A Comparison of Sample Size and Power in Case-Only Association Studies of Gene-Environment Interaction

Assuming continuous, normally distributed environmental and categorical genotype variables, the authors compare 6 case-only designs for tests of association in gene-environment interaction. Novel tests modeling the environmental variable as either the response or the predictor and allowing a genetic variable with multiallelic variants are included. The authors show that tests imposing the same genotypic pattern of inheritance perform similarly regardless of whether genotype is the response variable or the predictor variable. The novel tests using the genetic variable as the response variable are advantageous because they are robust to non-normally distributed environmental exposures. Dominance deviance—deviation from additivity in the main or interaction effects—is key to test performance: When it is zero or modest, tests searching for a trend with increasing risk alleles are optimal; when it is large, tests for genotypic effects are optimal. However, the authors show that dominance deviance is attenuated when it is observed at a proxy locus, which is common in genome-wide association studies, so large dominance deviance is likely to be rare. The authors conclude that the trend test is the appropriate tool for large-scale association scans where the true gene-environment interaction model is unknown. The common practice of assuming a dominant pattern of inheritance can cause serious losses of power in the presence of any recessive, or modest dominant, effects

Investigating Impacts of Health Policies Using Staggered Difference-in-Differences: The Effects of Adoption of an Online Consultation System on Prescribing Patterns of Antibiotics

We use a recently proposed staggered difference-in-differences approach to investigate effects of adoption of an online consultation system in English general practice on antibiotic prescribing patterns. The target estimand is the average effect for each group of practices (defined by year of adoption) in each year, which we aggregate across all adopting practices, by group, and by time since adoption. We find strong evidence of a positive effect of adoption on antibiotic prescribing rates, though the magnitude of effect is relatively small. As time since adoption increases, the effect size increases, while effects vary across groups

SCOPA and META-SCOPA: software for the analysis and aggregation of genome-wide association studies of multiple correlated phenotypes

Abstract Background: Genome-wide association studies (GWAS) of single nucleotide polymorphisms (SNPs) have been successful in identifying loci contributing genetic effects to a wide range of complex human diseases and quantitative traits. The traditional approach to GWAS analysis is to consider each phenotype separately, despite the fact that many diseases and quantitative traits are correlated with each other, and often measured in the same sample of individuals. Multivariate analyses of correlated phenotypes have been demonstrated, by simulation, to increase power to detect association with SNPs, and thus may enable improved detection of novel loci contributing to diseases and quantitative traits

Consultation Rate and Mode by Deprivation in English General Practice From 2018 to 2022: Population-Based Study

BACKGROUND: The COVID-19 pandemic has had a significant impact on primary care service delivery with an increased use of remote consultations. With general practice delivering record numbers of appointments and rising concerns around access, funding, and staffing in the UK National Health Service, we assessed contemporary trends in consultation rate and modes (ie, face-to-face versus remote). OBJECTIVE: This paper describes trends in consultation rates in general practice in England for key demographics before and during the COVID-19 pandemic. We explore the use of remote and face-to-face consultations with regard to socioeconomic deprivation to understand the possible effect of changes in consultation modes on health inequalities. METHODS: We did a retrospective analysis of 9,429,919 consultations by general practitioners, nurses, or other health care professionals between March 2018 and February 2022 for patients registered at 397 general practices in England. We used routine electronic health records from Clinical Practice Research Datalink Aurum with linkage to national data sets. Negative binomial models were used to predict consultation rates and modes (ie, remote versus face-to-face) by age, sex, and socioeconomic deprivation over time. RESULTS: Overall consultation rates increased by 15% from 4.92 in 2018-2019 to 5.66 in 2021-2022 with some fluctuation during the start of the COVID-19 pandemic. The breakdown into face-to-face and remote consultations shows that the pandemic precipitated a rapid increase in remote consultations across all groups, but the extent varies by age. Consultation rates increased with increasing levels of deprivation. Socioeconomic differences in consultation rates, adjusted for sex and age, halved during the pandemic (from 0.36 to 0.18, indicating more consultations in the most deprived), effectively narrowing relative differences between deprivation quintiles. This trend remains when stratified by sex, but the difference across deprivation quintiles is smaller for men. The most deprived saw a relatively larger increase in remote and decrease in face-to-face consultation rates compared to the least deprived. CONCLUSIONS: The substantial increases in consultation rates observed in this study imply an increased pressure on general practice. The narrowing of consultation rates between deprivation quintiles is cause for concern, given ample evidence that health needs are greater in more deprived areas

Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study

Background: Human genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms—many related to the structure or function of red blood cells—and risk for severe Plasmodium falciparum malaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respiratory distress. Methods: We did a case-control study in Kilifi County, Kenya. We recruited as cases children presenting with severe malaria to the high-dependency ward of Kilifi County Hospital. We included as controls infants born in the local community between Aug 1, 2006, and Sept 30, 2010, who were part of a genetics study. We tested for associations between a range of candidate malaria-protective genes and risk for severe malaria and its specific phenotypes. We used a permutation approach to account for multiple comparisons between polymorphisms and severe malaria. We judged p values less than 0·005 significant for the primary analysis of the association between candidate genes and severe malaria. Findings: Between June 11, 1995, and June 12, 2008, 2244 children with severe malaria were recruited to the study, and 3949 infants were included as controls. Overall, 263 (12%) of 2244 children with severe malaria died in hospital, including 196 (16%) of 1233 with cerebral malaria. We investigated 121 polymorphisms in 70 candidate severe malaria-associated genes. We found significant associations between risk for severe malaria overall and polymorphisms in 15 genes or locations, of which most were related to red blood cells: ABO, ATP2B4, ARL14, CD40LG, FREM3, INPP4B, G6PD, HBA (both HBA1 and HBA2), HBB, IL10, LPHN2 (also known as ADGRL2), LOC727982, RPS6KL1, CAND1, and GNAS. Combined, these genetic associations accounted for 5·2% of the variance in risk for developing severe malaria among individuals in the general population. We confirmed established associations between severe malaria and sickle-cell trait (odds ratio [OR] 0·15, 95% CI 0·11–0·20; p=2·61 × 10−58), blood group O (0·74, 0·66–0·82; p=6·26 × 10−8), and –α3·7-thalassaemia (0·83, 0·76–0·90; p=2·06 × 10−6). We also found strong associations between overall risk of severe malaria and polymorphisms in both ATP2B4 (OR 0·76, 95% CI 0·63–0·92; p=0·001) and FREM3 (0·64, 0·53–0·79; p=3·18 × 10−14). The association with FREM3 could be accounted for by linkage disequilibrium with a complex structural mutation within the glycophorin gene region (comprising GYPA, GYPB, and GYPE) that encodes for the rare Dantu blood group antigen. Heterozygosity for Dantu was associated with risk for severe malaria (OR 0·57, 95% CI 0·49–0·68; p=3·22 × 10−11), as was homozygosity (0·26, 0·11–0·62; p=0·002). Interpretation: Both ATP2B4 and the Dantu blood group antigen are associated with the structure and function of red blood cells. ATP2B4 codes for plasma membrane calcium-transporting ATPase 4 (the major calcium pump on red blood cells) and the glycophorins are ligands for parasites to invade red blood cells. Future work should aim at uncovering the mechanisms by which these polymorphisms can result in severe malaria protection and investigate the implications of these associations for wider health. Funding: Wellcome Trust, UK Medical Research Council, European Union, and Foundation for the National Institutes of Health as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative

"I try and smile, I try and be cheery, I try not to be pushy. I try to say ‘I’m here for help’ but I leave feeling… worried’’: A qualitative study of perceptions of interactions with health professionals by community-based older adults with chronic pain

Background: Over 50% of community-dwelling older adults experience chronic pain, which threatens their quality of life. Of importance to their pain management is older people’s interaction with health professionals that, if unsatisfactory, may impair the outcome. Aims: To add to the limited research specific to older people living with chronic pain in the community, we explored how they perceive their experiences of interacting with health professionals, seeking factors that might optimise these interactions. Methods: Purposive sampling was used to recruit men and women .65 years with self-reported musculoskeletal chronic pain. Qualitative individual interviews and one group interview were undertaken with 23 participants. Data were transcribed verbatim and underwent Framework Analysis. Results: Three themes were identified. Seeking help illustrates issues around why older people in the community may or may not seek help for chronic pain, and highlights the potential involvement of social comparison. Importance of diagnosis illustrates the desire for professional validation of their condition and an aversion to vague explanations based on the person’s age. Being listened to and being heard illustrates the importance of empathic communication and understanding expectations, with due respect for the person’s age. Conclusions: In common with people of all ages, an effective partnership between an older person in pain and health professionals is essential if pain is to be reported, appropriately assessed and managed, because of the subjective nature of pain and its treatment responses. For older people with pain, perception about their age, by both parties in the partnership, is an additional factor that can unnecessarily interfere with the effectiveness of this partnership. Health professionals should engage with older adults to clarify their expectations about pain and its management, which may be influenced by perceptions about age; and to encourage expression of their concerns, which may also be affected by perceptions about age

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Gene-Lifestyle Interaction and Type 2 Diabetes: The EPIC InterAct Case-Cohort Study

Background: Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention. Methods and Findings: The InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a cohort of 340,234 European participants with 3.99 million person-years of follow-up. We studied the combined effects of an additive genetic T2D risk score and modifiable and non-modifiable risk factors using Prentice-weighted Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly greater in younger individuals (p for interaction = 1.20x10(-4)). Relative genetic risk (per standard deviation [4.4 risk alleles]) was also larger in participants who were leaner, both in terms of body mass index (p for interaction = 1.50x10(-3)) and waist circumference (p for interaction = 7.49x10(-9)). Examination of absolute risks by strata showed the importance of obesity for T2D risk. The 10-y cumulative incidence of T2D rose from 0.25% to 0.89% across extreme quartiles of the genetic score in normal weight individuals, compared to 4.22% to 7.99% in obese individuals. We detected no significant interactions between the genetic score and sex, diabetes family history, physical activity, or dietary habits assessed by a Mediterranean diet score. Conclusions: The relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this subgroup is at low absolute risk and would not be a logical target for preventive interventions. The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention