 -1.7014100 -1.8519938 0.3011674 2 9.013977 29.954553 0.0001043 0.0075831 Lipopolysaccharide-binding protein
P54652 -1.5859216 -2.7252456 -2.1555836 -1.1393240 2 9.007166 29.940008 0.0001049 0.0075831 Heat shock-related 70 kDa protein 2
P24844 -2.5518015 -1.7836148 -2.1677081 0.7681867 2 9.330669 28.358116 0.0001083 0.0075831 Myosin regulatory light polypeptide 9
P51888 -3.1995487 -1.9468369 -2.5731928 1.2527118 2 6.959924 42.594973 0.0001247 0.0081957 Prolargin
Q9BW30 -2.7386840 -2.3263164 -2.5325002 0.4123676 2 9.049210 28.443735 0.0001252 0.0081957 Tubulin polymerization-promoting protein family member 3
O43677 -2.7580901 -2.9654848 -2.8617874 -0.2073947 2 7.933870 33.631479 0.0001335 0.0082984 NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial
P00748 -2.0030563 -1.9489960 -1.9760261 0.0540602 2 9.091376 27.735769 0.0001349 0.0082984 Coagulation factor XII;Coagulation factor XIIa heavy chain;Beta-factor XIIa part 1;Coagulation factor XIIa light chain
P48681 -1.3300808 -1.4933277 -1.4117043 -0.1632468 2 9.321612 26.157695 0.0001501 0.0089644 Nestin
P02775 -1.9521262 -2.1690290 -2.0605776 -0.2169029 2 9.385413 25.639727 0.0001573 0.0090542 Platelet basic protein;Connective tissue-activating peptide III;TC-2;Connective tissue-activating peptide III(1-81);Beta-thromboglobulin;Neutrophil-activating peptide 2(74);Neutrophil-activating peptide 2(73);Neutrophil-activating peptide 2;TC-1;Neutrophil-activating peptide 2(1-66);Neutrophil-activating peptide 2(1-63)
P08294 -2.7564583 -1.8981910 -2.3273246 0.8582673 2 7.979491 31.192375 0.0001691 0.0090542 Extracellular superoxide dismutase [Cu-Zn]
P23083 -4.2742932 -2.2755749 -3.2749341 1.9987183 2 7.385413 35.088072 0.0001693 0.0090542 Ig heavy chain V-I region V35
P36955 -2.3236197 -1.0657353 -1.6946775 1.2578843 2 8.456893 28.729923 0.0001695 0.0090542 Pigment epithelium-derived factor
P02743 -2.2737781 -1.6607108 -1.9672445 0.6130673 2 9.385413 24.776129 0.0001801 0.0093742 Serum amyloid P-component;Serum amyloid P-component(1-203)
O00180 -4.0967217 -4.7553461 -4.4260339 -0.6586245 2 8.385413 28.272422 0.0001875 0.0095158 Potassium channel subfamily K member 1
P51884 -2.4022338 -1.4533109 -1.9277723 0.9489230 2 7.936878 29.702993 0.0002064 0.0099663 Lumican
P00325 -2.1088138 -0.8991435 -1.5039787 1.2096703 2 9.141096 24.684486 0.0002066 0.0099663 Alcohol dehydrogenase 1B
Q5NDL2 -2.3376295 -2.7045789 -2.5211042 -0.3669494 2 8.686198 25.916946 0.0002180 0.0099663 EGF domain-specific O-linked N-acetylglucosamine transferase
Q92604 -2.2702815 -1.9257953 -2.0980384 0.3444862 2 9.345516 23.715791 0.0002181 0.0099663 Acyl-CoA:lysophosphatidylglycerol acyltransferase 1
Q53GQ0 -2.4308529 -1.2156054 -1.8232291 1.2152475 2 9.334954 23.651824 0.0002215 0.0099663 Very-long-chain 3-oxoacyl-CoA reductase
P60468 -1.5229242 -2.4541896 -1.9885569 -0.9312654 2 8.241407 27.348175 0.0002300 0.0099663 Protein transport protein Sec61 subunit beta
P07451 -1.8415388 -0.7406077 -1.2910732 1.1009311 2 9.385413 23.260186 0.0002307 0.0099663 Carbonic anhydrase 3
Q92508 4.0710006 2.9423812 3.5066909 -1.1286194 2 6.385413 40.291134 0.0002393 0.0101201 Piezo-type mechanosensitive ion channel component 1
Q6PCB0 -1.3297806 -2.3007919 -1.8152862 -0.9710113 2 9.198450 23.100847 0.0002591 0.0107360 von Willebrand factor A domain-containing protein 1
P28066 -1.1096114 -2.1707758 -1.6401936 -1.0611644 2 8.500773 25.051701 0.0002730 0.0108002 Proteasome subunit alpha type-5
Q9UBG0 -2.5762099 -0.7476767 -1.6619433 1.8285332 2 9.131671 22.977636 0.0002731 0.0108002 C-type mannose receptor 2
P30405 -1.5402735 -1.8282016 -1.6842375 -0.2879280 2 9.385413 22.200005 0.0002767 0.0108002 Peptidyl-prolyl cis-trans isomerase F, mitochondrial
P01031 -1.3223783 -1.6526586 -1.4875185 -0.3302802 2 8.183937 25.866283 0.0002898 0.0111012 Complement C5;Complement C5 beta chain;Complement C5 alpha chain;C5a anaphylatoxin;Complement C5 alpha chain
P05997 -3.0688637 -1.9991154 -2.5339895 1.0697482 2 8.864434 23.034598 0.0003082 0.0114681 Collagen alpha-2(V) chain
Q9ULD0 -0.5232010 -3.5070276 -2.0151143 -2.9838266 2 6.128068 39.648177 0.0003119 0.0114681 2-oxoglutarate dehydrogenase-like, mitochondrial
Q15327 -1.3545314 -2.2217826 -1.7881570 -0.8672512 2 9.280457 21.682263 0.0003179 0.0114681 Ankyrin repeat domain-containing protein 1
Q8TBP6 -1.8932428 -1.5272808 -1.7102618 0.3659619 2 8.851865 22.802350 0.0003220 0.0114681 Solute carrier family 25 member 40
Q14195-2 -2.5272781 -1.9904875 -2.2588828 0.5367907 2 9.262403 21.354010 0.0003397 0.0115202 Dihydropyrimidinase-related protein 3
P35625 -1.9848027 -3.9792035 -2.9820031 -1.9944008 2 7.962134 25.589243 0.0003412 0.0115202 Metalloproteinase inhibitor 3
O14980 -1.2303520 -1.0484463 -1.1393991 0.1819057 2 9.382448 20.935701 0.0003473 0.0115202 Exportin-1
Q8WWA0 -5.8069752 -3.0892056 -4.4480904 2.7177697 2 8.244689 24.246612 0.0003521 0.0115202 Intelectin-1
P46060 -1.9706423 -1.5112752 -1.7409587 0.4593671 2 8.385413 23.700667 0.0003543 0.0115202 Ran GTPase-activating protein 1
P36021 -3.1383009 -1.9362318 -2.5372663 1.2020690 2 8.385413 23.640542 0.0003575 0.0115202 Monocarboxylate transporter 8
Q69YU5 1.7637858 3.2208428 2.4923143 1.4570570 2 8.841525 21.866238 0.0003778 0.0119831 Uncharacterized protein C12orf73
O95980 -2.5524206 -1.3836422 -1.9680314 1.1687784 2 7.980660 24.630656 0.0003851 0.0120269 Reversion-inducing cysteine-rich protein with Kazal motifs
Q7L4S7 -1.7474498 -2.5477609 -2.1476054 -0.8003111 2 7.157555 27.778526 0.0004233 0.0128614 Protein ARMCX6
Q8TBQ9 -2.7618057 -0.7242810 -1.7430434 2.0375247 2 8.170120 23.247359 0.0004245 0.0128614 Protein kish-A
P04004 -1.6339729 -1.9329355 -1.7834542 -0.2989626 2 8.981078 20.612102 0.0004402 0.0128719 Vitronectin;Vitronectin V65 subunit;Vitronectin V10 subunit;Somatomedin-B
P12110 -2.1364562 -1.2366997 -1.6865779 0.8997564 2 8.535409 21.831782 0.0004403 0.0128719 Collagen alpha-2(VI) chain
P41240 -1.5691477 -1.1536153 -1.3613815 0.4155324 2 8.922337 20.715046 0.0004439 0.0128719 Tyrosine-protein kinase CSK
O15230 -1.4150113 -1.3512669 -1.3831391 0.0637444 2 9.044210 19.855982 0.0004913 0.0138534 Laminin subunit alpha-5
Q9NZ01 -2.3460403 -1.3540953 -1.8500678 0.9919450 2 8.691035 20.740126 0.0004914 0.0138534 Very-long-chain enoyl-CoA reductase
Q07954 -1.6748321 -0.9719344 -1.3233833 0.7028977 2 9.385413 18.940512 0.0005073 0.0140821 Prolow-density lipoprotein receptor-related protein 1;Low-density lipoprotein receptor-related protein 1 85 kDa subunit;Low-density lipoprotein receptor-related protein 1 515 kDa subunit;Low-density lipoprotein receptor-related protein 1 intracellular domain
Q9BXN1 -2.6709234 -1.9091316 -2.2900275 0.7617918 2 8.937487 19.871226 0.0005133 0.0140821 Asporin
Q15274 -1.9282879 -2.1785858 -2.0534369 -0.2502979 2 7.757883 23.240643 0.0005296 0.0141879 Nicotinate-nucleotide pyrophosphorylase [carboxylating]
Q6YN16 1.5271671 1.5467735 1.5369703 0.0196064 2 9.222955 19.046286 0.0005312 0.0141879 Hydroxysteroid dehydrogenase-like protein 2
P04083 -1.5245384 -1.1749000 -1.3497192 0.3496384 2 9.385413 18.571596 0.0005462 0.0143987 Annexin A1
P04003 -1.4790527 -1.3920940 -1.4355734 0.0869587 2 9.090898 19.007793 0.0005655 0.0147162 C4b-binding protein alpha chain
Q9UL18 -2.6023120 -0.0688510 -1.3355815 2.5334610 2 8.037138 21.366792 0.0006069 0.0154288 Protein argonaute-1
O60760 -3.5000288 -1.0631593 -2.2815940 2.4368695 2 8.385413 20.152153 0.0006268 0.0154288 Hematopoietic prostaglandin D synthase
Q9Y6X5 -1.4114347 -1.5449603 -1.4781975 -0.1335256 2 8.750753 19.161143 0.0006350 0.0154288 Bis(5-adenosyl)-triphosphatase ENPP4
P23142 -1.8527598 -2.8190443 -2.3359021 -0.9662845 2 7.590129 22.566639 0.0006390 0.0154288 Fibulin-1
Q92736-2 -3.3307404 1.0781855 -1.1262774 4.4089259 2 8.908498 18.724478 0.0006447 0.0154288 Ryanodine receptor 2
Q96LL9 -2.4266405 -0.1255693 -1.2761049 2.3010712 2 8.842792 18.847708 0.0006474 0.0154288 DnaJ homolog subfamily C member 30
O75828 -1.6417394 -1.3689557 -1.5053475 0.2727838 2 9.385413 17.702832 0.0006530 0.0154288 Carbonyl reductase [NADPH] 3
P04196 -1.9171807 -1.4596228 -1.6884017 0.4575579 2 7.683140 22.070959 0.0006536 0.0154288 Histidine-rich glycoprotein
P30711 -1.2535537 -2.3235254 -1.7885395 -1.0699717 2 9.018645 18.192306 0.0006834 0.0159469 Glutathione S-transferase theta-1
P23434 1.1268218 1.4139379 1.2703798 0.2871161 2 9.385413 17.425133 0.0006923 0.0159707 Glycine cleavage system H protein, mitochondrial
Q5JPH6 3.5060169 3.2437535 3.3748852 -0.2622634 2 6.212234 28.881640 0.0007149 0.0163056 Probable glutamate–tRNA ligase, mitochondrial
Q92681 -2.1530541 -1.4997046 -1.8263794 0.6533496 2 8.133279 19.834425 0.0007448 0.0167504 Regulatory solute carrier protein family 1 member 1
Q9BZH6 1.9311553 3.4204862 2.6758207 1.4893309 2 8.367230 19.171225 0.0007509 0.0167504 WD repeat-containing protein 11
P49207 -1.5348292 -1.2156675 -1.3752484 0.3191617 2 8.970773 17.586091 0.0007870 0.0173652 60S ribosomal protein L34
P07357 -1.1549122 -1.2564148 -1.2056635 -0.1015026 2 9.290174 16.879989 0.0008065 0.0174685 Complement component C8 alpha chain
P04275 -1.0540996 -1.3623248 -1.2082122 -0.3082252 2 8.991784 17.410957 0.0008089 0.0174685 von Willebrand factor;von Willebrand antigen 2
P48163 -0.8742508 -2.9539287 -1.9140897 -2.0796779 2 7.960353 19.749073 0.0008201 0.0175233 NADP-dependent malic enzyme
Q9NRG4 2.1576737 2.5530787 2.3553762 0.3954050 2 8.385413 18.346713 0.0008659 0.0182138 N-lysine methyltransferase SMYD2
Q9BUF5 -1.9343777 -1.6205004 -1.7774391 0.3138773 2 9.217423 16.653562 0.0008703 0.0182138 Tubulin beta-6 chain
P50453 -1.0571443 -1.4224494 -1.2397969 -0.3653051 2 9.052869 16.851253 0.0008877 0.0183877 Serpin B9
P40261 -2.3067271 -0.5611559 -1.4339415 1.7455712 2 9.340024 16.214682 0.0009165 0.0186174 Nicotinamide N-methyltransferase
O14967 -2.3931306 -0.8808598 -1.6369952 1.5122708 2 8.430438 17.938253 0.0009171 0.0186174 Calmegin
Q9HCB6 -1.8088797 -2.4163742 -2.1126269 -0.6074945 2 8.648303 17.394332 0.0009313 0.0186367 Spondin-1
Q86WV6 -1.0645731 -1.3366433 -1.2006082 -0.2720702 2 9.239827 16.281293 0.0009364 0.0186367 Stimulator of interferon genes protein
P01024 -1.1482973 -1.1510164 -1.1496569 -0.0027191 2 9.197920 16.269998 0.0009533 0.0187877 Complement C3;Complement C3 beta chain;C3-beta-c;Complement C3 alpha chain;C3a anaphylatoxin;Acylation stimulating protein;Complement C3b alpha chain;Complement C3c alpha chain fragment 1;Complement C3dg fragment;Complement C3g fragment;Complement C3d fragment;Complement C3f fragment;Complement C3c alpha chain fragment 2
Q8WZA9 -1.5022008 -0.7123621 -1.1072814 0.7898387 2 9.101344 16.199917 0.0010030 0.0192980 Immunity-related GTPase family Q protein
Q8WY22 -1.8394420 -1.2560002 -1.5477211 0.5834418 2 8.385413 17.535888 0.0010096 0.0192980 BRI3-binding protein
O00264 -1.9992421 -0.8347285 -1.4169853 1.1645136 2 9.079390 16.165900 0.0010187 0.0192980 Membrane-associated progesterone receptor component 1
P49458 -2.3208229 -1.5193157 -1.9200693 0.8015072 2 7.120983 20.998598 0.0010323 0.0192980 Signal recognition particle 9 kDa protein
Q00G26 0.9705589 1.9366811 1.4536200 0.9661222 2 7.788675 18.796138 0.0010453 0.0192980 Perilipin-5
P24298 1.3010640 1.9631743 1.6321192 0.6621103 2 8.623072 16.855736 0.0010485 0.0192980 Alanine aminotransferase 1
P12814 -1.7261945 -2.1924895 -1.9593420 -0.4662950 2 8.144626 17.867453 0.0010509 0.0192980 Alpha-actinin-1
P62760 -1.9296447 -1.8525435 -1.8910941 0.0771012 2 9.120970 15.908955 0.0010620 0.0192980 Visinin-like protein 1
Q92621 -1.7555813 -0.7290578 -1.2423196 1.0265235 2 9.385413 15.486770 0.0010647 0.0192980 Nuclear pore complex protein Nup205
P14550 -1.3940797 -1.2147931 -1.3044364 0.1792867 2 8.301450 17.330401 0.0010881 0.0195469 Alcohol dehydrogenase [NADP(+)]
Q9UHG2 -1.5781315 -3.3052829 -2.4417072 -1.7271515 2 8.796297 16.293511 0.0011019 0.0195842 ProSAAS;KEP;Big SAAS;Little SAAS;Big PEN-LEN;PEN;Little LEN;Big LEN
Q9UQ35 -1.3675109 -1.1283860 -1.2479485 0.2391249 2 9.385413 15.310560 0.0011095 0.0195842 Serine/arginine repetitive matrix protein 2
Q9UNW9 4.0970526 2.5592726 3.3281626 -1.5377800 2 9.054127 15.777880 0.0011203 0.0196049 RNA-binding protein Nova-2
P02747 -2.6809142 -1.0489855 -1.8649499 1.6319287 2 7.138784 20.155201 0.0011582 0.0200961 Complement C1q subcomponent subunit C
O94919 -1.1585816 -1.1506677 -1.1546247 0.0079139 2 9.248102 15.281924 0.0011709 0.0201441 Endonuclease domain-containing 1 protein
Q9UBB5 2.6733014 0.1376498 1.4054756 -2.5356516 2 6.385413 22.969050 0.0012118 0.0206722 Methyl-CpG-binding domain protein 2
Q9Y3B4 -1.2545628 -1.3433144 -1.2989386 -0.0887516 2 9.218746 15.129931 0.0012255 0.0207013 Splicing factor 3B subunit 6
Q92930 -0.1821330 -2.8031266 -1.4926298 -2.6209936 2 7.597170 18.350597 0.0012339 0.0207013 Ras-related protein Rab-8B
Q09161 1.6000882 2.4230607 2.0115745 0.8229726 2 6.358037 22.719676 0.0012705 0.0210567 Nuclear cap-binding protein subunit 1
Q9ULC3 -1.6748081 -1.2521086 -1.4634583 0.4226994 2 8.669265 15.832512 0.0012759 0.0210567 Ras-related protein Rab-23
Q5M9N0 -3.5370655 -2.0324007 -2.7847331 1.5046647 2 8.350040 16.314342 0.0013050 0.0213638 Coiled-coil domain-containing protein 158
Q6SZW1 -2.5636873 -1.5366583 -2.0501728 1.0270290 2 7.385413 18.512262 0.0013274 0.0215565 Sterile alpha and TIR motif-containing protein 1
Q53GG5-2 -2.9233739 -1.9547211 -2.4390475 0.9686528 2 8.429675 16.001178 0.0013491 0.0215717 PDZ and LIM domain protein 3
P31994-2 -1.6555661 -0.0246523 -0.8401092 1.6309138 2 8.992524 15.052398 0.0013496 0.0215717 Low affinity immunoglobulin gamma Fc region receptor II-b
P08603 -0.8156387 -1.4932560 -1.1544473 -0.6776173 2 9.385413 14.422402 0.0013730 0.0217748 Complement factor H
Q96FN9 -0.7351941 -2.6479617 -1.6915779 -1.9127675 2 8.385413 15.887535 0.0014054 0.0221164 Probable D-tyrosyl-tRNA(Tyr) deacylase 2
P11586 0.5240804 2.0119956 1.2680380 1.4879152 2 7.881516 16.870189 0.0014189 0.0221574 C-1-tetrahydrofolate synthase, cytoplasmic;Methylenetetrahydrofolate dehydrogenase;Methenyltetrahydrofolate cyclohydrolase;Formyltetrahydrofolate synthetase;C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed
Q9H1K0 -1.0302150 -2.2836483 -1.6569316 -1.2534333 2 7.385413 18.059570 0.0014323 0.0221947 Rabenosyn-5
Q9BUH6 -0.7048278 -1.5164145 -1.1106212 -0.8115867 2 9.115985 14.547929 0.0014559 0.0223900 Protein PAXX
Q53T59 -1.8521243 -1.8154181 -1.8337712 0.0367062 2 7.876061 16.521863 0.0015200 0.0230978 HCLS1-binding protein 3
P25940 -1.6803001 -1.5733256 -1.6268129 0.1069744 2 9.043783 14.456074 0.0015247 0.0230978 Collagen alpha-3(V) chain
Q9NY15 -2.1774225 -0.7897346 -1.4835786 1.3876880 2 9.336638 14.011059 0.0015443 0.0232216 Stabilin-1
Q8NAT1 -1.4164507 -0.3174685 -0.8669596 1.0989822 2 9.385413 13.914217 0.0015581 0.0232449 Protein O-linked-mannose beta-1,4-N-acetylglucosaminyltransferase 2
O43464 -1.9007206 0.7261872 -0.5872667 2.6269078 2 9.072346 14.297299 0.0015687 0.0232449 Serine protease HTRA2, mitochondrial
P07585 -1.9272925 -2.3418627 -2.1345776 -0.4145702 2 9.163968 14.130035 0.0015853 0.0233194 Decorin
Q99983 -2.4961356 -3.5746196 -3.0353776 -1.0784839 2 6.904704 18.806830 0.0016058 0.0234514 Osteomodulin
Q9BS26 -1.2263582 -1.1041391 -1.1652487 0.1222191 2 9.249914 13.727711 0.0017043 0.0246056 Endoplasmic reticulum resident protein 44
Q9UKR5 -3.2086830 -4.2783690 -3.7435260 -1.0696861 2 8.595465 14.600416 0.0017210 0.0246056 Probable ergosterol biosynthetic protein 28
Q9HAV4 -2.2052737 -1.1596644 -1.6824690 1.0456093 2 7.987893 15.661958 0.0017212 0.0246056 Exportin-5
Q9BTV4 -1.8104632 -1.4010178 -1.6057405 0.4094454 2 9.284468 13.566939 0.0017561 0.0248698 Transmembrane protein 43
P35052 -0.6193263 -1.9557489 -1.2875376 -1.3364227 2 7.703314 16.101781 0.0017721 0.0248698 Glypican-1;Secreted glypican-1
P01008 -1.5471922 -1.5321558 -1.5396740 0.0150364 2 9.310907 13.489881 0.0017764 0.0248698 Antithrombin-III
P13671 -1.1914382 -1.5383124 -1.3648753 -0.3468742 2 9.385413 13.329057 0.0018101 0.0249035 Complement component C6
P14543 -1.3845506 -1.2999894 -1.3422700 0.0845612 2 9.204669 13.536114 0.0018145 0.0249035 Nidogen-1
Q12996 -1.6674028 -1.2935582 -1.4804805 0.3738446 2 7.207709 17.128176 0.0018261 0.0249035 Cleavage stimulation factor subunit 3
Q2TAA5 -1.3192452 -0.9694554 -1.1443503 0.3497898 2 9.249693 13.452203 0.0018279 0.0249035 GDP-Man:Man(3)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase
Q6PI78 1.1229874 1.9484794 1.5357334 0.8254920 2 9.040261 13.666187 0.0018499 0.0249839 Transmembrane protein 65
P01042 -2.2563158 -1.7570236 -2.0066697 0.4992922 2 7.210294 17.020705 0.0018584 0.0249839 Kininogen-1;Kininogen-1 heavy chain;T-kinin;Bradykinin;Lysyl-bradykinin;Kininogen-1 light chain;Low molecular weight growth-promoting factor
Q96H79 -3.0216701 -1.3331324 -2.1774013 1.6885377 2 6.334231 19.561690 0.0019464 0.0259943 Zinc finger CCCH-type antiviral protein 1-like
Q8TDB4 -1.8386665 -2.8602879 -2.3494772 -1.0216214 2 6.330306 19.494450 0.0019690 0.0261246 Protein MGARP
P45877 -1.2597920 -0.7394688 -0.9996304 0.5203232 2 9.343571 13.002295 0.0019971 0.0261892 Peptidyl-prolyl cis-trans isomerase C
P20774 -2.2367735 -1.9653377 -2.1010556 0.2714358 2 8.210882 14.549345 0.0019997 0.0261892 Mimecan
Q9HAT2 1.3442519 1.8668820 1.6055669 0.5226301 2 9.216677 13.044682 0.0020515 0.0266959 Sialate O-acetylesterase
Q9UJC5 -1.1262301 -1.3257262 -1.2259781 -0.1994961 2 9.326832 12.870624 0.0020783 0.0268689 SH3 domain-binding glutamic acid-rich-like protein 2
P34932 -1.1634292 -0.6217632 -0.8925962 0.5416660 2 9.385413 12.783000 0.0020913 0.0268689 Heat shock 70 kDa protein 4
Q9GZY4 -3.1677681 -0.0954235 -1.6315958 3.0723446 2 7.703311 15.142943 0.0021422 0.0271006 Cytochrome c oxidase assembly factor 1 homolog
Q96C86 -1.5155718 -0.2524683 -0.8840200 1.2631035 2 9.145534 12.949577 0.0021488 0.0271006 m7GpppX diphosphatase
Q16082 -1.3619821 -1.2847033 -1.3233427 0.0772788 2 9.207589 12.877393 0.0021494 0.0271006 Heat shock protein beta-2
Q96KC8 0.8980074 -2.5287840 -0.8153883 -3.4267914 2 8.321700 13.939197 0.0022045 0.0276241 DnaJ homolog subfamily C member 1
P56539 -2.0519177 0.6926641 -0.6796268 2.7445818 2 8.553679 13.356405 0.0023380 0.0291177 Caveolin-3
P62857 -0.6453035 -2.1384365 -1.3918700 -1.4931330 2 7.956911 14.197256 0.0023720 0.0293602 40S ribosomal protein S28
P06727 -1.3583680 -0.7667083 -1.0625381 0.5916597 2 8.884167 12.814824 0.0024096 0.0295719 Apolipoprotein A-IV
P02461 -3.5976656 -2.2738894 -2.9357775 1.3237762 2 8.323445 13.522376 0.0024274 0.0295719 Collagen alpha-1(III) chain
Q14314 -1.7692180 -2.0953097 -1.9322639 -0.3260917 2 9.382448 12.231706 0.0024328 0.0295719 Fibroleukin
P09619 -1.6757284 -0.9093138 -1.2925211 0.7664146 2 9.154490 12.419073 0.0024667 0.0298056 Platelet-derived growth factor receptor beta
O15061 -0.4856308 -1.7028211 -1.0942259 -1.2171903 2 9.385413 12.086427 0.0025311 0.0304031 Synemin
P19429 2.0373090 2.1009541 2.0691315 0.0636451 2 7.976624 13.699861 0.0026302 0.0313664 Troponin I, cardiac muscle
P02790 -1.1921329 -1.4568633 -1.3244981 -0.2647304 2 9.385413 11.933537 0.0026422 0.0313664 Hemopexin
P01034 -1.6893296 -1.2428420 -1.4660858 0.4464875 2 8.837162 12.445434 0.0026903 0.0317523 Cystatin-C
P01699 -4.0259605 0.3400879 -1.8429363 4.3660484 2 6.314916 17.240217 0.0027650 0.0323664 Ig lambda chain V-I region VOR
Q07507 -0.9566123 -1.6741554 -1.3153838 -0.7175431 2 8.160106 13.191734 0.0027743 0.0323664 Dermatopontin
P46063 -1.3869124 -0.2234828 -0.8051976 1.1634296 2 9.154885 11.934461 0.0028156 0.0326607 ATP-dependent DNA helicase Q1
Q9Y2Z0 -1.7579777 1.2068202 -0.2755788 2.9647978 2 9.385413 11.674630 0.0028441 0.0327268 Suppressor of G2 allele of SKP1 homolog
P50479 -1.9052893 -2.3347923 -2.1200408 -0.4295030 2 8.131897 13.113069 0.0028535 0.0327268 PDZ and LIM domain protein 4
Q86VP6 -1.0974174 -1.6122394 -1.3548284 -0.5148220 2 8.542953 12.540888 0.0028725 0.0327590 Cullin-associated NEDD8-dissociated protein 1
P28300 -1.2607685 -1.6978873 -1.4793279 -0.4371188 2 7.649016 13.768131 0.0029194 0.0330790 Protein-lysine 6-oxidase
Q15126 -1.0340183 -0.9865904 -1.0103044 0.0474279 2 9.342811 11.607013 0.0029331 0.0330790 Phosphomevalonate kinase
Q86VU5 1.5740900 1.1899321 1.3820110 -0.3841579 2 9.385413 11.512614 0.0029801 0.0334227 Catechol O-methyltransferase domain-containing protein 1
O43143 -1.0109780 -0.7834921 -0.8972350 0.2274859 2 9.289616 11.574983 0.0030027 0.0334915 Pre-mRNA-splicing factor ATP-dependent RNA helicase DHX15
P82663 -0.7938408 -1.9350886 -1.3644647 -1.1412478 2 9.302714 11.525853 0.0030347 0.0336069 28S ribosomal protein S25, mitochondrial
O43175 -2.0890071 -2.0660744 -2.0775407 0.0229327 2 9.173117 11.629663 0.0030510 0.0336069 D-3-phosphoglycerate dehydrogenase
P26447 -1.8777689 -1.1686882 -1.5232285 0.7090807 2 8.774968 12.025412 0.0030627 0.0336069 Protein S100-A4
P13667 -1.1592112 -1.0499894 -1.1046003 0.1092218 2 9.181460 11.588346 0.0030799 0.0336143 Protein disulfide-isomerase A4
Q04760 0.5615089 2.2161884 1.3888487 1.6546795 2 8.599181 12.147102 0.0031249 0.0338146 Lactoylglutathione lyase
Q96CS3 -1.3291851 -1.0516357 -1.1904104 0.2775494 2 9.119924 11.588823 0.0031316 0.0338146 FAS-associated factor 2
P50552 -1.5231187 -0.3481323 -0.9356255 1.1749865 2 9.074476 11.556793 0.0031996 0.0343659 Vasodilator-stimulated phosphoprotein
O95183 -1.3898689 -1.5291947 -1.4595318 -0.1393258 2 9.371170 11.184431 0.0032924 0.0351768 Vesicle-associated membrane protein 5
Q15582 -2.0883637 -2.4627789 -2.2755713 -0.3744151 2 7.899813 12.560835 0.0035188 0.0370726 Transforming growth factor-beta-induced protein ig-h3
Q6UWS5 0.9342388 1.7762603 1.3552496 0.8420216 2 7.068224 13.945225 0.0035193 0.0370726 Protein PET117 homolog, mitochondrial
P46940 -1.2205560 -1.0146605 -1.1176083 0.2058955 2 9.306592 11.010224 0.0035246 0.0370726 Ras GTPase-activating-like protein IQGAP1
Q96JB2 -1.5453539 -2.4514355 -1.9983947 -0.9060817 2 8.142504 12.081209 0.0036586 0.0381425 Conserved oligomeric Golgi complex subunit 3
Q9H1E5 -1.3888294 -0.6312590 -1.0100442 0.7575704 2 9.385413 10.814657 0.0036639 0.0381425 Thioredoxin-related transmembrane protein 4
P62328 -1.2899569 -1.6678529 -1.4789049 -0.3778960 2 7.220282 13.330964 0.0037678 0.0388339 Thymosin beta-4;Hematopoietic system regulatory peptide
Q08945 -2.0713524 -0.7768868 -1.4241196 1.2944656 2 8.385413 11.678065 0.0037686 0.0388339 FACT complex subunit SSRP1
Q5VIR6-4 -1.7550575 -0.0614140 -0.9082357 1.6936435 2 9.130015 10.919027 0.0037890 0.0388469 Vacuolar protein sorting-associated protein 53 homolog
P15924 1.2742208 0.5869741 0.9305974 -0.6872468 2 9.350459 10.675543 0.0038552 0.0391584 Desmoplakin
P01019 -1.0362862 -1.0127277 -1.0245069 0.0235585 2 9.093510 10.889809 0.0038580 0.0391584 Angiotensinogen;Angiotensin-1;Angiotensin-2;Angiotensin-3;Angiotensin-4;Angiotensin 1-9;Angiotensin 1-7;Angiotensin 1-5;Angiotensin 1-4
P83916 -1.9742521 -1.3616457 -1.6679489 0.6126064 2 6.385413 14.963203 0.0038901 0.0392877 Chromobox protein homolog 1
O95486 -1.5003000 -1.1213028 -1.3108014 0.3789972 2 9.187800 10.736201 0.0039420 0.0396155 Protein transport protein Sec24A
P03950 -2.2142952 -1.3775033 -1.7958993 0.8367919 2 8.216113 11.647751 0.0039967 0.0399668 Angiogenin
Q9NRX4 1.2804301 1.4870941 1.3837621 0.2066640 2 9.339127 10.535987 0.0040345 0.0400138 14 kDa phosphohistidine phosphatase
Q9Y5U8 -3.9888327 -0.8866380 -2.4377353 3.1021947 2 9.327097 10.540498 0.0040408 0.0400138 Mitochondrial pyruvate carrier 1
Q8N5M1 -2.0221430 -0.6423210 -1.3322320 1.3798221 2 8.937206 10.851063 0.0040640 0.0400479 ATP synthase mitochondrial F1 complex assembly factor 2
Q562R1 1.3201209 -1.9616415 -0.3207603 -3.2817624 2 9.266665 10.545352 0.0040950 0.0401588 Beta-actin-like protein 2
P05455 -1.2042291 -0.5305125 -0.8673708 0.6737166 2 9.178555 10.565065 0.0041602 0.0403946 Lupus La protein
O15118 -1.6169068 -2.6334712 -2.1251890 -1.0165644 2 6.385413 14.553122 0.0041844 0.0403946 Niemann-Pick C1 protein
Q04721 1.5310391 0.6944075 1.1127233 -0.8366316 2 9.201253 10.522611 0.0041905 0.0403946 Neurogenic locus notch homolog protein 2;Notch 2 extracellular truncation;Notch 2 intracellular domain
P54577 -1.3097944 -0.7452704 -1.0275324 0.5645241 2 8.964139 10.716040 0.0041986 0.0403946 Tyrosine–tRNA ligase, cytoplasmic;Tyrosine–tRNA ligase, cytoplasmic, N-terminally processed
P00747 -0.7054831 -0.9638979 -0.8346905 -0.2584148 2 9.172800 10.440542 0.0043269 0.0413862 Plasminogen;Plasmin heavy chain A;Activation peptide;Angiostatin;Plasmin heavy chain A, short form;Plasmin light chain B
P02748 -1.3394634 -1.1229428 -1.2312031 0.2165205 2 8.865762 10.685485 0.0043459 0.0413862 Complement component C9;Complement component C9a;Complement component C9b
Q9BXR6 -2.3526616 -0.3476437 -1.3501527 2.0050179 2 9.382448 10.250529 0.0043629 0.0413862 Complement factor H-related protein 5
Q7Z3T8 -1.5768427 -1.2158882 -1.3963655 0.3609544 2 8.413206 11.050965 0.0044277 0.0417033 Zinc finger FYVE domain-containing protein 16
Q9Y287 -1.9187015 -1.3340175 -1.6263595 0.5846840 2 9.385413 10.194354 0.0044376 0.0417033 Integral membrane protein 2B;BRI2, membrane form;BRI2 intracellular domain;BRI2C, soluble form;Bri23 peptide
P01303 -0.6538416 -2.1633002 -1.4085709 -1.5094586 2 8.890312 10.577519 0.0044579 0.0417033 Pro-neuropeptide Y;Neuropeptide Y;C-flanking peptide of NPY
Q8WWQ0 -1.3655434 -1.2188019 -1.2921726 0.1467415 2 9.385413 10.140256 0.0045140 0.0420343 PH-interacting protein
O95445 -2.7585923 -2.3195737 -2.5390830 0.4390186 2 9.052359 10.351660 0.0045797 0.0421706 Apolipoprotein M
P27658 -1.5409469 -1.7449610 -1.6429540 -0.2040141 2 9.385413 10.090334 0.0045860 0.0421706 Collagen alpha-1(VIII) chain;Vastatin
Q9UK22 -1.9689505 -0.9835733 -1.4762619 0.9853772 2 6.372396 14.069977 0.0045960 0.0421706 F-box only protein 2
P80723 -1.6385395 -1.4066562 -1.5225978 0.2318833 2 7.910668 11.448438 0.0046195 0.0421706 Brain acid soluble protein 1
P01611 -0.4068850 -2.2194112 -1.3131481 -1.8125261 2 9.385413 10.058567 0.0046325 0.0421706 Ig kappa chain V-I region Wes
Q9UBV8 -1.1877604 -1.1566251 -1.1721927 0.0311353 2 8.885488 10.413473 0.0046866 0.0424726 Peflin
Q9UKX3 2.0400959 1.3472678 1.6936818 -0.6928281 2 9.208912 10.120583 0.0047349 0.0427193 Myosin-13
Q8TDB6 -1.6113146 -0.2207985 -0.9160565 1.3905161 2 9.153547 10.138005 0.0047718 0.0428622 E3 ubiquitin-protein ligase DTX3L
P07360 -0.3859901 -1.5479619 -0.9669760 -1.1619718 2 8.752393 10.443655 0.0048053 0.0429727 Complement component C8 gamma chain
P08582 -1.6638598 0.4414480 -0.6112059 2.1053079 2 9.299314 9.966955 0.0048656 0.0432000 Melanotransferrin
O60262 -1.5147797 -0.9563725 -1.2355761 0.5584072 2 8.388576 10.731124 0.0048733 0.0432000 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7
P52907 -0.6186589 -1.0777393 -0.8481991 -0.4590804 2 9.339311 9.904666 0.0049178 0.0432527 F-actin-capping protein subunit alpha-1
P07384 -1.1069382 -0.6510097 -0.8789740 0.4559285 2 9.333139 9.906524 0.0049219 0.0432527 Calpain-1 catalytic subunit
P00352 -1.1650439 -1.1023149 -1.1336794 0.0627289 2 8.402816 10.653653 0.0049615 0.0434132 Retinal dehydrogenase 1
Q6P1N0 -1.6996040 -1.6333624 -1.6664832 0.0662416 2 6.936107 12.521980 0.0049892 0.0434683 Coiled-coil and C2 domain-containing protein 1A
O75348 -1.8464170 -0.7442245 -1.2953207 1.1021925 2 9.377764 9.811092 0.0050240 0.0434758 V-type proton ATPase subunit G 1
P14555 -4.5949034 -1.7126693 -3.1537863 2.8822341 2 6.867951 12.600143 0.0050329 0.0434758 Phospholipase A2, membrane associated
Q9UKS6 1.4436881 0.5239624 0.9838252 -0.9197256 2 8.943424 10.075794 0.0051177 0.0438921 Protein kinase C and casein kinase substrate in neurons protein 3
Q9BSD7 -0.1234697 2.9508964 1.4137133 3.0743661 2 7.080846 12.162214 0.0051243 0.0438921 Cancer-related nucleoside-triphosphatase
Q9BYN0 -1.2973636 -1.2743737 -1.2858687 0.0229898 2 9.180640 9.864374 0.0051672 0.0440735 Sulfiredoxin-1
P04350 -0.5004642 -2.8380383 -1.6692512 -2.3375741 2 6.967833 12.257034 0.0052259 0.0443875 Tubulin beta-4A chain
Q9BXV9 1.5862723 1.2391702 1.4127212 -0.3471021 2 9.163202 9.797960 0.0052989 0.0448202 Uncharacterized protein C14orf142
Q9UL26 -1.2168882 7.9238349 3.3534734 9.1407231 2 8.784585 10.041159 0.0053777 0.0451937 Ras-related protein Rab-22A
Q96A65 -0.6560056 -1.0764957 -0.8662506 -0.4204901 2 9.382448 9.593458 0.0053876 0.0451937 Exocyst complex component 4
P24311 1.7257653 0.4145062 1.0701358 -1.3112591 2 9.295713 9.617255 0.0054499 0.0454918 Cytochrome c oxidase subunit 7B, mitochondrial
P62745 -1.4954700 -0.9675811 -1.2315256 0.5278889 2 8.788016 9.983785 0.0054680 0.0454918 Rho-related GTP-binding protein RhoB
A5D6W6 -2.3613596 -2.0136134 -2.1874865 0.3477462 2 7.868778 10.815729 0.0055206 0.0457417 Fat storage-inducing transmembrane protein 1
Q8IYI6 -1.0552142 -0.8759545 -0.9655844 0.1792596 2 9.385413 9.452880 0.0056398 0.0465401 Exocyst complex component 8
Q8IYU8 -2.9245934 -3.1789343 -3.0517638 -0.2543409 2 6.385413 12.905411 0.0057115 0.0468485 Calcium uptake protein 2, mitochondrial
Q6IC98 -1.1266523 -0.6748287 -0.9007405 0.4518236 2 8.888308 9.747386 0.0057422 0.0468485 GRAM domain-containing protein 4
Q8N142 0.9014180 1.2636791 1.0825486 0.3622611 2 9.201572 9.519259 0.0057464 0.0468485 Adenylosuccinate synthetase isozyme 1
P50991 -1.7861491 -1.1833510 -1.4847501 0.6027981 2 8.685140 9.847405 0.0058465 0.0474077 T-complex protein 1 subunit delta
Q01581 -0.9331228 -2.3288187 -1.6309708 -1.3956959 2 7.186730 11.425555 0.0058617 0.0474077 Hydroxymethylglutaryl-CoA synthase, cytoplasmic
O00625 -1.3732244 -0.9202215 -1.1467230 0.4530029 2 9.385413 9.307306 0.0059204 0.0476208 Pirin
P25311 -1.4767985 -0.6753214 -1.0760599 0.8014770 2 8.673237 9.807893 0.0059350 0.0476208 Zinc-alpha-2-glycoprotein
O75746 -1.5784821 0.3782752 -0.6001034 1.9567573 2 8.893946 9.603894 0.0059996 0.0479394 Calcium-binding mitochondrial carrier protein Aralar1
P62277 -1.5716452 -1.0577672 -1.3147062 0.5138780 2 9.269754 9.331127 0.0060219 0.0479394 40S ribosomal protein S13
Q96GK7 -1.0910279 -1.4460031 -1.2685155 -0.3549752 2 7.917392 10.382537 0.0061228 0.0485522 Fumarylacetoacetate hydrolase domain-containing protein 2A
Q14019 -3.9736692 -0.8629223 -2.4182957 3.1107469 2 6.385413 12.535016 0.0061522 0.0485950 Coactosin-like protein
P61009 -1.0881392 -0.6944647 -0.8913019 0.3936745 2 8.621704 9.660391 0.0062888 0.0494818 Signal peptidase complex subunit 3
P36551 -1.3385428 0.0293104 -0.6546162 1.3678532 2 9.112223 9.290120 0.0063182 0.0495212 Oxygen-dependent coproporphyrinogen-III oxidase, mitochondrial
Q96CX2 -0.8346353 -0.9677810 -0.9012081 -0.1331456 2 9.290787 9.153981 0.0063604 0.0496603 BTB/POZ domain-containing protein KCTD12
P19447 -1.4553757 -1.7864940 -1.6209348 -0.3311183 2 7.385413 10.812410 0.0063956 0.0496608 TFIIH basal transcription factor complex helicase XPB subunit
Q9NS69 -1.0286368 -1.1141766 -1.0714067 -0.0855398 2 8.946979 9.359253 0.0064094 0.0496608 Mitochondrial import receptor subunit TOM22 homolog

5.3.3 Confirmation stage

library(stageR)
## 
## Attaching package: 'stageR'
## The following object is masked from 'package:methods':
## 
##     getMethod
pAll <- sapply(
  c("omnibusTest",
    "tissueV",
    "tissueV + locationR:tissueV",
    "tissueV + 0.5 * locationR:tissueV",
    "locationR:tissueV"),
    function(name,assay)
      pull(rowData(assay)[,name],"pval"),
  assay = pe[["proteinRobust"]])
rownames(pAll) <- rownames(pe[["proteinRobust"]])

stageWiseAnalysis <- stageR(pAll[,1], pAll[,-1])
stageWiseAnalysis <- stageWiseAdjustment(stageWiseAnalysis, method = "holm", alpha = 0.05, allowNA = TRUE)
## Removing 1263 features with NA screening hypothesis p-values.
rowData(pe[["proteinRobust"]])$stageWiseAnalysis <- data.frame(pAll)
rowData(pe[["proteinRobust"]])$stageWiseAnalysis[] <- NA
rowData(pe[["proteinRobust"]])$stageWiseAnalysis[getPScreen(stageWiseAnalysis) %>% is.na %>% `!`,] <- getAdjustedPValues(stageWiseAnalysis, onlySignificantGenes=FALSE, order=FALSE)
## The returned adjusted p-values are based on a stage-wise testing approach and are only valid for the provided target OFDR level of 5%. If a different target OFDR level is of interest,the entire adjustment should be re-run.
sigNamesStageWise <- apply(rowData(pe[["proteinRobust"]])$stageWiseAnalysis, 2, function(x) (x < 0.05) %>% which %>% names)

sapply(sigNamesStageWise,length)
##                       omnibusTest                           tissueV 
##                               262                               130 
##       tissueV...locationR.tissueV tissueV...0.5...locationR.tissueV 
##                                95                               221 
##                 locationR.tissueV 
##                                13
for (i in 1:length(sigNamesStageWise))
heatmap(assay(pe[["proteinRobust"]])[sigNamesStageWise[[i]], ], main=names(sigNamesStageWise)[i])

5.4 Confirmation improved

Instead of the Holm correction, we can use a better correction for this specific design in the confirmation stage. If we pass the screening stage we know that at least one null hypothesis related to the contrasts is false. If this is not the case we have made an false positive conclusion, but the multiple testing correction in the screening stage already accounts for that.

In the confirmation stage we have to correct for the maximum number of hypotheses that we can falsely reject. The omnibus hypothesis test essentially tests the overall null hypothesis that the log2 protein abundance is on average equal between atrium and ventriculum both in the left and right heart region. This involves testing simultaneously two model parameters: the main effect for ventriculum and the ventriculum:location interaction. All our hypotheses are based on these two model parameters, so the tests are not independent. The following configurations can occur: - None of the model parameters differ from zero, in which we can falsely reject all hypotheses. However, we already corrected for that in the screening stage! - If only the main ventriculum effect differs from zero, we know that the average log2 fold change between atrium and ventriculum left, right and overall differ from zero. So we falsely reject at most one null hypothesis, i.e. the interaction. - If only interaction differs from zero, only the null hypothesis related to log2 fold change in the left heart region can be falsely rejected. - If both the main effect and the interaction differ from zero it is possible that - the interaction is as large in magnitude as the main effect but opposite in sign. This would mean that the log2 fold change in the right heart region is zero, which we can falsely reject. - the interaction effect is twice as large in magnitude as the main effect but opposite in sign. This would mean that the log2 fold change in left and right side are equal in size but opposite in sign, implying that contrast that averages over the average log2 fold changes left and right would be zeor, which we could falsely reject - all effects are true.

Hence, as soon as we enter the confirmation stage that we can at maximum make one false rejection so for this design and for our hypotheses of interest we do not have to correct for multiple testing in the second stage because we only have to account for the fact that we can at most make one false rejection.

So we can set the method="none"

stageWiseAnalysis <- stageWiseAdjustment(stageWiseAnalysis, method = "none", alpha = 0.05, allowNA = TRUE)
## Removing 1263 features with NA screening hypothesis p-values.
rowData(pe[["proteinRobust"]])$stageWiseAnalysis <- data.frame(pAll)
rowData(pe[["proteinRobust"]])$stageWiseAnalysis[] <- NA
rowData(pe[["proteinRobust"]])$stageWiseAnalysis[getPScreen(stageWiseAnalysis) %>% is.na %>% `!`,] <- getAdjustedPValues(stageWiseAnalysis, onlySignificantGenes=FALSE, order=FALSE)
## The returned adjusted p-values are based on a stage-wise testing approach and are only valid for the provided target OFDR level of 5%. If a different target OFDR level is of interest,the entire adjustment should be re-run.
sigNamesStageWise <- apply(rowData(pe[["proteinRobust"]])$stageWiseAnalysis, 2, function(x) (x < 0.05) %>% which %>% names)

sapply(sigNamesStageWise,length)
##                       omnibusTest                           tissueV 
##                               262                               183 
##       tissueV...locationR.tissueV tissueV...0.5...locationR.tissueV 
##                               145                               248 
##                 locationR.tissueV 
##                                18
for (i in 1:length(sigNamesStageWise))
heatmap(assay(pe[["proteinRobust"]])[sigNamesStageWise[[i]], ], main=names(sigNamesStageWise)[i])

Note, that - our more relaxed FDR correction enables us to reject more null hypotheses in the second stage. - we can recover 18 proteins with significant interactions.

It is also very important to realise that setting the method to correct for multiple testing in the second stage at method = none is only correct for very specific designs and research hypotheses that are assessed. For most analyses we suggest to use the Holm method, which always we provide correct results.

---
title: "Proteomics data analysis: heart"
author: "Lieven Clement"
date: "statOmics, Ghent University (https://statomics.github.io)"
output:
    html_document:
      code_download: true
      theme: cosmo
      toc: true
      toc_float: true
      highlight: tango
      number_sections: true
---
# Background
Researchers have assessed the proteome in different regions of the heart for 3 patients (identifiers 3, 4, and 8). For each patient they sampled the left atrium (LA), right atrium (RA), left ventricle (LV) and the right ventricle (RV). The data are a small subset of the public dataset PXD006675 on PRIDE.

Suppose that researchers are mainly interested in comparing the ventricular to the atrial proteome. Particularly, they would like to compare the left atrium to the left ventricle, the right atrium to the right ventricle, the average ventricular vs atrial proteome and if ventricular vs atrial proteome shifts differ between left and right heart region.


# Data

We first import the peptides.txt file. This is the file that contains your peptide-level intensities. For a MaxQuant search [6], this peptides.txt file can be found by default in the "path_to_raw_files/combined/txt/" folder from the MaxQuant output, with "path_to_raw_files" the folder where raw files were saved. In this tutorial, we will use a MaxQuant peptides file from MaxQuant that can be found in the data tree of the SGA2020 github repository https://github.com/statOmics/SGA2020/tree/data/quantification/heart .

To import the data we use the `QFeatures` package.

We generate the object peptideRawFile with the path to the peptideRaws.txt file.
Using the `grepEcols` function, we find the columns that contain the expression
data of the peptideRaws in the peptideRaws.txt file.

```{r, warning=FALSE, message=FALSE}
library(tidyverse)
library(limma)
library(QFeatures)
library(msqrob2)
library(plotly)

peptidesFile <- "https://raw.githubusercontent.com/statOmics/SGA2020/data/quantification/heart/peptides.txt"

ecols <- MSnbase::grepEcols(
  peptidesFile,
  "Intensity ",
  split = "\t")

pe <- readQFeatures(
  table = peptidesFile,
  fnames = 1,
  ecol = ecols,
  name = "peptideRaw", sep="\t")

pe
pe[["peptideRaw"]]
```

We will make use from data wrangling functionalities from the tidyverse package.
The %>% operator allows us to pipe the output of one function to the next function.

```{r}
colData(pe)$location <- substr(
  colnames(pe[["peptideRaw"]]),
  11,
  11) %>%
  unlist %>%
  as.factor

colData(pe)$tissue <- substr(
    colnames(pe[["peptideRaw"]]),
    12,
    12) %>%
    unlist %>%
    as.factor

colData(pe)$patient <- substr(
  colnames(pe[["peptideRaw"]]),
  13,
  13) %>%
  unlist %>%
  as.factor
```


We calculate how many non zero intensities we have per peptide and this
will be useful for filtering.

```{r}
rowData(pe[["peptideRaw"]])$nNonZero <- rowSums(assay(pe[["peptideRaw"]]) > 0)
```


Peptides with zero intensities are missing peptides and should be represent
with a `NA` value rather than `0`.
```{r}
pe <- zeroIsNA(pe, "peptideRaw") # convert 0 to NA
```


## Data exploration

We can inspect the missingness in our data with the `plotNA()` function
provided with `MSnbase`.
`r format(mean(is.na(assay(pe[["peptideRaw"]])))*100,digits=2)`% of all peptide
intensities are missing and for some peptides we do not even measure a signal
in any sample. The missingness is similar across samples.


```{r}
MSnbase::plotNA(assay(pe[["peptideRaw"]])) +
  xlab("Peptide index (ordered by data completeness)")
```

# Preprocessing

This section preforms standard preprocessing for the peptide data. This
include log transformation, filtering and summarisation of the data.

## Log transform the data

```{r}
pe <- logTransform(pe, base = 2, i = "peptideRaw", name = "peptideLog")
limma::plotDensities(assay(pe[["peptideLog"]]))
```


## Filtering

### Handling overlapping protein groups
In our approach a peptide can map to multiple proteins, as long as there is
none of these proteins present in a smaller subgroup.

```{r}
pe <- filterFeatures(pe,
  ~ Proteins %in% smallestUniqueGroups(rowData(pe[["peptideLog"]])$Proteins)
)
```

### Remove reverse sequences (decoys) and contaminants

We now remove the contaminants, peptides that map to decoy sequences, and proteins
which were only identified by peptides with modifications.

First look to the names of the variables for the peptide features
```{r}
pe[["peptideLog"]] %>%
  rowData %>%
  names
```

No information on decoys.

```{r}
pe <- filterFeatures(pe, ~ Potential.contaminant != "+")
```

### Remove peptides of proteins that were only identified with modified peptides

I will skip this step for the moment. Large protein groups file needed for this.

### Drop peptides that were only identified in one sample

We keep peptides that were observed at last twice.

```{r}
pe <- filterFeatures(pe, ~ nNonZero >= 2)
nrow(pe[["peptideLog"]])
```

We keep `r nrow(pe[["peptideLog"]])` peptides after filtering.

## Quantile normalize the data
```{r}
pe <- normalize(pe, i = "peptideLog", method = "quantiles", name = "peptideNorm")
```


## Explore quantile normalized data

After quantile normalisation the density curves for all samples coincide.

```{r}
limma::plotDensities(assay(pe[["peptideNorm"]]))
```

This is more clearly seen is a boxplot.

```{r,}
boxplot(assay(pe[["peptideNorm"]]), col = palette()[-1],
       main = "Peptide distribtutions after normalisation", ylab = "intensity")
```


We can visualize our data using a Multi Dimensional Scaling plot,
eg. as provided by the `limma` package.

```{r}
limma::plotMDS(assay(pe[["peptideNorm"]]),
  col = colData(pe)$location:colData(pe)$tissue %>%
    as.numeric,
  labels = colData(pe) %>%
    rownames %>%
    substr(start = 11, stop = 13)
  )
```

The first axis in the plot is showing the leading log fold changes
(differences on the log scale) between the samples.


## Summarization to protein level

We use robust summarization in aggregateFeatures. This is the default workflow of aggregateFeatures so you do not have to specifiy the argument `fun`.
However, because we compare methods we have included the `fun` argument to show the summarization method explicitely.

```{r,warning=FALSE}
pe <- aggregateFeatures(pe,
 i = "peptideNorm",
 fcol = "Proteins",
 na.rm = TRUE,
 name = "proteinRobust",
 fun = MsCoreUtils::robustSummary)
```

```{r}
plotMDS(assay(pe[["proteinRobust"]]),
  col = colData(pe)$location:colData(pe)$tissue %>%
    as.numeric,
  labels = colData(pe) %>%
    rownames %>%
    substr(start = 11, stop = 13)
)
```

# Data Analysis

## Estimation

We model the protein level expression values using `msqrob`.
By default `msqrob2` estimates the model parameters using robust regression.

```{r, warning=FALSE}
pe <- msqrob(
  object = pe,
  i = "proteinRobust",
  formula = ~ location*tissue + patient)
```

## Inference

First, we extract the parameter names of the model.
```{r}
getCoef(rowData(pe[["proteinRobust"]])$msqrobModels[[2]])
```

```{r}
L <- makeContrast(
  c(
    "tissueV = 0",
    "tissueV + locationR:tissueV = 0",
    "tissueV + 0.5*locationR:tissueV = 0","locationR:tissueV = 0"),
  parameterNames =
    rowData(pe[["proteinRobust"]])$msqrobModels[[2]] %>%
    getCoef %>%
    names
  )


pe <- hypothesisTest(object = pe, i = "proteinRobust", contrast = L, overwrite=TRUE)
```

## Evaluate results contrast $\log_2 FC_{V-A}^L$

### Volcano-plot


```{r,warning=FALSE}
volcanoLeft <- ggplot(rowData(pe[["proteinRobust"]])$"tissueV + locationR:tissueV",
                 aes(x = logFC, y = -log10(pval), color = adjPval < 0.05)) +
 geom_point(cex = 2.5) +
 scale_color_manual(values = alpha(c("black", "red"), 0.5)) + theme_minimal()
volcanoLeft
```


### Heatmap

We first select the names of the proteins that were declared signficant.

```{r}
sigNamesLeft <- rowData(pe[["proteinRobust"]])$tissueV %>%
 rownames_to_column("proteinRobust") %>%
 filter(adjPval<0.05) %>%
 pull(proteinRobust)
heatmap(assay(pe[["proteinRobust"]])[sigNamesLeft, ])
```

There are `r length(sigNamesLeft)` proteins significantly differentially expressed at the 5% FDR level.

```{r}
rowData(pe[["proteinRobust"]])$tissueV %>%
  cbind(.,rowData(pe[["proteinRobust"]])$Protein.names) %>%
  na.exclude %>%
  filter(adjPval<0.05) %>%
  arrange(pval)  %>%
  knitr::kable(.)
```

## Evaluate results contrast $\log_2 FC_{V-A}^R$

### Volcano-plot


```{r,warning=FALSE}
volcanoRight <- ggplot(rowData(pe[["proteinRobust"]])$"tissueV + locationR:tissueV",
                 aes(x = logFC, y = -log10(pval), color = adjPval < 0.05)) +
 geom_point(cex = 2.5) +
 scale_color_manual(values = alpha(c("black", "red"), 0.5)) + theme_minimal()
volcanoRight
```


### Heatmap

We first select the names of the proteins that were declared signficant.

```{r}
sigNamesRight <- rowData(pe[["proteinRobust"]])$"tissueV + locationR:tissueV" %>%
 rownames_to_column("proteinRobust") %>%
 filter(adjPval<0.05) %>%
 pull(proteinRobust)
heatmap(assay(pe[["proteinRobust"]])[sigNamesRight, ])
```

There are `r length(sigNamesRight)` proteins significantly differentially expressed at the 5% FDR level.

```{r}
rowData(pe[["proteinRobust"]])$"tissueV + locationR:tissueV"  %>%
  cbind(.,rowData(pe[["proteinRobust"]])$Protein.names) %>%
  na.exclude %>%
  filter(adjPval<0.05) %>%
  arrange(pval) %>%
  knitr::kable(.)
```


## Evaluate results average contrast $\log_2 FC_{V-A}$

### Volcano-plot


```{r,warning=FALSE}
volcanoAvg <- ggplot(rowData(pe[["proteinRobust"]])$"tissueV + 0.5 * locationR:tissueV",
                 aes(x = logFC, y = -log10(pval), color = adjPval < 0.05)) +
 geom_point(cex = 2.5) +
 scale_color_manual(values = alpha(c("black", "red"), 0.5)) + theme_minimal()
volcanoAvg
```


### Heatmap

We first select the names of the proteins that were declared signficant.

```{r}
sigNamesAvg <- rowData(pe[["proteinRobust"]])$"tissueV + 0.5 * locationR:tissueV" %>%
 rownames_to_column("proteinRobust") %>%
 filter(adjPval<0.05) %>%
 pull(proteinRobust)
heatmap(assay(pe[["proteinRobust"]])[sigNamesAvg, ])
```

There are `r length(sigNamesAvg)` proteins significantly differentially expressed at the 5% FDR level.

```{r}
rowData(pe[["proteinRobust"]])$"tissueV + 0.5 * locationR:tissueV" %>%
  cbind(.,rowData(pe[["proteinRobust"]])$Protein.names) %>%
  na.exclude %>%
  filter(adjPval<0.05) %>%
  arrange(pval) %>%
  knitr::kable(.)
```



## Interaction

### Volcano-plot


```{r,warning=FALSE}
volcanoInt <- ggplot(rowData(pe[["proteinRobust"]])$"locationR:tissueV",
                 aes(x = logFC, y = -log10(pval), color = adjPval < 0.05)) +
 geom_point(cex = 2.5) +
 scale_color_manual(values = alpha(c("black", "red"), 0.5)) + theme_minimal()
volcanoInt
```

### Heatmap

There were no genes significant at the 5% FDR level.
We return the top 25 genes.

```{r}
sigNamesInt <- rowData(pe[["proteinRobust"]])$"locationR:tissueV" %>%
 rownames_to_column("proteinRobust") %>%
 filter(adjPval<0.05) %>%
 pull(proteinRobust)
hlp <- order((rowData(pe[["proteinRobust"]])$"locationR:tissueV")[,"adjPval"])[1:25]
heatmap(assay(pe[["proteinRobust"]])[hlp, ])
```

There are `r length(sigNamesInt)` proteins significantly differentially expressed at the 5% FDR level.

```{r}
rowData(pe[["proteinRobust"]])$"locationR:tissueV" %>%
  cbind(.,rowData(pe[["proteinRobust"]])$Protein.names) %>%
  na.exclude %>%
  filter(adjPval<0.05) %>%
  arrange(pval)
```

#  Large difference in number of proteins that are returned

Note, that much more proteins are returned significant for average contrast ($\log_2 FC_{V-A}$) as compared to contrast for assessing the fold change between ventriculum and atrium left and right. The power for the average contrast is larger than for the contrast left or right because the log2 FC can be estimated with higher precision.

For none of the proteins the interaction was significant (change in log2 FC between ventriculum and atrium in the right vs the left heart region). The power for the interaction is typically low.

## Reason

Part of variance covariance matrix of model parameters due to design:

```{r}
X <- model.matrix(~ location*tissue + patient, colData(pe))
covarUnscaled <- solve(t(X) %*% X)
```

Variance of contrasts (diagonal elements) due to design
```{r}
varContrasts <- t(L)%*%covarUnscaled%*%L %>%
  diag
varContrasts
sqrt(varContrasts)
```

So it is clear that the standard error of the log2 FC left and right is the same.
That of the average contrast is a factor $\sqrt{2}$ smaller!
Indeed, we use double the number of samples to estimate it!

```{r}
varContrasts[3]/varContrasts[2]
sqrt(varContrasts)[3]/sqrt(varContrasts)[2]
1/sqrt(2)
```

The standard error of the interaction is a factor $\sqrt{2}$ larger than that of the main effects!
```{r}
varContrasts[4]/varContrasts[2]
sqrt(varContrasts)[4]/sqrt(varContrasts)[2]
sqrt(2)
```

## Msqrob

This is not the case for the standard errors of protein 2???

```{r}
rowData(pe[["proteinRobust"]])$"tissueV"[2,]
rowData(pe[["proteinRobust"]])$"tissueV + locationR:tissueV"[2,]
rowData(pe[["proteinRobust"]])$"tissueV + 0.5 * locationR:tissueV"[2,]
rowData(pe[["proteinRobust"]])$"locationR:tissueV"[2,]
```

Because msqrob is using robust regression to assess DE!

```{r}
pe %>%
  colData %>%
  as_tibble %>%
  mutate(w=getModel(rowData(pe[["proteinRobust"]])$msqrobModels[[2]])$w)
```

For protein 2 the samples at the left and right side have different weights!


### Part of standard error due to design:

```{r}
covUnscaledRobust <- solve(
  t(X) %*%
  diag(
    getModel(rowData(pe[["proteinRobust"]])$msqrobModels[[2]])$w) %*% X)

varContrastsRobust <- t(L)%*%covUnscaledRobust%*%L %>%
  diag
varContrastsRobust
sqrt(varContrastsRobust)
```

### Standard errors Contrasts

```{r}
sqrt(varContrastsRobust) * getSigmaPosterior(rowData(pe[["proteinRobust"]])$msqrobModels[[2]])
```

```{r}
rowData(pe[["proteinRobust"]])$"tissueV"[2,]
rowData(pe[["proteinRobust"]])$"tissueV + locationR:tissueV"[2,]
rowData(pe[["proteinRobust"]])$"tissueV + 0.5 * locationR:tissueV"[2,]
rowData(pe[["proteinRobust"]])$"locationR:tissueV"[2,]
```


## Stagewise testing

### Omnibus test

```{r}
source("https://raw.githubusercontent.com/statOmics/SGA2020/gh-pages/assets/topFeaturesOmnibus.R")
pe <- omnibusTest(pe, "proteinRobust", L)
```

### Heatmap significant proteins Omnibus test

We first select the names of the proteins that were declared signficant.

```{r}
sigNamesOmnibus <- rowData(pe[["proteinRobust"]])$omnibusTest %>%
 rownames_to_column("proteinRobust") %>%
 filter(adjPval<0.05) %>%
 pull(proteinRobust)
heatmap(assay(pe[["proteinRobust"]])[sigNamesOmnibus, ])
```

There are `r length(sigNamesOmnibus)` proteins significantly differentially expressed at the 5% FDR level.

```{r}
rowData(pe[["proteinRobust"]])$omnibusTest  %>%
  cbind(.,rowData(pe[["proteinRobust"]])$Protein.names) %>%
  na.exclude %>%
  filter(adjPval<0.05) %>%
  arrange(pval) %>%
  knitr::kable(.)
```

### Confirmation stage


```{r}
library(stageR)
pAll <- sapply(
  c("omnibusTest",
    "tissueV",
    "tissueV + locationR:tissueV",
    "tissueV + 0.5 * locationR:tissueV",
    "locationR:tissueV"),
    function(name,assay)
      pull(rowData(assay)[,name],"pval"),
  assay = pe[["proteinRobust"]])
rownames(pAll) <- rownames(pe[["proteinRobust"]])

stageWiseAnalysis <- stageR(pAll[,1], pAll[,-1])
stageWiseAnalysis <- stageWiseAdjustment(stageWiseAnalysis, method = "holm", alpha = 0.05, allowNA = TRUE)

rowData(pe[["proteinRobust"]])$stageWiseAnalysis <- data.frame(pAll)
rowData(pe[["proteinRobust"]])$stageWiseAnalysis[] <- NA
rowData(pe[["proteinRobust"]])$stageWiseAnalysis[getPScreen(stageWiseAnalysis) %>% is.na %>% `!`,] <- getAdjustedPValues(stageWiseAnalysis, onlySignificantGenes=FALSE, order=FALSE)
```

```{r}
sigNamesStageWise <- apply(rowData(pe[["proteinRobust"]])$stageWiseAnalysis, 2, function(x) (x < 0.05) %>% which %>% names)

sapply(sigNamesStageWise,length)

for (i in 1:length(sigNamesStageWise))
heatmap(assay(pe[["proteinRobust"]])[sigNamesStageWise[[i]], ], main=names(sigNamesStageWise)[i])
```

## Confirmation improved

Instead of the Holm correction, we can use a better correction for this specific design in the confirmation stage.
If we pass the screening stage we know that at least one null hypothesis related to the contrasts is false.
If this is not the case we have made an false positive conclusion, but the multiple testing correction in the screening stage already accounts for that.

In the confirmation stage we have to correct for the maximum number of hypotheses that we can falsely reject.
The omnibus hypothesis test essentially tests the overall null hypothesis that the log2 protein abundance is on average equal between atrium and ventriculum both in the left and right heart region.
This involves testing simultaneously two model parameters: the main effect for ventriculum and the ventriculum:location interaction.
All our hypotheses are based on these two model parameters, so the tests are not independent.
The following configurations can occur:
- None of the model parameters differ from zero, in which we can falsely reject all hypotheses. However, we already corrected for that in the screening stage!
- If only the main ventriculum effect differs from zero, we know that the average log2 fold change between  atrium and ventriculum left, right and overall differ from zero. So we falsely reject at most one null hypothesis, i.e. the interaction.
- If only interaction differs from zero, only the null hypothesis related to log2 fold change in the left heart region can be falsely rejected.
- If both the main effect and the interaction differ from zero it is possible that
    - the interaction is as large in magnitude as the main effect but opposite in sign. This would mean that the log2 fold change in the right heart region is zero, which we can falsely reject.
    - the interaction effect is twice as large in magnitude as the main effect but opposite in sign. This would mean that the log2 fold change in left and right side are equal in size but opposite in sign, implying that contrast that averages over the average log2 fold changes left and right would be zeor, which we could falsely reject
    - all effects are true.

Hence, as soon as we enter the confirmation stage that we can at maximum make one false rejection so for this design and for our hypotheses of interest we do not have to correct for multiple testing in the second stage because we only have to account for the fact that we can at most make one false rejection.

So we can set the ```method="none"```
```{r}
stageWiseAnalysis <- stageWiseAdjustment(stageWiseAnalysis, method = "none", alpha = 0.05, allowNA = TRUE)

rowData(pe[["proteinRobust"]])$stageWiseAnalysis <- data.frame(pAll)
rowData(pe[["proteinRobust"]])$stageWiseAnalysis[] <- NA
rowData(pe[["proteinRobust"]])$stageWiseAnalysis[getPScreen(stageWiseAnalysis) %>% is.na %>% `!`,] <- getAdjustedPValues(stageWiseAnalysis, onlySignificantGenes=FALSE, order=FALSE)
```

```{r}
sigNamesStageWise <- apply(rowData(pe[["proteinRobust"]])$stageWiseAnalysis, 2, function(x) (x < 0.05) %>% which %>% names)

sapply(sigNamesStageWise,length)

for (i in 1:length(sigNamesStageWise))
heatmap(assay(pe[["proteinRobust"]])[sigNamesStageWise[[i]], ], main=names(sigNamesStageWise)[i])
```

Note, that
- our more relaxed FDR correction enables us to reject more null hypotheses in the second stage.
- we can recover `r length(sigNamesStageWise[[5]])` proteins with significant interactions.

It is also very important to realise that setting the method to correct for multiple testing in the second stage at `method = none` is only correct for very specific designs and research hypotheses that are assessed. For most analyses we suggest to use the Holm method, which always we provide correct results.
