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Equity in cancer genomics in the UK: a cross-sectional analysis of a national cancer cohort.
Get PDFBACKGROUND: Most research on genetic screening and precision oncology is based on individuals of European ancestry. We applied the National Health Service (NHS) England's cancer variant prioritisation workflow to evaluate the performance of these approaches in ethinically and ancestrally diverse populations. The second aim of the study was to assess the representativeness of the 100 000 Genomes Project cancer cohort of the population of England. METHODS: In this cross-sectional analysis, whole-genome sequencing data from patients with cancer recruited into the 100 000 Genomes Project between February 2015 to December 2018 were analysed. Clinical information, including tumour stage and grade, was gathered from the NHS England National Cancer Registration and Analysis Service. Patients with cancer types with fewer than five individuals, haematological cancers, childhood cancers, unknown primary carcinomas, patients with indeterminate sex, and patients missing somatic mutations in genes were excluded. To assess ethnicity representation in the 100 000 Genomes Project, we calculated the recruitment ratios for self-reported ethnicities for patients with cancer recruited to the 100 000 Genomes Project and patients with cancer in England. We also analysed differences in classification rates for potentially pathogenic variants to assess ancestry-related differences in germline and somatic mutations of different ancestry groups. FINDINGS: 14 775 patients with cancer were recruited between February, 2015, and December, 2018, into the 100 000 Genomes Project. There was no evidence of under-representation of diverse ethnic groups in the 100 000 Genomes Project when compared with the national statistics. The recruitment rate ratio for breast cancer was 2·2 (95% CI 1·6-3·0) for Black versus White women in the 100 000 Genomes Project compared with 0·81 (0·79-0·83) for Black versus White women in the national data (fold-change in rate ratios 2·7; 95% CI 2·0-3·7, p<0·0001), suggesting higher representation of Black women in the 100 000 Genomes Project than expected given the ethnicity-specific incidence rates in England. Compared with national rates, the 100 000 Genomes Project also had higher recruitment rates of Black versus White men with prostate cancer (fold-change in rate ratios 3·7; 1·8-7·5, p=0·0004), Black versus White men with bladder cancer (fold change in rate ratios 6·1; 2·0-18·8, p=0·0016), and Asian versus White women with breast cancer (fold change in rate ratios 1·4; 1·2-1·7, p=0·0008). Ancestry had a significant association with the likelihood of carrying a variant classified as a potentially pathogenic (likelihood ratio test p=0·0011). Potentially pathogenic variants were identified in 23 (4·6%) of 500 South Asian (adjusted model odds ratio [OR] 1·88, 95% CI 1·21-2·93, p=0·0052) and 24 (5·3%) of 453 African ancestry patients (OR 2·24, 1·44-3·48, p=0·0003) compared with 263 (2·2%) of 11 955 in European-ancestry patients. However, we found that fewer tumour mutations in actionable genes were identified for patients of non-European ancestry compared with patients of European ancestry when adjusting for sex and cancer type (likelihood ratio test p<0·0001). INTERPRETATION: The was an excess of germline variants classified as potentially pathogenic variants in patients with non-European ancestry, which might impede the diagnostic process. Improved variant prioritisation workflows and more research in diverse groups are needed to ensure equitable implementation of genomics in cancer care. FUNDING: The UK Department of Health and Social Care and the EU's Horizon 2020 Research and Innovation Programme
24-week, all-oral regimens for pulmonary rifampicin-resistant tuberculosis in TB-PRACTECAL trial sites: an economic evaluation.
Get PDFBACKGROUND: New 6-month rifampicin-resistant tuberculosis treatment regimens containing bedaquiline, pretomanid, and linezolid (BPaL) with or without moxifloxacin or clofazimine, could improve treatment efficacy, safety, and tolerability, and free up resources within the health system. Following a change to WHO rifampicin-resistant tuberculosis treatment guidelines, countries are facing difficult decisions about when and how to incorporate new drug regimens into national guidelines. We aimed to assess the probability of BPaL-based regimens being cost-saving using data collected in the TB-PRACTECAL trial. METHODS: This economic evaluation using a cost-utility analysis was embedded in five TB-PRACTECAL trial sites in Belarus, Uzbekistan, and South Africa. Between Nov 19, 2020, and Sept 27, 2022, we collected detailed primary unit cost data in six hospitals and four ambulatory health facilities and collected data on patient-incurred costs from 73 trial participants. The primary efficacy endpoint of the main trial, a composite of unfavourable outcomes (death, disease recurrence, treatment failure, early discontinuation of therapy, withdrawal, or loss to follow-up) and clinically important safety outcomes by 72 weeks of follow-up were incorporated into the analysis. Societal perspective cost data and effect outcome data were input into a Markov model to estimate the cost per disability-adjusted life-year (DALY) averted by BPaL-based regimens compared with the standard of care over a 20-year time horizon. We conducted a range of univariate and probabilistic sensitivity analyses to test our findings. FINDINGS: BPaL-based regimens averted a mean of 1·28 DALYs and saved a mean of US172 (SD 0·84) in BPaL-based regimen groups compared with standard of care. The main cost drivers for both providers and patients were inpatient bed-days; the duration of the inpatient period varied across countries. Varying a range of model parameters affected the degree of cost savings but did not change the finding that BPaL-based regimens are cost-saving compared with standard of care. INTERPRETATION: This trial-based evidence adds to consistent indications from modelling studies that BPaL-based regimens are cost-saving for both the patient and health system. Urgent implementation of BPaL-based regimens in countries with a high burden of tuberculosis could improve treatment of rifampicin-resistant tuberculosis, reduce pill burden, and free up desperately needed resources within the health system. FUNDING: Médecins Sans Frontières
Local authorities need tailored research ethics processes to support research capacity building
Get PDFBackground: Local authorities (LAs) are increasingly aiming to become more research active. Research ethics review is an important prerequisite of high-quality research. It is not clear what a LA ethics review process can (or should) look like, or whether it is needed in addition to external review processes. We aim to describe the scope and purpose of research ethics processes in LAs across England, and factors that are salient to their design. Study design: Qualitative interview study. Methods: Staff from 15 LAs in England were recruited to describe their research ethics process using purposeful and snowball sampling. One-hour interviews were conducted using a topic guide with five scenarios, drawn from LA projects. Interview transcripts were thematically analysed using a consensus building process among the research team. Results: Factors salient to the design of research ethics processes in LAs included: definitions of research, research ownership, and the distinct relationship LAs have with research participants. A typology with four models is used to describe existing processes. These models are: No Process; The Assurance Model (where LAs assure an external ethics committee has reviewed projects); The Advice Model (where there is no formal review, but ethical considerations are made through formal and informal advice); and The Review Model (where LAs establish their own formal internal ethics committees). These typologies emerged from divergent understandings of the role of research in LAs and can reflect varied views of research as an activity “done to a local authority”, “done with a local authority” or “owned by a local authority”. Discussion: Research ethics processes in LAs need to reflect various LA approaches to what constitutes research, who owns the research process, and how a LAs relationship with research participants may vary from other settings. As LAs continue articulating what research means in their setting, they need support and guidance to establish research ethics processes that enable research activity, while simultaneously being sensitive to the level of research readiness and distinct LA need
Analyzing Coarsened and Missing Data by Imputation Methods.
Get PDFIn various missing data problems, values are not entirely missing, but are coarsened. For coarsened observations, instead of observing the true value, a subset of values - strictly smaller than the full sample space of the variable - is observed to which the true value belongs. In our motivating example for patients with endometrial carcinoma, the degree of lymphovascular space invasion (LVSI) can be either absent, focally present, or substantially present. For a subset of individuals, however, LVSI is reported as being present, which includes both non-absent options. In the analysis of such a dataset, difficulties arise when coarsened observations are to be used in an imputation procedure. To our knowledge, no clear-cut method has been described in the literature on how to handle an observed subset of values, and treating them as entirely missing could lead to biased estimates. Therefore, in this paper, we evaluated the best strategy to deal with coarsened and missing data in multiple imputation. We tested a number of plausible ad hoc approaches, possibly already in use by statisticians. Additionally, we propose a principled approach to this problem, consisting of an adaptation of the SMC-FCS algorithm (SMC-FCS CoCo : Coarsening compatible), that ensures that imputed values adhere to the coarsening information. These methods were compared in a simulation study. This comparison shows that methods that prevent imputations of incompatible values, like the SMC-FCS CoCo method, perform consistently better in terms of a lower bias and RMSE, and achieve better coverage than methods that ignore coarsening or handle it in a more naïve way. The analysis of the motivating example shows that the way the coarsening information is handled can matter substantially, leading to different conclusions across methods. Overall, our proposed SMC-FCS CoCo method outperforms other methods in handling coarsened data, requires limited additional computation cost and is easily extendable to other scenarios
Medical therapy and outcomes in REVIVED-BCIS2 and STICHES: an individual patient data analysis.
Get PDFBACKGROUND AND AIMS: In the Surgical Treatment for Ischaemic Heart Failure Trial Extension Study (STICHES), coronary artery bypass grafting (CABG) improved outcomes of patients with ischaemic left ventricular dysfunction receiving medical therapy, whereas in the Revascularization for Ischaemia Ventricular Dysfunction trial (REVIVED-BCIS2), percutaneous coronary intervention (PCI) did not. The aim of this study was to explore differences in outcomes of participants treated with medical therapy alone in STICHES vs. REVIVED-BCIS2 and to assess the incremental benefit of CABG or PCI. METHODS: Pooled analysis of adjusted individual participant data from two multicentre randomized trials. All patients had left ventricular ejection fraction ≤35% and coronary artery disease and received medical therapy. Participants were randomized 1:1 to CABG (STICHES) or PCI (REVIVED-BCIS2). The primary outcome was the composite of all-cause death and hospitalization for heart failure over all available follow-up. RESULTS: A total of 1912 participants (88% male, 76% white ethnicity) were included with 98.3% completeness of follow-up for the primary outcome. The median follow-up was 118 months in STICHES and 41 months in REVIVED-BCIS2. Those receiving medical therapy alone in REVIVED-BCIS2 had fewer primary outcome events than those receiving medical therapy alone in STICHES (adjusted hazard ratio 0.60, 95% confidence interval 0.48-0.74, P < .001). Patients receiving PCI in REVIVED-BCIS2 were less likely to experience a primary outcome event than those receiving CABG in STICHES. Adjusted outcomes of patients treated with CABG in STICHES were worse than those receiving medical therapy alone in REVIVED-BCIS2. CONCLUSIONS: Patients with ischaemic cardiomyopathy receiving medical therapy in REVIVED-BCIS2 had better outcomes than those in STICHES, with or without CABG surgery. Further trials comparing CABG, PCI, and medical therapy in this population are warranted
Longitudinal leucocyte DNA methylation changes in Mesoamerican nephropathy.
Get PDFMesoamerican nephropathy (MeN) is a leading cause of morbidity and mortality in Central America, yet its aetiology remains unclear. Environmental exposures including heat stress, pesticides, and heavy metals have all been suggested as possible causes or exacerbating factors of the disease, but intermittent and cumulative exposures are difficult to capture using conventional biomonitoring. Locus-specific differential DNA-methylation (DNAm) which is known to occur in association with these environmental exposures can be readily measured in peripheral blood leucocytes, and therefore have the potential to be used as biomarkers of these exposures. In this study, we aimed first to perform a hypothesis-free epigenome-wide association study of MeN to identify disease-specific methylation signatures, and second to explore the association of DNAm changes associated with potentially relevant environmental exposures and MeN onset. Whole-blood epigenome-wide DNAm was analysed from a total of 312 blood samples: 53 incident cases (pre- and post-evidence of disease onset), 61 matched controls and 16 established cases, collected over a 5-year period. Mixed-effect models identified three unique differentially methylated regions that associated with incident kidney injury, two of which lie within the intron of genes (Amphiphysin on chromosome 7, and SLC29A3 chromosome 10), none of which have been previously reported with any other kidney disease. Next, we conducted a hypothesis-driven analysis examining the coefficients of CpG sites reported to be associated with ambient temperature, pesticides, arsenic, cadmium, and chromium. However, none showed an association with MeN disease onset. Therefore, we did not observe previously reported patterns of DNA methylation that might support a role of pesticides, temperature, or the examined metals in causing MeN
Assessment of Relative Contributions of Lifestyle, Behavioral and Biological Risk Factors for Cervical Human Papillomavirus Infections in Female Sex Workers
No full textThis study aimed to identify and quantify the relative and collective contributions of lifestyle, behavioral, and biological risk factors to cervical HPV infections among female sex workers (FSWs) in Ibadan, Nigeria. This cross-sectional study was part of the Sexual Behavior and HPV Infections in Nigerians in Ibadan project and involved 182 FSWs for whom complete data on HPV genotypes were available. Quantile-based g-computation was employed to assess the relative and collective contributions of risk factors to any cervical HPV/hrHPV infections and multiple cervical HPV/hrHPV. The collective contribution of all selected risk factors to multiple high-risk cervical HPV was 2.47 (95% CI: 0.97–3.23). The number of other anatomic sites with HPV infections showed the highest positive relative contribution to multiple cervical HPV/hrHPV. Alcohol consumption and the total number of sexual partners contributed to high-risk cervical HPV and multiple cervical HPV/hrHPV, while age at first vaginal sex had a negative relative contribution. This study highlights the significant contribution of HPV infections in multiple anatomic sites as a risk to the acquisition of cervical HPV in FSWs. Routine screening protocols should be enhanced to include multiple anatomic sites, and targeted educational programs are recommended to address the specific risks faced by FSWs
The Burden of Poor Reproductive Health in England: Results From a Cross-Sectional Survey.
Get PDFOBJECTIVE: To quantify the burden of poor reproductive health in England by age, ethnicity, and financial security. DESIGN: Cross-sectional survey. SETTING: England. SAMPLE: 59 332 women and people assigned female at birth aged 16-55 years. METHODS: The Reproductive Health Survey for England 2023 (RHSE2023) used an online convenience sampling strategy and a self-completion questionnaire. MAIN OUTCOME MEASURES: 13 indicators of reproductive health organised into three domains: reproductive morbidities (including endometriosis, fibroids); menstrual health (severely painful and/or heavy periods; menopausal symptoms); and pregnancy-related adverse experiences (pregnancy loss, infertility, unplanned pregnancy) in the last year. RESULTS: Compared to the general population, our sample over-represented those with higher education levels and under-represented minority ethnic groups. 28.0% of participants reported at least one reproductive morbidity; 61.9% reported menstrual-related issue(s); and 5.5% reported pregnancy-related adverse experience(s) in the last year, with considerable variation by age. Compiling the three domains, 73.7% reported at least one indicator of poor reproductive health. Inequalities were observed: Black British, Caribbean, and African women had increased odds of reporting reproductive morbidity (aOR: 1.69); heavy and/or severely painful periods (aOR: 1.28); and pregnancy-related adverse experience (aOR: 1.50). Financial insecurity was also associated with poor reproductive health. CONCLUSIONS: As the first study to simultaneously examine this broad range of indicators of reproductive health within a single sample, we highlight the substantial burden of poor reproductive health in England, with evident ethnic and financial inequalities
Uncovering the viral aetiology of undiagnosed acute febrile illness in Uganda using metagenomic sequencing.
Get PDFViruses associated with acute febrile illness in Africa cause a spectrum of clinical disease from mild to life-threatening. Routine diagnostic methods are insufficient to identify all viral pathogens in this region. In this study, 1281 febrile Ugandan patients were prospectively recruited as part of the CDC-UVRI Acute Febrile Illness Study and pre-screened for common pathogens. 210/1281 undiagnosed samples, and 20 additional samples from viral outbreaks were subjected to metagenomic sequencing. Viral pathogens were identified in 44/230 (19%), including respiratory, hepatitis, blood-borne, gastrointestinal and vector-borne viruses. Importantly, one case of Crimean-Congo haemorrhagic fever and two cases each of Rift Valley fever, dengue and yellow fever were detected in 7/230 (3%) of cases. Le Dantec virus, last reported in 1969, was also identified in one patient. The presence of high-consequence and (re-)emerging viruses of public health concern highlights the need for enhanced population-based diagnostic surveillance in the African region
School Meals Case Study: Morocco [Étude de cas sur l’alimentation scolaire: Maroc]
Get PDFCette étude de cas sur les repas scolaires fait partie d'une collection dirigée par la Communauté de Pratique « Bonnes Pratiques » du Consortium de Recherche pour la Santé et la Nutrition Scolaires. L’Étude de Cas sur l’alimentation scolaire au Maroc a pour objectif de documenter l'organisation, le financement et le suivi du programme national de repas scolaires à travers le pays. Les objectifs de cette étude de cas incluent la présentation d'une introduction au profil du pays, l'exposition de la conception et de la mise en œuvre des programmes de repas scolaires, la description de leurs processus de suivi et d'évaluation, ainsi que la mise en lumière des leçons apprises, des meilleures pratiques et des défis rencontrés. Cette étude de cas est rédigée sous forme de document de travail et peut être mise à jour pour refléter l'évolution des circonstances. La Communauté de Pratique « Bonnes Pratiques » soutient la production de preuves du Consortium de Recherche pour la Santé et la Nutrition Scolaires, la branche dédiée à la recherche de la Coalition pour l’alimentation scolaire. L'objectif du Consortium de Recherche est de mener des recherches indépendantes dans divers secteurs et de générer des preuves solides, convaincantes et exploitables concernant les avantages des programmes de repas scolaires afin d'informer la prise de décision basée sur des preuves en matière de politiques et de pratiques de santé et de nutrition scolaires.
This school meals case study forms part of a collection led by the Research Consortium for School Health and Nutrition’s "Good Examples" Community of Practice. The School Meals Case Study of Morocco serves to document how the national school meals programme is organized, funded, and monitored throughout the country. The objectives of this case study include presenting an introduction to the country profile, outlining the design and implementation of school feeding programmes, describing their monitoring and evaluation processes, and highlighting lessons learned, best practices, and challenges. This case study is written as a working paper, and can be updated to reflect evolving circumstances. The ‘Good Examples’ Community of Practice supports the evidence generation of the Research Consortium for School Health and Nutrition, the evidence-generating arm of the School Meals Coalition. The Research Consortium’s objective is to carry out independent research across diverse sectors and generate solid, compelling, and actionable evidence regarding the benefits of school food programs to inform evidence-based decision-making on school health and nutrition policies and practices