Toward the blood-borne mirnome of human diseases

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1 Nature Methods Toward the blood-borne mirnome of human diseases Andreas Keller, Petra Leidinger, Andrea Bauer, Abdou ElSharawy, Jan Haas, Christina Backes, Anke Wendschlag, Nathalia Giese, Christine Tjaden, Katja Ott, Jens Werner, Thilo Hackert, Klemens Ruprecht, Hanno Huwer, Junko Huebers, Gunnar Jacobs, Philip Rosenstiel, Henrik Dommisch, Arne Schaefer, Joachim Müller-Quernheim, Bernd Wullich, Bastian Keck, Norbert Graf, Joerg Reichrath, Britta Vogel, Almut Nebel, Sven U Jager, Peer Staehler, Ioannis Amarantos, Valesca Boisguerin, Cord Staehler, Markus Beier, Matthias Scheffler, Markus W Büchler, Joerg Wischhusen, Sebastian F M Haeusler, Johannes Dietl, Sylvia Hofmann, Hans- Peter Lenhof, Stefan Schreiber, Hugo A Katus, Wolfgang Rottbauer, Benjamin Meder, Joerg D Hoheisel, Andre Franke & Eckart Meese Supplementary Figure 1 Supplementary Figure 2 Supplementary Figure 3 Supplementary Figure 4 Supplementary Figure 5 Supplementary Figure 6 Supplementary Table 1 Supplementary Table 2 Supplementary Table 3 Supplementary Table 4 Supplementary Table 5 Supplementary Table 6 Supplementary Table 7 Supplementary Table 8 Analysis of different control cohorts by Principal Component Analysis (PCA). Technical reproducibility of microarray data. Biological reproducibility of microarray data. Fold quotients for 45 deregulated mirnas analyzed both by qrt-pcr and microarrays. Accuracies of mirna based classifications shown as Box- Whisker plots. Examples for the classification performance and representative Disease Probability Plots (DPP). Analyzed diseases and controls. MiRNAs that were deregulated in at least six diseases. Deregulated mirna in specific diseases. Pathway analysis of the 62 mirnas that were deregulated in at least six diseases and the 121 mirnas that were not deregulated. Deregulated mirnas, which are in physical proximity to SNPs that were previously associated with diseases analyzed in this study. Separation between diseases and controls based on different subsets of mirnas. MiRNA expression analysis by qrt-pcr using SmartChip Real-Time PCR System (Wafergen). Summary of mirna validation.

2 Nature Methods reference number: NMETH-BC12369B Supplementary Information Supplementary Figure 1 Analysis of different control cohorts by Principal Component Analysis (PCA). PCA that allows for estimating the variance of data sets, was applied to the mirna pattern of the five different healthy control groups. The figure shows the plot of the first versus the second principal component of all control samples and was created using the prcomp and chplot R packages. The convex hulls and confidence ellipses of the five normal control groups, each represented by a different color, show similar profiles with the exception of one group (group 5) that includes only individuals between 95 and 105 years of age. 0

Supplementary Figure 2 Technical reproducibility of microarray data. Color-coded correlation matrix demonstrating technical reproducibility of mirna profiles obtained by the microarray platform.

3 Supplementary Figure 2 Technical reproducibility of microarray data. Color-coded correlation matrix demonstrating technical reproducibility of mirna profiles obtained by the microarray platform. Measurements were repeated for four samples including RNA from human heart and human brain tissues (numbered one and two), and from two normal blood samples (numbered three and four). Yellow color indicates a high correlation and blue color a low correlation. This figure clearly shows that the differences between heart and brain tissue are by far larger than the differences between different control blood samples. 1

Supplementary Figure 3 Biological reproducibility of microarray data. Color-coded correlation matrix demonstrating biological reproducibility of mirna profiles obtained by the microarray platform.

4 Supplementary Figure 3 Biological reproducibility of microarray data. Color-coded correlation matrix demonstrating biological reproducibility of mirna profiles obtained by the microarray platform. Measurements were repeated twice for blood samples from one healthy individual taken at three different time points during a day. Blood was drawn at 9 A.M. (time point 1), 12 noon (time point 2), and 3 P.M. (time point 3). Yellow color indicates a high correlation and blue color a low correlation. We found that mirna profiles across one day are very stable. Notably, the correlation among the three time points was not lower than the correlation among the technical replicates. 2

5 Supplementary Figure 4: Fold quotients for 45 deregulated mirnas analyzed both by qrt-pcr (y-axis) and microarrays (x-axis). The correlation between both technologies was The bisecting line is indicated. Only four pairs have not been successfully validated. 3

6 Supplementary Figure 5: Accuracies of mirna based classifications shown as Box-Whisker plots. The blot shows the accuracies that were obtained for the classification of all diseases by using a subset of only 2 mirnas, 10 mirnas and by using the number of mirnas required to obtain the best possible classification. As indicated a median accuracy of 80% is already reached by using 10 markers only. 4

7 Supplementary Figures 5 A-C: 5

8 Examples for the classification performance and representative Disease Probability Plots (DPP). The classification performance is displayed for melanoma versus healthy controls (A), for multiple sclerosis versus healthy controls (B), and for lung cancer versus COPD (C). In the left column, the x-axis indicates the sample number and the y-axis indicates the logarithmized probabilities for each sample to fall either in the disease class or in the control class; the horizontal dashed line denotes the classification threshold. Vertical dashed lines separate controls from patients samples. For melanoma (A) and multiple sclerosis (B) we used control samples of health donors collected by five different institutions and for lung cancer (C) we used samples of COPD patients. Circles indicate false positive and false negative predictions, respectively. The right column shows the DPPS for three representative patients with melanoma, multiple sclerosis, or lung cancer. The chance of each patient having one of the diseases analyzed is given in percent and indicated by an arrowhead. 6

9 Supplementary Table 1: Analyzed diseases and controls. Cancers are indicated in blue and non-malignant (mainly chronic inflammatory) diseases in red. Annotations in brackets refer to OMIM ID and ICD-10. micrornas were classified as significantly deregulated for Benjamini Hochberg adjusted t-test P < Group Number of samples Institution providing RNA Controls 70 All institutions Lung cancer (211980; C33,C34) 32 Saarland University Prostate cancer (176807; C61) 23 Saarland University Melanoma (155600; C43) 35 Saarland University Wilms tumors (194070; C64) 5 Saarland University Ovarian cancer (167000; C56, D27) 15 Julius-Maximilians-University Wuerzburg gastric cancers (137215; C16) 13 DKFZ / Heidelberg University Pancreatic ductal adenocarcinoma (260350; C25.3) 45 DKFZ / Heidelberg University Other pancr. tumors and diseases 48 DKFZ / Heidelberg University Pancreatitis (167800, ; K85, K86) 38 DKFZ / Heidelberg University Chronic Obstructive Pulmonary Disease (606963; J40-J44, J47) 24 Saarland University Periodontitis (170650, ; K05.4) 18 Christian-Albrechts-University Kiel Sarcoidosis (181000, ; D86) 45 Christian-Albrechts-University Kiel Acute myocardial infarction (608320; I21-I22) 20 Heidelberg University Multiple sclerosis (126200; G35) 23 Saarland University SUM 454 7

10 Supplementary Table 2: MiRNAs that were deregulated in at least six diseases. The mirnas were grouped according to the numbers of diseases for which a deregulated mirna was found. Magenta labeled mirnas are the 24 mirnas that were significantly deregulated in > 50 % of all diseases. For those 24 mirnas additional information is given. Numbers in brackets indicate the numbers of up- and down-regulations, respectively. mirnas Number of diseases % of all diseases % of all mirnas Function hsa-mir-320d (1, 10) deregulated in colon cancer stem cells hsa-mir-423-5p (3,6) differentially expressed in lupus nephritis across different racial groups and all specimen types tested (EBVtransformed B-cell lines and PBMCs) hsa-mir-146b-3p (2, 7) identified in mirna classifiers that may predict recurrence of localized stage I non-small cell lung cancer / upregulated in K-ras-mutated colorectal cancer samples / hsa-mir-532-3p (1, 8) - hsa-mir-107 (3,5) mirna-107 transcription is directly activated by p53. mirna-107 regulates two important regulators of G(1)/S progression, CDK6 and the RB-related 2 gene RBL2 (p130) / mir-107 expression tends to be lower relative to other mirnas as Alzheimer disease progresses / hsa-mir-320c (1,7) - hsa-mir-324-3p (1,7) - hsa-mir-148a (0,8) down-regulated in osteo-differentiated multipotent mesenchymal stromal cells hsa-mir-320a (2,6) MicroRNA 320a functions as a novel endogenous modulator of aquaporins 1 and 4 as well as a potential therapeutic target in cerebral ischemia. / down-regulated after osteogenic differentiation of human ligament fibroblasts induced by conditioned medium of osteoclastlike cells / hsa-mir-1256 (1,7) - hsa-mir-556-5p (0,7) down-regulated in primary squamous cell lung carcinoma specimens compared to matched normal lung tissue / deregulated in HCT-116 (wt-p53) and HCT-116 (null-p53) colon cancer cell lines, here decreasing p53 expression via sirna treatment significantly decreased hsa-mir-26a hsa-mir-26a (6,1) expression / hsa-mir-197 (1,6) significantly associated with pericellular fibrosis in nonalcoholic steatohepatitis patients hsa-mir-500* (1,6) - hsa-mir-1295 (1,6) - PMID hsa-mir-646 (1,6) hsa-mir-646/ak is a candidate predisposing copy number variants in familial and early-onset colorectal cancer patients hsa-mir-339-5p (1,6) MiR-339-5p inhibits breast cancer cell migration and invasion in vitro and may be a potential biomarker for breast cancer prognosis hsa-mir-550* (1,6) - hsa-let-7d (5,2) Low-level expression of micrornas let-7d and mir-205 are prognostic markers of head and neck squamous cell carcinoma hsa-mir-595 (4,3) hsa-mir-1301 (1,6) deregulated in malignant mesothelioma /up-regulated inwi-38 human fibroblasts from replicating to reversible and irreversible growth arrest states /

11 hsa-mir-26b (5,2) down-regulated in primary squamous cell lung carcinoma specimens compared to matched normal lung tissue hsa-mir-1305 (0,7) - hsa-mir-1913 (0,7) - hsa-mir-27a (4,2) hsa-mir-145 (6,0) hsa-mir-541 (0,6) hsa-mir-500 (4,2) hsa-mir-146b-5p (4,2) hsa-mir-378 (3,3) hsa-mir-1226* (1,5) hsa-mir-455-3p (1,5) hsa-mir-182 (4,2) hsa-mir-1826 (0,6) hsa-mir-604 (1,5) hsa-mir-217 (0,6) hsa-mir-1258 (6,0) hsa-mir-196a* (0,6) hsa-mir-144 (3,3) hsa-mir-593* (1,5) hsa-mir-363* (2,4) hsa-mir-103 (1,5) hsa-let-7g (5,1) hsa-mir-30e* (6,0) hsa-mir-513b (0,6) hsa-mir-214 (0,6) hsa-mir-584 (4,2) hsa-mir-454* (5,1) hsa-mir-566 (0,6) hsa-mir-24-2* (0,6) hsa-mir-342-3p (1,5) hsa-mir-125a-5p (6,0) hsa-mir-126* (6,0) hsa-mir-1266 (1,5) hsa-mir-720 (1,5) hsa-mir-564 (1,5) hsa-mir-192* (0,6) hsa-mir-16 (5,1) hsa-mir-367 (1,5) hsa-mir-574-5p (3,3) hsa-mir-1272 (0,6) hsa-mir-21* (0,6)

12 Supplementary Table 3: Deregulated mirna in specific diseases. The first column shows the total number of diseases for which a deregulated mirna was found. The second column shows the number of diseases for which a deregulated mirna was found. Significant deregulation of mirna is indicated by (1); the lack of deregulation is indicated by (0). mirnas that were listed as deregulated in tissue in the human mirna disease database (HMDD) are indicated in bold. lung cancer pancreatic cancer ducatal ovarian cancer prostate cancer wilms tumor other pancreatic tumors and diseases gastric cancers multiple sclerosis sarcoidosis peridontitis COPD acute myocardial infarction mirna sum melanoma pancreatitis hsa-mir- 320d hsa-mir p hsa-mir- 146b-3p hsa-mir p hsa-mir hsa-mir- 320c hsa-mir p hsa-mir- 148a hsa-mir- 320a hsa-mir hsa-mir p hsa-mir-26a hsa-mir hsa-mir- 500* hsa-mir hsa-mir hsa-mir p hsa-mir- 550* hsa-let-7d hsa-mir hsa-mir hsa-mir-26b hsa-mir hsa-mir missmatch blood and tissue 6 match blood and tissue 9 10

13 Supplementary Table 4: Pathway analysis of the 62 mirnas that were deregulated in at least six diseases and the 121 mirnas that were not deregulated. For each pathway, the number of expected and detected target genes and the respective p-value is provided. Pathways that include significantly more mirna targets than statistically expected are indicated in magenta and pathways that include significantly less mirna targets than statistically expected are indicated in turquoise. The latter pathways may be enriched for "non-targets" of the analyzed mirnas. Pathway analysis of the 62 mirnas that were deregulated in at least six diseases p-value Subcategory expected observed (fdr) enrichment Metabolic pathways for targets Pathways in cancer for targets Pyrimidine metabolism for targets Arginine and proline metabolism for targets Lysosome for targets Cell cycle for targets Sphingolipid metabolism for targets Fc epsilon RI signaling pathway for targets Purine metabolism for targets Olfactory transduction <0.001 for non targets Ribosome 18 2 <0.001 for non targets Systemic lupus erythematosus for non targets Cell adhesion molecules (CAMs) for non targets Taste transduction for non targets Pathway analysis of the 121 mirnas that were not deregulated in any disease p-value Subcategory expected observed (fdr) enrichment Olfactory transduction <0.001 for non targets Systemic lupus erythematosus for non targets Metabolism of xenobiotics by cytochrome P for non targets 11

14 Supplementary Table 5: Deregulated mirnas, which are in physical proximity to SNPs that were previously associated with diseases analyzed in this study. The distance between mirnas and SNPs is given in base pairs. Column four lists the associated disease for each deregulated mirna and column five the disease that was previously associated with one of the listed SNPs by genome wide association studies (gwas) mirna SNP distance (bp) mirna diseases gwas disease hsa-mir- Cardiac structure and 346 rs acute myocardial infarction function hsa-mir rs acute myocardial infarction Mean platelet volume hsa-mir- 214 rs melanoma AND tumor of stomach AND multiple sclerosis AND sarcoidosis AND COPD AND acute myocardial infarction Mean platelet volume hsa-mir- 148b rs prostate cancer AND sarcoidosis AND acute myocardial infarction Mean platelet volume hsa-mir- 644 rs melanomaand multiple sclerosis AND periodontitis Melanoma hsa-mir- 616 rs multiple sclerosis AND periodontitis Multiple sclerosis hsa-mir rs prostate cancer Multiple sclerosis 12

15 Supplementary Table 6: Separation between diseases and controls based on different subsets of mirnas. Classification results are given for subsets of mirnas that achieved the best results, for subsets of 2 mirnas and subsets of 10 mirnas. For the first classification values greater than are indicated in bold. Positive and Negative Predictive values are provided for a disease prevalence of 1 %. disease # of mirnas Accuracy Specificity Sensitivity PPV NPV lung cancer other pancreatic tumors and diseases pancreatitis ovarian cancer COPD pancreatic cancer ducatal tumor of stomach sarcoidosis prostate cancer accute myocardial infarction peridontitis multiple sclerosis melanoma disease # of mirnas Accuracy Specificity Sensitivity lung cancer other pancreatic tumors and diseases pancreatitis ovarian cancer COPD pancreatic cancer ducatal tumor of stomach sarcoidosis prostate cancer accute myocardial infarction peridontitis multiple sclerosis melanoma

16 disease # of mirnas Accuracy Specificity Sensitivity lung cancer other pancreatic tumors and diseases pancreatitis ovarian cancer COPD pancreatic cancer ducatal tumor of stomach sarcoidosis prostate cancer accute myocardial infarction peridontitis multiple sclerosis melanoma

17 Supplementary Table 7: MiRNA expression analysis by qrt-pcr using SmartChip Real-Time PCR System (Wafergen). Columns 1 lists the names of the samples and column 2 the names of the mirnas. qrt-pcr Ct (cycle threshold) values, and standard deviation of the Ct values (Ct SD) are given for each mirna. Disease Sample Primer Ct Ct SD lung L463 HSA-MIR cancer L469 HSA-MIR L485 HSA-MIR L490 HSA-MIR L492 HSA-MIR L503 HSA-MIR L507 HSA-MIR L508 HSA-MIR L509 HSA-MIR L513 HSA-MIR L517 HSA-MIR L523 HSA-MIR L524 HSA-MIR L525 HSA-MIR L536 HSA-MIR L537 HSA-MIR L577 HSA-MIR L585 HSA-MIR L586 HSA-MIR L596 HSA-MIR L605 HSA-MIR L606 HSA-MIR L633 HSA-MIR L637 HSA-MIR L642 HSA-MIR L657 HSA-MIR L662 HSA-MIR L669 HSA-MIR L672 HSA-MIR L682 HSA-MIR L701 HSA-MIR L702 HSA-MIR L703 HSA-MIR L711 HSA-MIR L723 HSA-MIR L726 HSA-MIR L731 HSA-MIR L746 HSA-MIR L747 HSA-MIR L748 HSA-MIR

18 L749 HSA-MIR L755 HSA-MIR L756 HSA-MIR L760 HSA-MIR L463 HSA-MIR L469 HSA-MIR L485 HSA-MIR L490 HSA-MIR L492 HSA-MIR L503 HSA-MIR L507 HSA-MIR L508 HSA-MIR L509 HSA-MIR L513 HSA-MIR L517 HSA-MIR L523 HSA-MIR L524 HSA-MIR L525 HSA-MIR L536 HSA-MIR L537 HSA-MIR L577 HSA-MIR L585 HSA-MIR L586 HSA-MIR L596 HSA-MIR L605 HSA-MIR L606 HSA-MIR L633 HSA-MIR L637 HSA-MIR L642 HSA-MIR L657 HSA-MIR L662 HSA-MIR L669 HSA-MIR L672 HSA-MIR L682 HSA-MIR L701 HSA-MIR L702 HSA-MIR L703 HSA-MIR L711 HSA-MIR L723 HSA-MIR L726 HSA-MIR L731 HSA-MIR L746 HSA-MIR L747 HSA-MIR L748 HSA-MIR L749 HSA-MIR L755 HSA-MIR L756 HSA-MIR L760 HSA-MIR L463 HSA-MIR L469 HSA-MIR L485 HSA-MIR

19 L490 HSA-MIR L492 HSA-MIR L503 HSA-MIR L507 HSA-MIR L508 HSA-MIR L509 HSA-MIR L513 HSA-MIR-1271 NaN NaN L517 HSA-MIR L523 HSA-MIR L524 HSA-MIR L525 HSA-MIR L536 HSA-MIR L537 HSA-MIR L577 HSA-MIR L585 HSA-MIR L586 HSA-MIR L596 HSA-MIR L605 HSA-MIR L606 HSA-MIR L633 HSA-MIR-1271 NaN NaN L637 HSA-MIR L642 HSA-MIR L657 HSA-MIR L662 HSA-MIR L669 HSA-MIR L672 HSA-MIR L682 HSA-MIR L701 HSA-MIR L702 HSA-MIR L703 HSA-MIR L711 HSA-MIR-1271 NaN NaN L723 HSA-MIR L726 HSA-MIR L731 HSA-MIR L746 HSA-MIR L747 HSA-MIR L748 HSA-MIR L749 HSA-MIR-1271 NaN NaN L755 HSA-MIR L756 HSA-MIR L760 HSA-MIR L463 HSA-MIR-130B L469 HSA-MIR-130B L485 HSA-MIR-130B L490 HSA-MIR-130B L492 HSA-MIR-130B L503 HSA-MIR-130B L507 HSA-MIR-130B L508 HSA-MIR-130B L509 HSA-MIR-130B L513 HSA-MIR-130B

20 L517 HSA-MIR-130B L523 HSA-MIR-130B L524 HSA-MIR-130B L525 HSA-MIR-130B L536 HSA-MIR-130B L537 HSA-MIR-130B L577 HSA-MIR-130B L585 HSA-MIR-130B L586 HSA-MIR-130B L596 HSA-MIR-130B L605 HSA-MIR-130B L606 HSA-MIR-130B L633 HSA-MIR-130B L637 HSA-MIR-130B L642 HSA-MIR-130B L657 HSA-MIR-130B L662 HSA-MIR-130B L669 HSA-MIR-130B L672 HSA-MIR-130B L682 HSA-MIR-130B L701 HSA-MIR-130B L702 HSA-MIR-130B L703 HSA-MIR-130B L711 HSA-MIR-130B L723 HSA-MIR-130B L726 HSA-MIR-130B L731 HSA-MIR-130B L746 HSA-MIR-130B L747 HSA-MIR-130B L748 HSA-MIR-130B L749 HSA-MIR-130B L755 HSA-MIR-130B L756 HSA-MIR-130B L760 HSA-MIR-130B L463 HSA-MIR-181C L469 HSA-MIR-181C L485 HSA-MIR-181C L490 HSA-MIR-181C L492 HSA-MIR-181C L503 HSA-MIR-181C L507 HSA-MIR-181C L508 HSA-MIR-181C L509 HSA-MIR-181C L513 HSA-MIR-181C L517 HSA-MIR-181C L523 HSA-MIR-181C L524 HSA-MIR-181C L525 HSA-MIR-181C L536 HSA-MIR-181C L537 HSA-MIR-181C L577 HSA-MIR-181C

21 L585 HSA-MIR-181C L586 HSA-MIR-181C L596 HSA-MIR-181C L605 HSA-MIR-181C L606 HSA-MIR-181C L633 HSA-MIR-181C L637 HSA-MIR-181C L642 HSA-MIR-181C L657 HSA-MIR-181C L662 HSA-MIR-181C L669 HSA-MIR-181C L672 HSA-MIR-181C L682 HSA-MIR-181C L701 HSA-MIR-181C L702 HSA-MIR-181C L703 HSA-MIR-181C L711 HSA-MIR-181C L723 HSA-MIR-181C L726 HSA-MIR-181C L731 HSA-MIR-181C L746 HSA-MIR-181C L747 HSA-MIR-181C L748 HSA-MIR-181C L749 HSA-MIR-181C L755 HSA-MIR-181C L756 HSA-MIR-181C L760 HSA-MIR-181C L463 HSA-MIR L469 HSA-MIR L485 HSA-MIR L490 HSA-MIR L492 HSA-MIR L503 HSA-MIR L507 HSA-MIR L508 HSA-MIR L509 HSA-MIR L513 HSA-MIR L517 HSA-MIR L523 HSA-MIR L524 HSA-MIR L525 HSA-MIR L536 HSA-MIR L537 HSA-MIR L577 HSA-MIR L585 HSA-MIR L586 HSA-MIR L596 HSA-MIR L605 HSA-MIR L606 HSA-MIR L633 HSA-MIR L637 HSA-MIR

22 L642 HSA-MIR L657 HSA-MIR L662 HSA-MIR L669 HSA-MIR L672 HSA-MIR L682 HSA-MIR L701 HSA-MIR L702 HSA-MIR L703 HSA-MIR L711 HSA-MIR L723 HSA-MIR L726 HSA-MIR L731 HSA-MIR L746 HSA-MIR L747 HSA-MIR L748 HSA-MIR L749 HSA-MIR L755 HSA-MIR L756 HSA-MIR L760 HSA-MIR L463 HSA-MIR-193A-3P L469 HSA-MIR-193A-3P L485 HSA-MIR-193A-3P NaN NaN L490 HSA-MIR-193A-3P L492 HSA-MIR-193A-3P L503 HSA-MIR-193A-3P L507 HSA-MIR-193A-3P L508 HSA-MIR-193A-3P L509 HSA-MIR-193A-3P L513 HSA-MIR-193A-3P L517 HSA-MIR-193A-3P L523 HSA-MIR-193A-3P L524 HSA-MIR-193A-3P L525 HSA-MIR-193A-3P L536 HSA-MIR-193A-3P L537 HSA-MIR-193A-3P L577 HSA-MIR-193A-3P L585 HSA-MIR-193A-3P L586 HSA-MIR-193A-3P L596 HSA-MIR-193A-3P L605 HSA-MIR-193A-3P L606 HSA-MIR-193A-3P L633 HSA-MIR-193A-3P L637 HSA-MIR-193A-3P L642 HSA-MIR-193A-3P L657 HSA-MIR-193A-3P L662 HSA-MIR-193A-3P L669 HSA-MIR-193A-3P L672 HSA-MIR-193A-3P L682 HSA-MIR-193A-3P L701 HSA-MIR-193A-3P

23 L702 HSA-MIR-193A-3P L703 HSA-MIR-193A-3P L711 HSA-MIR-193A-3P L723 HSA-MIR-193A-3P L726 HSA-MIR-193A-3P L731 HSA-MIR-193A-3P L746 HSA-MIR-193A-3P L747 HSA-MIR-193A-3P L748 HSA-MIR-193A-3P L749 HSA-MIR-193A-3P L755 HSA-MIR-193A-3P L756 HSA-MIR-193A-3P L760 HSA-MIR-193A-3P L463 HSA-MIR L469 HSA-MIR L485 HSA-MIR L490 HSA-MIR L492 HSA-MIR L503 HSA-MIR L507 HSA-MIR L508 HSA-MIR L509 HSA-MIR L513 HSA-MIR L517 HSA-MIR L523 HSA-MIR L524 HSA-MIR L525 HSA-MIR L536 HSA-MIR L537 HSA-MIR L577 HSA-MIR L585 HSA-MIR L586 HSA-MIR L596 HSA-MIR L605 HSA-MIR L606 HSA-MIR L633 HSA-MIR L637 HSA-MIR L642 HSA-MIR L657 HSA-MIR L662 HSA-MIR L669 HSA-MIR L672 HSA-MIR L682 HSA-MIR L701 HSA-MIR L702 HSA-MIR L703 HSA-MIR L711 HSA-MIR L723 HSA-MIR L726 HSA-MIR L731 HSA-MIR L746 HSA-MIR

24 L747 HSA-MIR L748 HSA-MIR L749 HSA-MIR L755 HSA-MIR L756 HSA-MIR L760 HSA-MIR L463 HSA-MIR-26A L469 HSA-MIR-26A L485 HSA-MIR-26A L490 HSA-MIR-26A L492 HSA-MIR-26A L503 HSA-MIR-26A L507 HSA-MIR-26A L508 HSA-MIR-26A L509 HSA-MIR-26A L513 HSA-MIR-26A L517 HSA-MIR-26A L523 HSA-MIR-26A L524 HSA-MIR-26A L525 HSA-MIR-26A L536 HSA-MIR-26A L537 HSA-MIR-26A L577 HSA-MIR-26A L585 HSA-MIR-26A L586 HSA-MIR-26A L596 HSA-MIR-26A L605 HSA-MIR-26A L606 HSA-MIR-26A L633 HSA-MIR-26A L637 HSA-MIR-26A L642 HSA-MIR-26A L657 HSA-MIR-26A L662 HSA-MIR-26A L669 HSA-MIR-26A L672 HSA-MIR-26A L682 HSA-MIR-26A L701 HSA-MIR-26A L702 HSA-MIR-26A NaN NaN L703 HSA-MIR-26A L711 HSA-MIR-26A L723 HSA-MIR-26A L726 HSA-MIR-26A L731 HSA-MIR-26A L746 HSA-MIR-26A L747 HSA-MIR-26A L748 HSA-MIR-26A L749 HSA-MIR-26A L755 HSA-MIR-26A L756 HSA-MIR-26A L760 HSA-MIR-26A L463 HSA-MIR-324-3P

25 L469 HSA-MIR-324-3P L485 HSA-MIR-324-3P L490 HSA-MIR-324-3P L492 HSA-MIR-324-3P L503 HSA-MIR-324-3P L507 HSA-MIR-324-3P L508 HSA-MIR-324-3P L509 HSA-MIR-324-3P L513 HSA-MIR-324-3P L517 HSA-MIR-324-3P L523 HSA-MIR-324-3P L524 HSA-MIR-324-3P L525 HSA-MIR-324-3P L536 HSA-MIR-324-3P L537 HSA-MIR-324-3P L577 HSA-MIR-324-3P L585 HSA-MIR-324-3P L586 HSA-MIR-324-3P L596 HSA-MIR-324-3P L605 HSA-MIR-324-3P L606 HSA-MIR-324-3P L633 HSA-MIR-324-3P L637 HSA-MIR-324-3P L642 HSA-MIR-324-3P L657 HSA-MIR-324-3P L662 HSA-MIR-324-3P L669 HSA-MIR-324-3P L672 HSA-MIR-324-3P L682 HSA-MIR-324-3P L701 HSA-MIR-324-3P L702 HSA-MIR-324-3P L703 HSA-MIR-324-3P L711 HSA-MIR-324-3P L723 HSA-MIR-324-3P L726 HSA-MIR-324-3P L731 HSA-MIR-324-3P L746 HSA-MIR-324-3P L747 HSA-MIR-324-3P L748 HSA-MIR-324-3P L749 HSA-MIR-324-3P L755 HSA-MIR-324-3P L756 HSA-MIR-324-3P L760 HSA-MIR-324-3P L463 HSA-MIR L469 HSA-MIR L485 HSA-MIR L490 HSA-MIR L492 HSA-MIR L503 HSA-MIR L507 HSA-MIR L508 HSA-MIR

26 L509 HSA-MIR L513 HSA-MIR L517 HSA-MIR L523 HSA-MIR L524 HSA-MIR L525 HSA-MIR L536 HSA-MIR L537 HSA-MIR L577 HSA-MIR L585 HSA-MIR L586 HSA-MIR L596 HSA-MIR L605 HSA-MIR L606 HSA-MIR L633 HSA-MIR L637 HSA-MIR L642 HSA-MIR L657 HSA-MIR L662 HSA-MIR L669 HSA-MIR L672 HSA-MIR L682 HSA-MIR L701 HSA-MIR L702 HSA-MIR L703 HSA-MIR L711 HSA-MIR L723 HSA-MIR L726 HSA-MIR L731 HSA-MIR L746 HSA-MIR L747 HSA-MIR L748 HSA-MIR L749 HSA-MIR L755 HSA-MIR L756 HSA-MIR L760 HSA-MIR L463 HSA-MIR L469 HSA-MIR L485 HSA-MIR L490 HSA-MIR L492 HSA-MIR L503 HSA-MIR L507 HSA-MIR L508 HSA-MIR L509 HSA-MIR L513 HSA-MIR L517 HSA-MIR L523 HSA-MIR L524 HSA-MIR L525 HSA-MIR L536 HSA-MIR

27 L537 HSA-MIR L577 HSA-MIR L585 HSA-MIR L586 HSA-MIR L596 HSA-MIR L605 HSA-MIR L606 HSA-MIR L633 HSA-MIR L637 HSA-MIR L642 HSA-MIR L657 HSA-MIR L662 HSA-MIR L669 HSA-MIR L672 HSA-MIR L682 HSA-MIR L701 HSA-MIR L702 HSA-MIR L703 HSA-MIR L711 HSA-MIR L723 HSA-MIR L726 HSA-MIR L731 HSA-MIR L746 HSA-MIR L747 HSA-MIR L748 HSA-MIR L749 HSA-MIR L755 HSA-MIR L756 HSA-MIR L760 HSA-MIR L463 HSA-MIR L469 HSA-MIR L485 HSA-MIR L490 HSA-MIR L492 HSA-MIR L503 HSA-MIR L507 HSA-MIR L508 HSA-MIR L509 HSA-MIR L513 HSA-MIR L517 HSA-MIR L523 HSA-MIR L524 HSA-MIR L525 HSA-MIR L536 HSA-MIR L537 HSA-MIR L577 HSA-MIR L585 HSA-MIR L586 HSA-MIR L596 HSA-MIR L605 HSA-MIR L606 HSA-MIR

28 L633 HSA-MIR L637 HSA-MIR L642 HSA-MIR L657 HSA-MIR L662 HSA-MIR L669 HSA-MIR L672 HSA-MIR L682 HSA-MIR L701 HSA-MIR L702 HSA-MIR L703 HSA-MIR L711 HSA-MIR L723 HSA-MIR L726 HSA-MIR L731 HSA-MIR L746 HSA-MIR L747 HSA-MIR L748 HSA-MIR L749 HSA-MIR L755 HSA-MIR L756 HSA-MIR L760 HSA-MIR L463 HSA-MIR L469 HSA-MIR L485 HSA-MIR L490 HSA-MIR L492 HSA-MIR L503 HSA-MIR L507 HSA-MIR L508 HSA-MIR L509 HSA-MIR L513 HSA-MIR L517 HSA-MIR L523 HSA-MIR L524 HSA-MIR L525 HSA-MIR L536 HSA-MIR L537 HSA-MIR L577 HSA-MIR L585 HSA-MIR L586 HSA-MIR L596 HSA-MIR L605 HSA-MIR L606 HSA-MIR L633 HSA-MIR L637 HSA-MIR L642 HSA-MIR L657 HSA-MIR L662 HSA-MIR L669 HSA-MIR L672 HSA-MIR

29 L682 HSA-MIR L701 HSA-MIR L702 HSA-MIR L703 HSA-MIR L711 HSA-MIR L723 HSA-MIR L726 HSA-MIR L731 HSA-MIR L746 HSA-MIR L747 HSA-MIR L748 HSA-MIR L749 HSA-MIR L755 HSA-MIR L756 HSA-MIR L760 HSA-MIR L463 HSA-MIR L469 HSA-MIR L485 HSA-MIR L490 HSA-MIR L492 HSA-MIR L503 HSA-MIR L507 HSA-MIR L508 HSA-MIR L509 HSA-MIR L513 HSA-MIR L517 HSA-MIR L523 HSA-MIR L524 HSA-MIR L525 HSA-MIR L536 HSA-MIR L537 HSA-MIR L577 HSA-MIR L585 HSA-MIR L586 HSA-MIR L596 HSA-MIR L605 HSA-MIR L606 HSA-MIR L633 HSA-MIR L637 HSA-MIR L642 HSA-MIR L657 HSA-MIR L662 HSA-MIR L669 HSA-MIR L672 HSA-MIR L682 HSA-MIR L701 HSA-MIR L702 HSA-MIR L703 HSA-MIR L711 HSA-MIR L723 HSA-MIR L726 HSA-MIR

30 L731 HSA-MIR L746 HSA-MIR L747 HSA-MIR L748 HSA-MIR L749 HSA-MIR L755 HSA-MIR L756 HSA-MIR L760 HSA-MIR L463 HSA-MIR L469 HSA-MIR L485 HSA-MIR L490 HSA-MIR L492 HSA-MIR L503 HSA-MIR L507 HSA-MIR L508 HSA-MIR L509 HSA-MIR L513 HSA-MIR L517 HSA-MIR L523 HSA-MIR L524 HSA-MIR L525 HSA-MIR L536 HSA-MIR-874 NaN NaN L537 HSA-MIR L577 HSA-MIR L585 HSA-MIR L586 HSA-MIR L596 HSA-MIR L605 HSA-MIR L606 HSA-MIR L633 HSA-MIR L637 HSA-MIR L642 HSA-MIR L657 HSA-MIR L662 HSA-MIR L669 HSA-MIR L672 HSA-MIR L682 HSA-MIR L701 HSA-MIR L702 HSA-MIR L703 HSA-MIR-874 NaN NaN L711 HSA-MIR L723 HSA-MIR L726 HSA-MIR L731 HSA-MIR L746 HSA-MIR L747 HSA-MIR L748 HSA-MIR L749 HSA-MIR L755 HSA-MIR L756 HSA-MIR

31 L760 HSA-MIR L463 HSA-MIR-92A L469 HSA-MIR-92A L485 HSA-MIR-92A L490 HSA-MIR-92A L492 HSA-MIR-92A L503 HSA-MIR-92A L507 HSA-MIR-92A L508 HSA-MIR-92A L509 HSA-MIR-92A L513 HSA-MIR-92A L517 HSA-MIR-92A L523 HSA-MIR-92A L524 HSA-MIR-92A L525 HSA-MIR-92A L536 HSA-MIR-92A L537 HSA-MIR-92A L577 HSA-MIR-92A L585 HSA-MIR-92A L586 HSA-MIR-92A L596 HSA-MIR-92A L605 HSA-MIR-92A NaN NaN L606 HSA-MIR-92A L633 HSA-MIR-92A L637 HSA-MIR-92A L642 HSA-MIR-92A L657 HSA-MIR-92A L662 HSA-MIR-92A L669 HSA-MIR-92A L672 HSA-MIR-92A L682 HSA-MIR-92A L701 HSA-MIR-92A L702 HSA-MIR-92A L703 HSA-MIR-92A L711 HSA-MIR-92A L723 HSA-MIR-92A L726 HSA-MIR-92A L731 HSA-MIR-92A L746 HSA-MIR-92A L747 HSA-MIR-92A L748 HSA-MIR-92A L749 HSA-MIR-92A L755 HSA-MIR-92A L756 HSA-MIR-92A L760 HSA-MIR-92A L463 HSA-MIR-93* L469 HSA-MIR-93* L485 HSA-MIR-93* L490 HSA-MIR-93* L492 HSA-MIR-93* NaN NaN L503 HSA-MIR-93*

32 L507 HSA-MIR-93* L508 HSA-MIR-93* L509 HSA-MIR-93* L513 HSA-MIR-93* L517 HSA-MIR-93* L523 HSA-MIR-93* L524 HSA-MIR-93* L525 HSA-MIR-93* L536 HSA-MIR-93* L537 HSA-MIR-93* L577 HSA-MIR-93* L585 HSA-MIR-93* L586 HSA-MIR-93* L596 HSA-MIR-93* L605 HSA-MIR-93* L606 HSA-MIR-93* L633 HSA-MIR-93* L637 HSA-MIR-93* L642 HSA-MIR-93* L657 HSA-MIR-93* L662 HSA-MIR-93* L669 HSA-MIR-93* L672 HSA-MIR-93* L682 HSA-MIR-93* L701 HSA-MIR-93* L702 HSA-MIR-93* L703 HSA-MIR-93* L711 HSA-MIR-93* L723 HSA-MIR-93* L726 HSA-MIR-93* L731 HSA-MIR-93* L746 HSA-MIR-93* L747 HSA-MIR-93* L748 HSA-MIR-93* L749 HSA-MIR-93* L755 HSA-MIR-93* L756 HSA-MIR-93* L760 HSA-MIR-93* COPD VK11 HSA-MIR VK12 HSA-MIR VK13 HSA-MIR VK14 HSA-MIR VK15 HSA-MIR VK16 HSA-MIR VK18 HSA-MIR VK2 HSA-MIR VK21 HSA-MIR VK22 HSA-MIR VK24 HSA-MIR VK26 HSA-MIR VK27 HSA-MIR

33 VK28 HSA-MIR VK29 HSA-MIR VK3 HSA-MIR VK30 HSA-MIR VK31 HSA-MIR VK32 HSA-MIR VK33 HSA-MIR VK34 HSA-MIR VK35 HSA-MIR VK36 HSA-MIR VK37 HSA-MIR VK40 HSA-MIR VK41 HSA-MIR VK42 HSA-MIR VK43 HSA-MIR VK44 HSA-MIR VK45 HSA-MIR VK46 HSA-MIR VK47 HSA-MIR VK48 HSA-MIR VK49 HSA-MIR VK50 HSA-MIR VK51 HSA-MIR VK52 HSA-MIR VK6 HSA-MIR VK7 HSA-MIR VK8 HSA-MIR VK9 HSA-MIR VK11 HSA-MIR VK12 HSA-MIR VK13 HSA-MIR VK14 HSA-MIR VK15 HSA-MIR VK16 HSA-MIR VK18 HSA-MIR VK2 HSA-MIR VK21 HSA-MIR VK22 HSA-MIR VK24 HSA-MIR VK26 HSA-MIR VK27 HSA-MIR VK28 HSA-MIR VK29 HSA-MIR VK3 HSA-MIR VK30 HSA-MIR VK31 HSA-MIR VK32 HSA-MIR VK33 HSA-MIR VK34 HSA-MIR VK35 HSA-MIR VK36 HSA-MIR

34 VK37 HSA-MIR VK40 HSA-MIR VK41 HSA-MIR VK42 HSA-MIR VK43 HSA-MIR VK44 HSA-MIR VK45 HSA-MIR VK46 HSA-MIR VK47 HSA-MIR VK48 HSA-MIR VK49 HSA-MIR VK50 HSA-MIR VK51 HSA-MIR VK52 HSA-MIR VK6 HSA-MIR VK7 HSA-MIR VK8 HSA-MIR VK9 HSA-MIR VK11 HSA-MIR VK12 HSA-MIR VK13 HSA-MIR VK14 HSA-MIR VK15 HSA-MIR VK16 HSA-MIR VK18 HSA-MIR VK2 HSA-MIR VK21 HSA-MIR VK22 HSA-MIR VK24 HSA-MIR VK26 HSA-MIR-1271 NaN NaN VK27 HSA-MIR VK28 HSA-MIR-1271 NaN NaN VK29 HSA-MIR VK3 HSA-MIR-1271 NaN NaN VK30 HSA-MIR VK31 HSA-MIR VK32 HSA-MIR VK33 HSA-MIR VK34 HSA-MIR VK35 HSA-MIR VK36 HSA-MIR VK37 HSA-MIR VK40 HSA-MIR VK41 HSA-MIR-1271 NaN NaN VK42 HSA-MIR VK43 HSA-MIR VK44 HSA-MIR VK45 HSA-MIR VK46 HSA-MIR VK47 HSA-MIR VK48 HSA-MIR

35 VK49 HSA-MIR VK50 HSA-MIR VK51 HSA-MIR VK52 HSA-MIR VK6 HSA-MIR VK7 HSA-MIR VK8 HSA-MIR VK9 HSA-MIR VK11 HSA-MIR-130B VK12 HSA-MIR-130B VK13 HSA-MIR-130B VK14 HSA-MIR-130B VK15 HSA-MIR-130B VK16 HSA-MIR-130B VK18 HSA-MIR-130B VK2 HSA-MIR-130B VK21 HSA-MIR-130B VK22 HSA-MIR-130B VK24 HSA-MIR-130B VK26 HSA-MIR-130B VK27 HSA-MIR-130B VK28 HSA-MIR-130B VK29 HSA-MIR-130B VK3 HSA-MIR-130B VK30 HSA-MIR-130B VK31 HSA-MIR-130B VK32 HSA-MIR-130B VK33 HSA-MIR-130B VK34 HSA-MIR-130B VK35 HSA-MIR-130B VK36 HSA-MIR-130B VK37 HSA-MIR-130B VK40 HSA-MIR-130B VK41 HSA-MIR-130B VK42 HSA-MIR-130B VK43 HSA-MIR-130B VK44 HSA-MIR-130B VK45 HSA-MIR-130B VK46 HSA-MIR-130B VK47 HSA-MIR-130B NaN NaN VK48 HSA-MIR-130B VK49 HSA-MIR-130B VK50 HSA-MIR-130B VK51 HSA-MIR-130B VK52 HSA-MIR-130B VK6 HSA-MIR-130B VK7 HSA-MIR-130B VK8 HSA-MIR-130B VK9 HSA-MIR-130B VK11 HSA-MIR-181C VK12 HSA-MIR-181C

36 VK13 HSA-MIR-181C VK14 HSA-MIR-181C VK15 HSA-MIR-181C VK16 HSA-MIR-181C VK18 HSA-MIR-181C VK2 HSA-MIR-181C VK21 HSA-MIR-181C VK22 HSA-MIR-181C VK24 HSA-MIR-181C VK26 HSA-MIR-181C VK27 HSA-MIR-181C VK28 HSA-MIR-181C VK29 HSA-MIR-181C VK3 HSA-MIR-181C VK30 HSA-MIR-181C VK31 HSA-MIR-181C VK32 HSA-MIR-181C VK33 HSA-MIR-181C VK34 HSA-MIR-181C VK35 HSA-MIR-181C VK36 HSA-MIR-181C VK37 HSA-MIR-181C VK40 HSA-MIR-181C VK41 HSA-MIR-181C VK42 HSA-MIR-181C VK43 HSA-MIR-181C VK44 HSA-MIR-181C VK45 HSA-MIR-181C VK46 HSA-MIR-181C VK47 HSA-MIR-181C VK48 HSA-MIR-181C VK49 HSA-MIR-181C VK50 HSA-MIR-181C VK51 HSA-MIR-181C VK52 HSA-MIR-181C VK6 HSA-MIR-181C VK7 HSA-MIR-181C VK8 HSA-MIR-181C VK9 HSA-MIR-181C VK11 HSA-MIR VK12 HSA-MIR VK13 HSA-MIR VK14 HSA-MIR VK15 HSA-MIR VK16 HSA-MIR VK18 HSA-MIR VK2 HSA-MIR VK21 HSA-MIR VK22 HSA-MIR VK24 HSA-MIR VK26 HSA-MIR

37 VK27 HSA-MIR VK28 HSA-MIR VK29 HSA-MIR VK3 HSA-MIR VK30 HSA-MIR VK31 HSA-MIR VK32 HSA-MIR VK33 HSA-MIR VK34 HSA-MIR VK35 HSA-MIR VK36 HSA-MIR VK37 HSA-MIR VK40 HSA-MIR VK41 HSA-MIR VK42 HSA-MIR VK43 HSA-MIR VK44 HSA-MIR VK45 HSA-MIR VK46 HSA-MIR VK47 HSA-MIR VK48 HSA-MIR VK49 HSA-MIR VK50 HSA-MIR VK51 HSA-MIR VK52 HSA-MIR VK6 HSA-MIR VK7 HSA-MIR VK8 HSA-MIR VK9 HSA-MIR VK11 HSA-MIR-193A-3P VK12 HSA-MIR-193A-3P VK13 HSA-MIR-193A-3P VK14 HSA-MIR-193A-3P VK15 HSA-MIR-193A-3P VK16 HSA-MIR-193A-3P VK18 HSA-MIR-193A-3P VK2 HSA-MIR-193A-3P VK21 HSA-MIR-193A-3P VK22 HSA-MIR-193A-3P VK24 HSA-MIR-193A-3P VK26 HSA-MIR-193A-3P VK27 HSA-MIR-193A-3P VK28 HSA-MIR-193A-3P VK29 HSA-MIR-193A-3P VK3 HSA-MIR-193A-3P VK30 HSA-MIR-193A-3P VK31 HSA-MIR-193A-3P VK32 HSA-MIR-193A-3P VK33 HSA-MIR-193A-3P VK34 HSA-MIR-193A-3P VK35 HSA-MIR-193A-3P

38 VK36 HSA-MIR-193A-3P VK37 HSA-MIR-193A-3P VK40 HSA-MIR-193A-3P VK41 HSA-MIR-193A-3P VK42 HSA-MIR-193A-3P VK43 HSA-MIR-193A-3P VK44 HSA-MIR-193A-3P VK45 HSA-MIR-193A-3P VK46 HSA-MIR-193A-3P VK47 HSA-MIR-193A-3P VK48 HSA-MIR-193A-3P VK49 HSA-MIR-193A-3P VK50 HSA-MIR-193A-3P VK51 HSA-MIR-193A-3P VK52 HSA-MIR-193A-3P VK6 HSA-MIR-193A-3P VK7 HSA-MIR-193A-3P VK8 HSA-MIR-193A-3P VK9 HSA-MIR-193A-3P VK11 HSA-MIR VK12 HSA-MIR VK13 HSA-MIR VK14 HSA-MIR VK15 HSA-MIR VK16 HSA-MIR VK18 HSA-MIR VK2 HSA-MIR VK21 HSA-MIR VK22 HSA-MIR VK24 HSA-MIR VK26 HSA-MIR VK27 HSA-MIR VK28 HSA-MIR VK29 HSA-MIR VK3 HSA-MIR VK30 HSA-MIR VK31 HSA-MIR VK32 HSA-MIR VK33 HSA-MIR VK34 HSA-MIR VK35 HSA-MIR VK36 HSA-MIR VK37 HSA-MIR VK40 HSA-MIR VK41 HSA-MIR VK42 HSA-MIR VK43 HSA-MIR VK44 HSA-MIR VK45 HSA-MIR VK46 HSA-MIR VK47 HSA-MIR

39 VK48 HSA-MIR VK49 HSA-MIR VK50 HSA-MIR VK51 HSA-MIR VK52 HSA-MIR VK6 HSA-MIR VK7 HSA-MIR VK8 HSA-MIR VK9 HSA-MIR VK11 HSA-MIR-26A VK12 HSA-MIR-26A VK13 HSA-MIR-26A VK14 HSA-MIR-26A VK15 HSA-MIR-26A VK16 HSA-MIR-26A VK18 HSA-MIR-26A VK2 HSA-MIR-26A VK21 HSA-MIR-26A VK22 HSA-MIR-26A VK24 HSA-MIR-26A VK26 HSA-MIR-26A VK27 HSA-MIR-26A VK28 HSA-MIR-26A NaN NaN VK29 HSA-MIR-26A NaN NaN VK3 HSA-MIR-26A VK30 HSA-MIR-26A VK31 HSA-MIR-26A VK32 HSA-MIR-26A VK33 HSA-MIR-26A VK34 HSA-MIR-26A VK35 HSA-MIR-26A VK36 HSA-MIR-26A VK37 HSA-MIR-26A VK40 HSA-MIR-26A VK41 HSA-MIR-26A VK42 HSA-MIR-26A VK43 HSA-MIR-26A VK44 HSA-MIR-26A VK45 HSA-MIR-26A VK46 HSA-MIR-26A VK47 HSA-MIR-26A VK48 HSA-MIR-26A VK49 HSA-MIR-26A VK50 HSA-MIR-26A VK51 HSA-MIR-26A VK52 HSA-MIR-26A VK6 HSA-MIR-26A VK7 HSA-MIR-26A VK8 HSA-MIR-26A VK9 HSA-MIR-26A VK11 HSA-MIR-324-3P

40 VK12 HSA-MIR-324-3P VK13 HSA-MIR-324-3P VK14 HSA-MIR-324-3P VK15 HSA-MIR-324-3P VK16 HSA-MIR-324-3P VK18 HSA-MIR-324-3P VK2 HSA-MIR-324-3P VK21 HSA-MIR-324-3P VK22 HSA-MIR-324-3P VK24 HSA-MIR-324-3P VK26 HSA-MIR-324-3P VK27 HSA-MIR-324-3P VK28 HSA-MIR-324-3P VK29 HSA-MIR-324-3P VK3 HSA-MIR-324-3P VK30 HSA-MIR-324-3P VK31 HSA-MIR-324-3P VK32 HSA-MIR-324-3P VK33 HSA-MIR-324-3P VK34 HSA-MIR-324-3P VK35 HSA-MIR-324-3P VK36 HSA-MIR-324-3P VK37 HSA-MIR-324-3P VK40 HSA-MIR-324-3P VK41 HSA-MIR-324-3P VK42 HSA-MIR-324-3P VK43 HSA-MIR-324-3P VK44 HSA-MIR-324-3P VK45 HSA-MIR-324-3P VK46 HSA-MIR-324-3P VK47 HSA-MIR-324-3P VK48 HSA-MIR-324-3P VK49 HSA-MIR-324-3P VK50 HSA-MIR-324-3P VK51 HSA-MIR-324-3P VK52 HSA-MIR-324-3P VK6 HSA-MIR-324-3P VK7 HSA-MIR-324-3P VK8 HSA-MIR-324-3P VK9 HSA-MIR-324-3P VK11 HSA-MIR VK12 HSA-MIR VK13 HSA-MIR VK14 HSA-MIR VK15 HSA-MIR VK16 HSA-MIR VK18 HSA-MIR VK2 HSA-MIR VK21 HSA-MIR VK22 HSA-MIR VK24 HSA-MIR

41 VK26 HSA-MIR VK27 HSA-MIR VK28 HSA-MIR VK29 HSA-MIR VK3 HSA-MIR VK30 HSA-MIR VK31 HSA-MIR VK32 HSA-MIR VK33 HSA-MIR VK34 HSA-MIR VK35 HSA-MIR VK36 HSA-MIR VK37 HSA-MIR VK40 HSA-MIR VK41 HSA-MIR VK42 HSA-MIR VK43 HSA-MIR VK44 HSA-MIR VK45 HSA-MIR VK46 HSA-MIR VK47 HSA-MIR VK48 HSA-MIR VK49 HSA-MIR VK50 HSA-MIR VK51 HSA-MIR VK52 HSA-MIR VK6 HSA-MIR VK7 HSA-MIR VK8 HSA-MIR VK9 HSA-MIR VK11 HSA-MIR VK12 HSA-MIR VK13 HSA-MIR VK14 HSA-MIR VK15 HSA-MIR VK16 HSA-MIR VK18 HSA-MIR VK2 HSA-MIR VK21 HSA-MIR VK22 HSA-MIR VK24 HSA-MIR VK26 HSA-MIR VK27 HSA-MIR VK28 HSA-MIR VK29 HSA-MIR VK3 HSA-MIR VK30 HSA-MIR VK31 HSA-MIR VK32 HSA-MIR VK33 HSA-MIR VK34 HSA-MIR

42 VK35 HSA-MIR VK36 HSA-MIR VK37 HSA-MIR VK40 HSA-MIR VK41 HSA-MIR VK42 HSA-MIR VK43 HSA-MIR VK44 HSA-MIR VK45 HSA-MIR VK46 HSA-MIR VK47 HSA-MIR VK48 HSA-MIR VK49 HSA-MIR VK50 HSA-MIR VK51 HSA-MIR VK52 HSA-MIR VK6 HSA-MIR VK7 HSA-MIR VK8 HSA-MIR VK9 HSA-MIR VK11 HSA-MIR VK12 HSA-MIR VK13 HSA-MIR VK14 HSA-MIR VK15 HSA-MIR VK16 HSA-MIR VK18 HSA-MIR VK2 HSA-MIR VK21 HSA-MIR VK22 HSA-MIR VK24 HSA-MIR VK26 HSA-MIR VK27 HSA-MIR VK28 HSA-MIR VK29 HSA-MIR VK3 HSA-MIR VK30 HSA-MIR VK31 HSA-MIR VK32 HSA-MIR VK33 HSA-MIR VK34 HSA-MIR VK35 HSA-MIR VK36 HSA-MIR VK37 HSA-MIR VK40 HSA-MIR VK41 HSA-MIR VK42 HSA-MIR VK43 HSA-MIR VK44 HSA-MIR VK45 HSA-MIR VK46 HSA-MIR

43 VK47 HSA-MIR VK48 HSA-MIR VK49 HSA-MIR VK50 HSA-MIR VK51 HSA-MIR VK52 HSA-MIR VK6 HSA-MIR VK7 HSA-MIR VK8 HSA-MIR VK9 HSA-MIR VK11 HSA-MIR VK12 HSA-MIR VK13 HSA-MIR VK14 HSA-MIR VK15 HSA-MIR VK16 HSA-MIR VK18 HSA-MIR VK2 HSA-MIR VK21 HSA-MIR VK22 HSA-MIR VK24 HSA-MIR VK26 HSA-MIR VK27 HSA-MIR VK28 HSA-MIR VK29 HSA-MIR VK3 HSA-MIR VK30 HSA-MIR VK31 HSA-MIR VK32 HSA-MIR VK33 HSA-MIR VK34 HSA-MIR VK35 HSA-MIR VK36 HSA-MIR VK37 HSA-MIR VK40 HSA-MIR VK41 HSA-MIR VK42 HSA-MIR VK43 HSA-MIR VK44 HSA-MIR VK45 HSA-MIR VK46 HSA-MIR VK47 HSA-MIR VK48 HSA-MIR VK49 HSA-MIR VK50 HSA-MIR VK51 HSA-MIR VK52 HSA-MIR VK6 HSA-MIR VK7 HSA-MIR VK8 HSA-MIR VK9 HSA-MIR

44 VK11 HSA-MIR VK12 HSA-MIR VK13 HSA-MIR VK14 HSA-MIR VK15 HSA-MIR VK16 HSA-MIR VK18 HSA-MIR VK2 HSA-MIR VK21 HSA-MIR VK22 HSA-MIR VK24 HSA-MIR VK26 HSA-MIR VK27 HSA-MIR VK28 HSA-MIR VK29 HSA-MIR VK3 HSA-MIR VK30 HSA-MIR VK31 HSA-MIR VK32 HSA-MIR VK33 HSA-MIR VK34 HSA-MIR VK35 HSA-MIR VK36 HSA-MIR VK37 HSA-MIR VK40 HSA-MIR VK41 HSA-MIR VK42 HSA-MIR VK43 HSA-MIR VK44 HSA-MIR VK45 HSA-MIR VK46 HSA-MIR VK47 HSA-MIR VK48 HSA-MIR VK49 HSA-MIR VK50 HSA-MIR VK51 HSA-MIR VK52 HSA-MIR VK6 HSA-MIR VK7 HSA-MIR VK8 HSA-MIR VK9 HSA-MIR VK11 HSA-MIR VK12 HSA-MIR VK13 HSA-MIR VK14 HSA-MIR VK15 HSA-MIR VK16 HSA-MIR VK18 HSA-MIR VK2 HSA-MIR VK21 HSA-MIR VK22 HSA-MIR

45 VK24 HSA-MIR VK26 HSA-MIR VK27 HSA-MIR VK28 HSA-MIR VK29 HSA-MIR VK3 HSA-MIR VK30 HSA-MIR VK31 HSA-MIR VK32 HSA-MIR VK33 HSA-MIR VK34 HSA-MIR VK35 HSA-MIR VK36 HSA-MIR VK37 HSA-MIR VK40 HSA-MIR VK41 HSA-MIR VK42 HSA-MIR VK43 HSA-MIR VK44 HSA-MIR VK45 HSA-MIR VK46 HSA-MIR VK47 HSA-MIR VK48 HSA-MIR VK49 HSA-MIR VK50 HSA-MIR VK51 HSA-MIR VK52 HSA-MIR VK6 HSA-MIR VK7 HSA-MIR VK8 HSA-MIR VK9 HSA-MIR VK11 HSA-MIR-92A VK12 HSA-MIR-92A VK13 HSA-MIR-92A VK14 HSA-MIR-92A VK15 HSA-MIR-92A VK16 HSA-MIR-92A VK18 HSA-MIR-92A VK2 HSA-MIR-92A VK21 HSA-MIR-92A VK22 HSA-MIR-92A VK24 HSA-MIR-92A VK26 HSA-MIR-92A NaN NaN VK27 HSA-MIR-92A VK28 HSA-MIR-92A VK29 HSA-MIR-92A VK3 HSA-MIR-92A VK30 HSA-MIR-92A VK31 HSA-MIR-92A VK32 HSA-MIR-92A VK33 HSA-MIR-92A

46 VK34 HSA-MIR-92A VK35 HSA-MIR-92A VK36 HSA-MIR-92A VK37 HSA-MIR-92A VK40 HSA-MIR-92A VK41 HSA-MIR-92A VK42 HSA-MIR-92A VK43 HSA-MIR-92A VK44 HSA-MIR-92A VK45 HSA-MIR-92A VK46 HSA-MIR-92A VK47 HSA-MIR-92A VK48 HSA-MIR-92A VK49 HSA-MIR-92A VK50 HSA-MIR-92A VK51 HSA-MIR-92A VK52 HSA-MIR-92A VK6 HSA-MIR-92A VK7 HSA-MIR-92A VK8 HSA-MIR-92A VK9 HSA-MIR-92A VK11 HSA-MIR-93* VK12 HSA-MIR-93* VK13 HSA-MIR-93* VK14 HSA-MIR-93* VK15 HSA-MIR-93* VK16 HSA-MIR-93* VK18 HSA-MIR-93* VK2 HSA-MIR-93* VK21 HSA-MIR-93* VK22 HSA-MIR-93* VK24 HSA-MIR-93* VK26 HSA-MIR-93* VK27 HSA-MIR-93* VK28 HSA-MIR-93* VK29 HSA-MIR-93* VK3 HSA-MIR-93* VK30 HSA-MIR-93* VK31 HSA-MIR-93* VK32 HSA-MIR-93* VK33 HSA-MIR-93* VK34 HSA-MIR-93* VK35 HSA-MIR-93* VK36 HSA-MIR-93* VK37 HSA-MIR-93* VK40 HSA-MIR-93* VK41 HSA-MIR-93* VK42 HSA-MIR-93* VK43 HSA-MIR-93* VK44 HSA-MIR-93* VK45 HSA-MIR-93*

47 VK46 HSA-MIR-93* VK47 HSA-MIR-93* VK48 HSA-MIR-93* VK49 HSA-MIR-93* VK50 HSA-MIR-93* VK51 HSA-MIR-93* VK52 HSA-MIR-93* VK6 HSA-MIR-93* VK7 HSA-MIR-93* VK8 HSA-MIR-93* VK9 HSA-MIR-93*

48 Supplemental Table 8: Summary of mirna validation. The table lists whether technical or biological validation has been performed (indicated by an X), shows the number of analyzed blood samples, and provides the fold change identified by either array or qrt-pcr analysis. Overview Publication (PMID) mirna condition Technical Validation Biological Validation hsa-mir-1260 lung diseases x x 85 hsa-mir-484 lung diseases x x 85 hsa-mir-92a lung diseases x x 85 hsa-mir-183 lung diseases x x 85 hsa-mir-25 lung diseases x x 85 hsa-mir-324-3p lung diseases x x 85 hsa-mir-126 lung diseases x x 85 hsa-mir-328 lung diseases x x 85 hsa-mir-363 lung diseases x x 85 hsa-mir-636 lung diseases x x 85 hsa-mir-93* lung diseases x x 85 hsa-mir-26a lung diseases x x 85 hsa-mir-627 lung diseases x x 85 hsa-mir-130b lung diseases x x 85 hsa-mir-874 lung diseases x x 85 hsa-mir-1271 lung diseases x x 85 hsa-mir-181c lung diseases x x 85 hsa-mir-193a-3p lung diseases x x hsa-mir-140-3p lung cancer x hsa-mir-22 lung cancer x hsa-let7d lung cancer x hsa-mir-106b lung cancer x hsa-mir-98 lung cancer x hsa-mir-126 lung cancer x hsa-let7c multiple sclerosis x hsa-mir-233 multiple sclerosis x hsa-mir-106b melanoma x hsa-mir-107 melanoma x hsa-mir-1280 melanoma x hsa-mir-151-3p melanoma x hsa-mir-17* melanoma x hsa-mir-18a melanoma x hsa-mir-199a-5p melanoma x hsa-mir-20a melanoma x hsa-mir-20b melanoma x hsa-mir-30a melanoma x hsa-mir-362-3p melanoma x hsa-mir-550* melanoma x hsa-mir-664 melanoma x - 20 #Samples 46

49 hsa-mir-128 glioblastoma - x hsa-mir-342-3p glioblastoma - x mir-455-3p acute myocardial infarction x mir-10b* acute myocardial infarction x mir-216a acute myocardial infarction x mir-1291 acute myocardial infarction x - 20 All details Publication (pmid) mirna condition Technical Validation Biological Validation #Samples fold change array hsa-let7c multiple sclerosis x hsa-let7d lung cancer x hsa-mir-106b lung cancer x hsa-mir-106b melanoma x hsa-mir-107 melanoma x hsa-mir-10b* Acute Myocardial Inf. x hsa-mir-126 lung diseases x x hsa-mir-126 lung cancer x hsa-mir-1260 lung diseases x x hsa-mir-1271 lung diseases x x hsa-mir-128 glioblastoma - x hsa-mir-1280 melanoma x hsa-mir-1291 Acute Myocardial Inf. x hsa-mir-130b lung diseases x x hsa-mir-140-3p lung cancer x hsa-mir-151-3p melanoma x hsa-mir-17* melanoma x hsa-mir-181c lung diseases x x hsa-mir-183 lung diseases x x hsa-mir-18a melanoma x hsa-mir-193a-3p lung diseases x x hsa-mir-199a-5p melanoma x hsa-mir-20a melanoma x hsa-mir-20b melanoma x hsa-mir-216a Acute Myocardial Inf. x hsa-mir-22 lung cancer x hsa-mir-233 multiple sclerosis x hsa-mir-25 lung diseases x x hsa-mir-26a lung diseases x x hsa-mir-30a melanoma x hsa-mir-324-3p lung diseases x x hsa-mir-328 lung diseases x x hsa-mir-342-3p glioblastoma - x hsa-mir-362-3p melanoma x hsa-mir-363 lung diseases x x hsa-mir-455-3p Acute Myocardial Inf. x hsa-mir-484 lung diseases x x hsa-mir-550* melanoma x hsa-mir-627 lung diseases x x hsa-mir-636 lung diseases x x hsa-mir-664 melanoma x hsa-mir-874 lung diseases x x hsa-mir-92a lung diseases x x hsa-mir-93* lung diseases x x hsa-mir-98 lung cancer x fold change qrt_pcr Correlation

Lung diseases mirna fold change array fold change qrt_pcr hsa-mir-1260 0.9 1.0 hsa-mir-484 0.7 0.7 hsa-mir-92a 0.7 0.7 hsa-mir-183 2.1 1.7 hsa-mir-25 0.6 0.8 hsa-mir-324-3p 0.7 0.8 hsa-mir-126 1.7 1.

50 Lung diseases mirna fold change array fold change qrt_pcr hsa-mir hsa-mir hsa-mir-92a hsa-mir hsa-mir hsa-mir-324-3p hsa-mir hsa-mir hsa-mir hsa-mir hsa-mir-93* hsa-mir-26a hsa-mir hsa-mir-130b hsa-mir hsa-mir hsa-mir-181c hsa-mir-193a-3p

Lung cancer fold change array fold change qrt_pcr mirna hsa-mir-140-3p 1.6 1.6 hsa-mir-22 1.2 1.2 hsa-let7d 0.5 0.4 hsa-mir-106b 0.5 0.5 hsa-mir-98 0.

51 Lung cancer fold change array fold change qrt_pcr mirna hsa-mir-140-3p hsa-mir hsa-let7d hsa-mir-106b hsa-mir hsa-mir Multiple Sclerosis fold change array fold change qrt_pcr mirna let-7c mir

Melanoma mirna fold change array fold change qrt_pcr hsa-mir-106b 0.6 0.9 hsa-mir-107 0.9 0.6 hsa-mir-1280 2.1 2.1 hsa-mir-151-3p 1.5 1.5 hsa-mir-17* 0.7 0.5 hsa-mir-18a 0.4 0.4 hsa-mir-199a-5p 1.9 1.

52 Melanoma mirna fold change array fold change qrt_pcr hsa-mir-106b hsa-mir hsa-mir hsa-mir-151-3p hsa-mir-17* hsa-mir-18a hsa-mir-199a-5p hsa-mir-20a hsa-mir-20b hsa-mir-30a hsa-mir-362-3p hsa-mir-550* hsa-mir Acute myocardial infarction fold change array fold change qrt_pcr mirna mir-455-3p mir-10b* mir-216a mir

mirnas can be generally associated with human pathologies as exemplified for mir-144*

Keller et al. BMC Medicine 2014, 12:224 RESEARCH ARTICLE Open Access mirnas can be generally associated with human pathologies as exemplified for mir-144* Andreas Keller 1*, Petra Leidinger 2, Britta Vogel