Reducing the Probability of False Positive Research Findings by Pre-Publication Validation - Experience with a Large Multiple Sclerosis Database

*Objective*
We have assessed the utility of a pre-publication validation policy in reducing the probability of publishing false positive research findings. 
*Study design and setting*
The large database of the Sylvia Lawry Centre for Multiple Sclerosis Research was split in two parts: one for hypothesis generation and a validation part for confirmation of selected results. We present case studies from 5 finalized projects that have used the validation policy and results from a simulation study.
*Results*
In one project, the "relapse and disability" project as described in section II (example 3), findings could not be confirmed in the validation part of the database. The simulation study showed that the percentage of false positive findings can exceed 20% depending on variable selection. 
*Conclusion*
We conclude that the validation policy has prevented the publication of at least one research finding that could not be validated in an independent data set (and probably would have been a "true" false-positive finding) over the past three years, and has led to improved data analysis, statistical programming, and selection of hypotheses. The advantages outweigh the lost statistical power inherent in the process

Polymorphisms in genes of melatonin biosynthesis and signaling support the light-at-night hypothesis for breast cancer.

Acknowledgements: We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. ABCFS thank Maggie Angelakos, Judi Maskiell, Gillian Dite. ESTHER thanks Hartwig Ziegler, Sonja Wolf, Volker Hermann, Christa Stegmaier, Katja Butterbach. GENICA thanks Christian Baisch, Hans-Peter Fischer, Anne Lotz, and Beate Pesch. KARMA and SASBAC thank the Swedish Medical Research Counsel. MARIE thanks Petra Seibold, Sabine Behrens, Ursula Eilber and Muhabbet Celik. MTLGEBCS would like to thank Martine Tranchant (CHU de Québec – Université Laval Research Center), Marie-France Valois, Annie Turgeon and Lea Heguy (McGill University Health Center, Royal Victoria Hospital; McGill University) for DNA extraction, sample management and skilful technical assistance. J.S. is Chair holder of the Canada Research Chair in Oncogenetics. NBHS thanks study participants and research staff for their contributions and commitment to the study. The OFBCR thanks Teresa Selander, Nayana Weerasooriya and Steve Gallinger. PBCS thanks Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, Michael Stagner. SBCS thanks Sue Higham, Helen Cramp, Dan Connley, Ian Brock, Sabapathy Balasubramanian and Malcolm W.R. Reed. We thank the SEARCH team.Funder: Genome Canada; doi: http://dx.doi.org/10.13039/100008762Funder: Canadian Institutes of Health Research; doi: http://dx.doi.org/10.13039/501100000024Funder: Ministère de l’Économie et de l'Innovation du QuébecFunder: Government of Canada; doi: http://dx.doi.org/10.13039/501100000023Funder: Génome Québec; doi: http://dx.doi.org/10.13039/100013062Funder: Fondation du cancer du sein du Québec; doi: http://dx.doi.org/10.13039/100016328Funder: Confluence project by National Cancer Institute Intramural Research Program, National Institutes of HealthFunder: Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast CancerFunder: Susan G. Komen for the Cure; doi: http://dx.doi.org/10.13039/100000869Funder: Breast Cancer Research FoundationFunder: Ovarian Cancer Research Fund; doi: http://dx.doi.org/10.13039/100001282Funder: National Health and Medical Research Council of AustraliaFunder: Cancer Council NSW; doi: http://dx.doi.org/10.13039/501100001102Funder: Victorian Health Promotion Foundation (Australia)Funder: Victorian Breast Cancer Research ConsortiumFunder: National Health and Medical Research CouncilFunder: Fondation de France; doi: http://dx.doi.org/10.13039/501100004431Funder: Institut National du Cancer (INCa)Funder: Ligue Nationale contre le CancerFunder: Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail; doi: http://dx.doi.org/10.13039/501100007546Funder: Agence Nationale de la RechercheFunder: Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg; doi: http://dx.doi.org/10.13039/501100003542Funder: Robert Bosch Stiftung; doi: http://dx.doi.org/10.13039/501100001646Funder: Deutsches Krebsforschungszentrum; doi: http://dx.doi.org/10.13039/100008658Funder: Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA)Funder: Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Bonn, GermanyFunder: Märit and Hans Rausings Initiative Against Breast CancerFunder: Hamburger Krebsgesellschaft; doi: http://dx.doi.org/10.13039/100018515Funder: Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USAFunder: Agency for Science, Technology and Research of SingaporeFunder: US National Institute of HealthFunder: Susan G. Komen; doi: http://dx.doi.org/10.13039/100009634Funder: Sheffield Experimental Cancer Medicine CentreFunder: Breast Cancer Now Tissue BankFunder: UK National Institute for Health Research Biomedical Research Centre at the University of CambridgeFunder: NHS in the East of England through the Clinical Academic ReserveFunder: Ruhr-Universität Bochum (1007)Light-at-night triggers the decline of pineal gland melatonin biosynthesis and secretion and is an IARC-classified probable breast-cancer risk factor. We applied a large-scale molecular epidemiology approach to shed light on the putative role of melatonin in breast cancer. We investigated associations between breast-cancer risk and polymorphisms at genes of melatonin biosynthesis/signaling using a study population of 44,405 women from the Breast Cancer Association Consortium (22,992 cases, 21,413 population-based controls). Genotype data of 97 candidate single nucleotide polymorphisms (SNPs) at 18 defined gene regions were investigated for breast-cancer risk effects. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CI) by logistic regression for the main-effect analysis as well as stratified analyses by estrogen- and progesterone-receptor (ER, PR) status. SNP-SNP interactions were analyzed via a two-step procedure based on logic regression. The Bayesian false-discovery probability (BFDP) was used for all analyses to account for multiple testing. Noteworthy associations (BFDP < 0.8) included 10 linked SNPs in tryptophan hydroxylase 2 (TPH2) (e.g. rs1386492: OR = 1.07, 95% CI 1.02-1.12), and a SNP in the mitogen-activated protein kinase 8 (MAPK8) (rs10857561: OR = 1.11, 95% CI 1.04-1.18). The SNP-SNP interaction analysis revealed noteworthy interaction terms with TPH2- and MAPK-related SNPs (e.g. rs1386483R ∧ rs1473473D ∧ rs3729931D: OR = 1.20, 95% CI 1.09-1.32). In line with the light-at-night hypothesis that links shift work with elevated breast-cancer risks our results point to SNPs in TPH2 and MAPK-genes that may impact the intricate network of circadian regulation