Adjustment for index event bias in genome-wide association studies of subsequent events.

Following numerous genome-wide association studies of disease susceptibility, there is increasing interest in genetic associations with prognosis, survival or other subsequent events. Such associations are vulnerable to index event bias, by which selection of subjects according to disease status creates biased associations if common causes of incidence and prognosis are not accounted for. We propose an adjustment for index event bias using the residuals from the regression of genetic effects on prognosis on genetic effects on incidence. Our approach eliminates this bias when direct genetic effects on incidence and prognosis are independent, and otherwise reduces bias in realistic situations. In a study of idiopathic pulmonary fibrosis, we reverse a paradoxical association of the strong susceptibility gene MUC5B with increased survival, suggesting instead a significant association with decreased survival. In re-analysis of a study of Crohn's disease prognosis, four regions remain associated at genome-wide significance but with increased standard errors

Preliminary Results from Genome-wide Meta-analysis of Survival Time in Idiopathic Pulmonary Fibrosis

Introduction: Idiopathic pulmonary fibrosis (IPF) is a rare lung disease of unknown cause, with few effective treatments available and poor prognosis (median survival time of 3 years). Genome-wide studies have identified variants associated with susceptibility to IPF. Although the effects of those variants on survival time have been investigated, no study has investigated survival time genome-wide for IPF. We set out to identify novel signals of association with IPF survival time and to replicate previous reports that variants in MUC5B that are associated with increased susceptibility to IPF, are paradoxically associated with an increase in survival time. Methods: We performed genome-wide analyses investigating survival time in a UK IPF study and a USA IPF study and meta-analysed the results. Survival analyses were performed on variants with minor allele frequency (MAF)>0.5% in both studies using a Cox Proportional Hazards model. Independent variants meeting meta-analysis P−6 and P Results: A total of 963 individuals and 7,730,466 variants were included in the final meta-analysis with maximum follow-up of 16.5 years. A total of 79 independent signals (11 with MAF>5%) reached the criteria described above. Consistent with previous reports, the allele in rs35705950 in MUC5B that is associated with increased susceptibility to IPF, shows some association with increased survival time (HR=0.73, 95% CI: [0.61, 0.87], P=5.08×10−4). Conclusions: This details the first analysis to investigate survival time genome-wide in IPF.</p

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification. Funding: UK Research and Innovation and National Institute for Health Research