Learning from our GWAS mistakes: from experimental design to scientific method

Abstract

Many public and private genome-wide association studies that we have analyzed include flaws in design, with avoidable confounding appearing as a norm rather than the exception. Rather than recognizing flawed research design and addressing that, a category of quality-control statistical methods has arisen to treat only the symptoms. Reflecting more deeply, we examine elements of current genomic research in light of the traditional scientific method and find that hypotheses are often detached from data collection, experimental design, and causal theories. Association studies independent of causal theories, along with multiple testing errors, too often drive health care and public policy decisions. In an era of large-scale biological research, we ask questions about the role of statistical analyses in advancing coherent theories of diseases and their mechanisms. We advocate for reinterpretation of the scientific method in the context of large-scale data analysis opportunities and for renewed appreciation of falsifiable hypotheses, so that we can learn more from our best mistakes.