HFE haemochromatosis genetic variants have an uncertain clinical penetrance, especially to older ages and in undiagnosed groups. We estimated p.C282Y and p.H63D variant cumulative incidence of multiple clinical outcomes in a large community cohort.

Prospective cohort study.

22 assessment centres across England, Scotland, and Wales in the UK Biobank (2006–2010).

451 270 participants genetically similar to the 1000 Genomes European reference population, with a mean of 13.3-year follow-up through hospital inpatient, cancer registries and death certificate data.

Cox proportional HRs of incident clinical outcomes and mortality in those with HFE p.C282Y/p.H63D mutations compared with those with no variants, stratified by sex and adjusted for age, assessment centre and genetic stratification. Cumulative incidences were estimated from age 40 years to 80 years.

12.1% of p.C282Y+/+ males had baseline (mean age 57 years) haemochromatosis diagnoses, with a cumulative incidence of 56.4% at age 80 years. 33.1% died vs 25.4% without HFE variants (HR 1.29, 95% CI: 1.12 to 1.48, p=4.7x10^-4); 27.9% vs 17.1% had joint replacements, 20.3% vs 8.3% had liver disease, and there were excess delirium, dementia, and Parkinson’s disease but not depression. Associations, including excess mortality, were similar in the group undiagnosed with haemochromatosis. 3.4% of women with p.C282Y+/+ had baseline haemochromatosis diagnoses, with a cumulative incidence of 40.5% at age 80 years. There were excess incident liver disease (8.9% vs 6.8%; HR 1.62, 95% CI: 1.27 to 2.05, p=7.8x10^-5), joint replacements and delirium, with similar results in the undiagnosed. p.C282Y/p.H63D and p.H63D+/+ men or women had no statistically significant excess fatigue or depression at baseline and no excess incident outcomes.

Male and female p.C282Y homozygotes experienced greater excess morbidity than previously documented, including those undiagnosed with haemochromatosis in the community. As haemochromatosis diagnosis rates were low at baseline despite treatment being considered effective, trials of screening to identify people with p.C282Y homozygosity early appear justified.

Current choice models in healthcare (and beyond) can provide suboptimal predictions of healthcare users’ decisions. One reason for such inaccuracy is that standard microeconomic theory assumes that decisions of healthcare users are made in a social vacuum. Healthcare choices, however, can in fact be (entirely) socially determined. To achieve more accurate choice predictions within healthcare and therefore better policy decisions, the social influences that affect healthcare user decision-making need to be identified and explicitly integrated into choice models. The purpose of this study is to develop a socially interdependent choice framework of healthcare user decision-making.

A mixed-methods approach will be used. A systematic literature review will be conducted that identifies the social influences on healthcare user decision-making. Based on the outcomes of a systematic literature review, an interview guide will be developed that assesses which, and how, social influences affect healthcare user decision-making in four different medical fields. This guide will be used during two exploratory focus groups to assess the engagement of participants and clarity of questions and probes. The refined interview guide will be used to conduct the semistructured interviews with healthcare professionals and users. These interviews will explore in detail which, and how, social influences affect healthcare user decision-making. Focus group and interview transcripts will be analysed iteratively using a constant comparative approach based on a mix of inductive and deductive coding. Based on the outcomes, a social influence independent choice framework for healthcare user decision-making will be drafted. Finally, the Delphi technique will be employed to achieve consensus about the final version of this choice framework.

This study was approved by the Erasmus School of Health Policy and Management Research Ethics Review Committee (ESHPM, Rotterdam, The Netherlands; reference ETH2122-0666).