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1. Adjusting for Principal Components of Molecular Phenotypes Induces Replicating False Positives

Author

Dahl, Andy, Guillemot, Vincent, Mefford, Joel, Aschard, Hugues, and Zaitlen, Noah

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Animals, Genome-Wide Association Study, Humans, Models, Genetic, Phenotype, Principal Component Analysis, Quantitative Trait Loci, Reproducibility of Results, confounder, molecular trait, quantitative trait loci, eigenvector perturbation, Developmental Biology, Biochemistry and cell biology
Abstract

High-throughput measurements of molecular phenotypes provide an unprecedented opportunity to model cellular processes and their impact on disease. These highly structured datasets are usually strongly confounded, creating false positives and reducing power. This has motivated many approaches based on principal components analysis (PCA) to estimate and correct for confounders, which have become indispensable elements of association tests between molecular phenotypes and both genetic and nongenetic factors. Here, we show that these correction approaches induce a bias, and that it persists for large sample sizes and replicates out-of-sample. We prove this theoretically for PCA by deriving an analytic, deterministic, and intuitive bias approximation. We assess other methods with realistic simulations, which show that perturbing any of several basic parameters can cause false positive rate (FPR) inflation. Our experiments show the bias depends on covariate and confounder sparsity, effect sizes, and their correlation. Surprisingly, when the covariate and confounder have [Formula: see text], standard two-step methods all have [Formula: see text]-fold FPR inflation. Our analysis informs best practices for confounder correction in genomic studies, and suggests many false discoveries have been made and replicated in some differential expression analyses.

Published
2019

2. Covariate selection for association screening in multiphenotype genetic studies

Author

Aschard, Hugues, Guillemot, Vincent, Vilhjalmsson, Bjarni, Patel, Chirag J, Skurnik, David, Ye, Chun J, Wolpin, Brian, Kraft, Peter, and Zaitlen, Noah

Subjects
Biological Sciences, Genetics, Algorithms, Genetic Association Studies, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Models, Genetic, Multivariate Analysis, Phenotype, Reproducibility of Results, Sample Size, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Testing for associations in big data faces the problem of multiple comparisons, wherein true signals are difficult to detect on the background of all associations queried. This difficulty is particularly salient in human genetic association studies, in which phenotypic variation is often driven by numerous variants of small effect. The current strategy to improve power to identify these weak associations consists of applying standard marginal statistical approaches and increasing study sample sizes. Although successful, this approach does not leverage the environmental and genetic factors shared among the multiple phenotypes collected in contemporary cohorts. Here we developed covariates for multiphenotype studies (CMS), an approach that improves power when correlated phenotypes are measured on the same samples. Our analyses of real and simulated data provide direct evidence that correlated phenotypes can be used to achieve increases in power to levels often surpassing the power gained by a twofold increase in sample size.

Published
2017

3. Immune response profiling of patients with spondyloarthritis reveals signalling networks mediating TNF-blocker function in vivo

Author

Menegatti, Silvia, Guillemot, Vincent, Latis, Eleonora, Yahia-Cherbal, Hanane, Mittermüller, Daniela, Rouilly, Vincent, Mascia, Elena, Rosine, Nicolas, Koturan, Surya, Millot, Gaël, Leloup, Claire, Duffy, Darragh, Gleizes, Aude, Hacein-Bey-Abina, Salima, The Milieu Interieur, Consortium, Sellam, Jérémie, Berenbaum, Francis, Miceli-Richard, Corinne, Dougados, Maxime, Bianchi, Elisabetta, Rogge, Lars, Immunorégulation - Immunoregulation, Institut Pasteur [Paris], Université Sorbonne Paris Cité (USPC), Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Datactix, Immunologie Translationnelle - Translational Immunology lab, Service de Médecine Interne - Immunologie Clinique [AP-HP Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Institut de Chimie du CNRS (INC)-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de rhumatologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Université Paris Descartes - Paris 5 (UPD5), Service de rhumatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Equipe 2 : ECSTRA - Epidémiologie Clinique, STatistique, pour la Recherche en Santé (CRESS - U1153), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), SM was a scholar of the Pasteur-Paris University (PPU) International PhD programme and supported by a grant from the Fondation pour la Recherche Médicale. EL was supported by a fellowship from the Université Paris Diderot. This study was Institut Pasteur, the French Government’s Investissement d’Avenir Programme, Laboratoire d’Excellence 'Milieu Intérieur' (ANR-10-LABX-69-01), FOREUM Foundation for Research in Rheumatology, the Fondation Arthritis, MSD Avenir (Project iCARE-SpA), a Bourse Passerelle from Pfizer., Milieu Intérieur Consortium: Laurent Abel, Andres Alcover, Hugues Aschard, Kalla Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Ivo Gomperts-Boneca, Milena Hasan, Serge Hercberg, Olivier Lantz, Hugo Mouquet, Etienne Patin, Sandra Pellegrini, Stanislas Pol, Antonio Rausell, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Antoine Toubert, Mathilde Trouvier, Marie-Noëlle Ungeheuer, Darragh Duffy, Matthew L. Albert, Lluis Quintana-Murci., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris] (IP), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), and HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
rheumatoid arthritis, 0301 basic medicine, Chemokine, anti-TNF therapy, [SDV]Life Sciences [q-bio], tumor necrosis factor inhibitors, immune system diseases, Immunology, Inflammation, General Biochemistry, Genetics and Molecular Biology, TNF inhibitors, 03 medical and health sciences, 0302 clinical medicine, Immune system, Rheumatology, Immunity, Spondylarthritis, Spondyloarthritis, Humans, Immunology and Allergy, Medicine, Spondylitis, Ankylosing, 030203 arthritis & rheumatology, Innate immune system, biology, Tumor Necrosis Factor-alpha, business.industry, Interleukin, spondylitis, Chemotaxis, 3. Good health, chronic inflammatory diseases, ankylosing, 030104 developmental biology, biological therapy, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Tumor necrosis factor alpha, medicine.symptom, business
Abstract

ObjectivesAntitumour necrosis factor (TNF) therapy has revolutionised treatment of several chronic inflammatory diseases, including spondyloarthritis (SpA). However, TNF inhibitors (TNFi) are not effective in all patients and the biological basis for treatment failure remains unknown. We have analysed induced immune responses to define the mechanism of action of TNF blockers in SpA and to identify immunological correlates of responsiveness to TNFi.MethodsImmune responses to microbial and pathway-specific stimuli were analysed in peripheral blood samples from 80 patients with axial SpA before and after TNFi treatment, using highly standardised whole-blood stimulation assays. Cytokines and chemokines were measured in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, and gene expression was monitored using nCounter assays.ResultsAnti-TNF therapy induced profound changes in patients’ innate immune responses. TNFi action was selective, and had only minor effects on Th1/Th17 immunity. Modular transcriptional repertoire analysis identified prostaglandin E2 synthesis and signalling, leucocyte recirculation, macrophage polarisation, dectin and interleukin (IL)-1 signalling, as well as the nuclear factor kappa B (NF-kB) transcription factor family as key pathways targeted by TNF blockers in vivo. Analysis of induced immune responses before treatment initiation revealed that expression of molecules associated with leucocyte adhesion and invasion, chemotaxis and IL-1 signalling are correlated with therapeutic responses to anti-TNF.ConclusionsWe show that TNFi target multiple immune cell pathways that cooperate to resolve inflammation. We propose that immune response profiling provides new insight into the biology of TNF-blocker action in patients and can identify signalling pathways associated with therapeutic responses to biological therapies.

Published
2020
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4. High prevalence of small intestine bacteria overgrowth and asymptomatic carriage of enteric pathogens in stunted children in Antananarivo, Madagascar

Author

Collard, Jean-Marc, Andrianonimiadana, Lova, Habib, Azimdine, Rakotondrainipiana, Maheninasy, Andriantsalama, Prisca, Randriamparany, Ravaka, Rabenandrasana, M., Weill, François-Xavier, Sauvonnet, Nathalie, Randremanana, Rindra Vatosoa, Guillemot, Vincent, Vonaesch, Pascale, Sansonetti, Philippe, Bidault, Floran, Unité de Bactériologie Expérimentale [Antananarivo, Madagascar] (IPM), Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Unité d’Épidémiologie et de Recherche clinique [Antananarivo, Madagascar], Bactéries pathogènes entériques (BPE), Institut Pasteur [Paris] (IP), Pathogénie microbienne moléculaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics, This project was funded by the Total and Petram Foundations and by Institut Pasteur. LA, PA and RR wages were supported by the Total Foundation and MR wage by the Petram Foundation. PV was supported by an Early Postdoctoral Fellowship (P2EZP3_152159), an Advanced Postdoctoral Fellowship (P300PA_177876) as well as a Return Grant (P3P3PA_17877) from the Swiss National Science Foundation, a Roux-Cantarini Fellowship (2016), a L'Oréal-UNESCO for Women in Science France Fellowship (2017) and an Excellence Scholarship from the University of Basel (Forschungsfonds, 2019)., We wish to thank all participating families, the AFRIBIOTA Consortium, the participating hospitals in Antananarivo, as well as the Institut Pasteur, the Institut Pasteur de Madagascar, and members of the scientific advisory board for their continuous support, Prof. Jean-Louis Demarquez for training sessions to teach the local health professionals the methods used for duodenal aspirations, Aurélie Etienne for precious help with the clinical procedures and first aspirations performed, the field workers Tseheno Harisoa and Rado Andrianantenaina, as well as all implicated community health workers, for countless hours spent in the field, and the Centre de Recherche Translationelle and the Direction Internationale of the Institut Pasteur, and especially Paméla Palvadeau, Jane Lynda Deuve, Marc Rovatiana Ranarijesy, Kanto Liantsoa Razanakolona, Cécile Artaud, Nathalie Jolly, Sophie Jarrijon, Mamy Ratsialonina, Jean-François Damaras, Marie-Noelle Ungeheuer, and Laurence Arowas for precious help in setting up and steering the AFRIBIOTA project and managing the funds and the biobank. We would like to thank the staff of the 'Plateforme de Microbiologie Mutualisée (P2M)' at Institut Pasteur Paris where the whole genome sequencing was performed, Sophie Lefevre from the Centre National de Référence des Escherichia coli, Shigella et Salmonella in Paris, France for Shigella serotyping, and Claude Parsot and Alexandre Grassart for the interesting discussions on Shigella.

Subjects
Adult, Diarrhea, MESH: Intestine, Small, MESH: Bacterial Infections, MESH: Shigella, MESH: Madagascar, Feces, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, Intestine, Small, Escherichia coli, Madagascar, Prevalence, Humans, Child, MESH: Prevalence, MESH: Humans, Bacteria, MESH: Escherichia coli, digestive, oral, and skin physiology, Public Health, Environmental and Occupational Health, MESH: Feces, MESH: Adult, Bacterial Infections, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Bacteria, MESH: Diarrhea, Infectious Diseases, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Shigella, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract

Environmental Enteric Dysfunction (EED) refers to an incompletely defined syndrome of inflammation, reduced absorptive capacity, and reduced barrier function in the small intestine. It is widespread among children and adults in low- and middle-income countries and is also associated with poor sanitation and certain gut infections possibly resulting in an abnormal gut microbiota, small intestinal bacterial overgrowth (SIBO) and stunting. We investigated bacterial pathogen exposure in stunted and non-stunted children in Antananarivo, Madagascar by collecting fecal samples from 464 children (96 severely stunted, 104 moderately stunted and 264 non-stunted) and the prevalence of SIBO in 109 duodenal aspirates from stunted children (61 from severely stunted and 48 from moderately stunted children). SIBO assessed by both aerobic and anaerobic plating techniques was very high: 85.3% when selecting a threshold of ≥105 CFU/ml of bacteria in the upper intestinal aspirates. Moreover, 58.7% of the children showed more than 106 bacteria/ml in these aspirates. The most prevalent cultivated genera recovered were Streptococcus, Neisseria, Staphylococcus, Rothia, Haemophilus, Pantoea and Branhamella. Feces screening by qPCR showed a high prevalence of bacterial enteropathogens, especially those categorized as being enteroinvasive or causing mucosal disruption, such as Shigella spp., enterotoxigenic Escherichia coli, enteropathogenic E. coli and enteroaggregative E. coli. These pathogens were detected at a similar rate in stunted children and controls, all showing no sign of severe diarrhea the day of inclusion but both living in a highly contaminated environment (slum-dwelling). Interestingly Shigella spp. was the most prevalent enteropathogen found in this study (83.3%) without overrepresentation in stunted children.

Published
2022
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5. Multitrait GWAS to connect disease variants and biological mechanisms

Author

Julienne, Hanna, Laville, Vincent, Mccaw, Zachary, He, Zihuai, Guillemot, Vincent, Lasry, Carla, Ziyatdinov, Andrey, Nerin, Cyril, Vaysse, Amaury, Lechat, Pierre, Ménager, Hervé, Le Goff, Wilfried, Dube, Marie-Pierre, Kraft, Peter, Ionita-Laza, Iuliana, Vilhjálmsson, Bjarni, Aschard, Hugues, Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Harvard T.H. Chan School of Public Health, Stanford University School of Medicine [CA, USA], Stanford University, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Montreal Heart Institute - Institut de Cardiologie de Montréal, Columbia University [New York], Aarhus University [Aarhus], This work has been conducted as part of the INCEPTION program (ANR-16-CONV-0005) (HA). It was also supported by NIH grant R03DE025665 to HA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), Aschard, hugues, and Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs - - INCEPTION2016 - ANR-16-CONV-0005 - CONV - VALID

Subjects
Single Nucleotide Polymorphisms, QH426-470, Biochemistry, [STAT.AP] Statistics [stat]/Applications [stat.AP], Medicine and Health Sciences, Genetics of the Immune System, Cluster Analysis, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], RISK, [STAT.AP]Statistics [stat]/Applications [stat.AP], [STAT.ME] Statistics [stat]/Methodology [stat.ME], Covariance, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, Genomics, Lipids, STATISTICS, Phenotypes, Cholesterol, Phenotype, DENSITY-LIPOPROTEIN CHOLESTEROL, Physical Sciences, [STAT.ME]Statistics [stat]/Methodology [stat.ME], MESH: Computational Biology, TRIGLYCERIDES, Research Article, Immunology, Quantitative Trait Loci, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Phenotype, Polymorphism, Single Nucleotide, ESTER TRANSFER PROTEIN, Genetics, Genome-Wide Association Studies, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, MESH: Humans, CORRELATED TRAITS, MORTALITY, Biology and Life Sciences, Computational Biology, Human Genetics, Random Variables, Genome Analysis, Probability Theory, MESH: Cluster Analysis, MESH: Quantitative Trait Loci, MODEL, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Genome-Wide Association Study, Genetics of Disease, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Clinical Immunology, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Clinical Medicine, Mathematics, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWASs) have uncovered a wealth of associations between common variants and human phenotypes. Here, we present an integrative analysis of GWAS summary statistics from 36 phenotypes to decipher multitrait genetic architecture and its link with biological mechanisms. Our framework incorporates multitrait association mapping along with an investigation of the breakdown of genetic associations into clusters of variants harboring similar multitrait association profiles. Focusing on two subsets of immunity and metabolism phenotypes, we then demonstrate how genetic variants within clusters can be mapped to biological pathways and disease mechanisms. Finally, for the metabolism set, we investigate the link between gene cluster assignment and the success of drug targets in randomized controlled trials., Author summary Genome-wide association studies (GWAS) established numerous associations between genetic variants and human traits. The anonymized summary of GWAS results is generally made publicly available to the scientific community and can be explored further. Amongst the many possible secondary analyses, one is to study the effect of a genetic variant on several traits (multi-trait GWAS) rather than a unique trait. We compared several tests to conduct multi-trait GWAS on simulated and real data. We detected 322 new associations that were not previously reported by standard univariate GWAS. We then detected clusters of genetic variants having a similar effect across several traits. Focusing on two subsets of immunity and metabolism traits, we demonstrate how genetic variants within clusters can be mapped to biological pathways and disease mechanisms. Finally, for the metabolism set, we investigate the link between gene cluster and success of drug targets in randomized controlled trials. We propose this method for improving the functional interpretation of GWAS results.

Published
2021
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