Use of genetic correlations to examine selection bias

Observational studies are rarely representative of their target population, because there are known and unknown factors that affect an individual’s choice to participate (known as the selection mechanism). Selection can cause bias in a given analysis, if the outcome is related to selection (conditional on the other variables in the model). However, the selection mechanism usually cannot be detected from the observed data if we have no data on the non-selected sample - for example, when the selected sample is participants in a research study. Here, we develop methods to examine the selection mechanism by comparing correlations among variables in the selected sample to those expected under no selection. We examine the use of four hypothesis tests to identify induced associations between genetic variants in the selected sample. We evaluate these approaches with Monte Carlo simulations. Finally, these approaches are demonstrated with an applied example, using data from UK Biobank (UKBB), with alcohol intake as exposure to test the presence of selection bias. The proposed tests have identified selection due to alcohol intake into UKBB, and the subsample of individuals with weekly alcohol intake. Analyses in UKBB with alcohol consumption as exposure or outcome may be biased by this selection. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement All authors works in a unit that receives support from the University of Bristol and the UK Medical Research Council (MC UU 00011/1 MC UU 00011/3). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The individual-level data that support the findings of this study are available with the permission of the UK Biobank (). We conducted this study using the UK Biobank resource under an approved data application (ref: 66074).