Population-based germline breast cancer gene association studies and meta-analysis to inform wider mainstream testing

Breast cancer; Mainstream genetic testing; Multigene panel testingCáncer de mama; Pruebas genéticas convencionales; Prueba de panel multigénicoCàncer de mama; Proves genètiques convencionals; Prova de panell multigènicBackground Germline genetic testing, previously restricted to familial and young-onset breast cancer, is now offered increasingly broadly to patients with ‘population-type’ breast cancer in mainstream oncology clinics, with wide variation in the genes included. Patients and methods Weighted meta-analysis was carried out for three population-based case–control studies (BRIDGES, CARRIERS and UK Biobank) comprising in total 101 397 women with breast cancer and 312 944 women without breast cancer, to quantify 37 putative breast cancer susceptibility genes (BCSGs) for the frequency of pathogenic variants (PVs) in unselected, ‘population-type’ breast cancer cases and their association with breast cancer and its subtypes. Results Meta-analysed odds ratios (ORs) and frequencies of PVs in ‘population-type’ breast cancer cases were generated for BRCA1 (OR 8.73, 95% confidence interval (CI) 7.47-10.20; 1 in 101), BRCA2 (OR 5.68, 95% CI 5.13-6.30; 1 in 68) and PALB2 (OR 4.30, 95% CI 3.68-5.03; 1 in 187). For both CHEK2 (OR 2.40, 95% CI 2.21-2.62; 1 in 73) and ATM (OR 2.16, 95% CI 1.93-2.41; 1 in 132) subgroup analysis showed a stronger association with oestrogen receptor-positive disease. The magnitude of association and frequency of PVs were low for RAD51C (OR 1.53, 95% CI 1.29-2.04; 1 in 913), RAD51D (OR 1.76, 95% CI 1.29-2.41; 1 in 1079) and BARD1 (OR 2.34, 95% CI 1.85-2.97; 1 in 672); frequencies and associations were higher when the analysis was restricted to triple-negative breast cancers. The PV frequency in ‘population-type’ breast cancer cases was very low for ‘syndromic’ BCSGs TP53 (1 in 1844), STK11 (1 in 11 525), CDH1 (1 in 2668), PTEN (1 in 3755) and NF1 (1 in 1470), with metrics of association also modest ranging from OR 3.62 (95% CI 1.98-6.61) for TP53 down to OR 1.60 (95% CI 0.48-5.30) for STK11. Conclusions These metrics reflecting ‘population-type’ breast cancer will be informative in defining the appropriate gene set as we continue to expand to germline testing to an increasingly unselected group of breast cancer cases.This work was supported by CG-MAVE, Cancer Research UK Programme Award [grant number EDDPGM-Nov22/100004 to CT funding CFR and SA] and the Canadian Institutes of Health Research [grant number FDN-148390 to WDF]. MT was supported by the NIHR Cambridge Biomedical Research Centre (grant number NIHR203312). HH was supported by the NIHR Exeter Biomedical Research Centre (grant number NIHR203320)

Inequalities in children’s mental health prescribing and referrals for specialist mental health services

Peer reviewe

Data provenance tracking and reporting in a high-security digital research environment.

Objective To protect privacy, routinely-collected data are processed and anonymised by third parties before being used for research. However, the methods used to do this are rarely shared, leaving the resulting research difficult to evaluate and liable to undetected errors. Here, we present a provenance-based approach for documenting and auditing such methods. Approach We designed the Safe Haven Provenance (SHP) ontology for representing provenance information about data, users, and activities within high-security environments as knowledge graphs. The work was based on a case study of the Grampian Data Safe Haven (DASH) which holds and processes medical records for 600,000 people in Scotland. The SHP ontology was designed as an extension to the standard W3C PROV-O ontology. The auditing capabilities of our approach were evaluated against a set of transparency requirements through a prototype interactive dashboard. Results We demonstrated the ability of the SHP ontology to document the workflow within DASH: capturing the extraction and anonymisation process using a structured vocabulary of entities (e.g. datasets), activities (e.g. linkage, anonymisation) and agents (e.g. analysts, data owners). Two provenance reporting templates were designed following interviews with DASH staff and clinical researchers: 1) a detailed report for use within DASH for quality assurance, and 2) a summary report for researchers that was safe for public release. Using a prototype data-linkage project, we formalised queries for report generation, and demonstrated use of automated rules for error detection (e.g., data discrepancies) using the structure of the SHP knowledge graphs. All of the project outputs are available under an open-source license. Conclusions This project lays a foundation for more transparent high-quality research using public data for health care and innovation. The SHP ontology is extendible for different domains and potentially represents a key component for further automation of provenance capture and reporting in high-security research environments

Serious mental health diagnoses in children on the child protection register: a record linkage study.

Children with experience of maltreatment, abuse or neglect are known to have a higher prevalence of poor mental health. Child Protection Services identify children most at risk of harm and in need of intervention. Mental healthcare usage in this population is not well understood as registration data is not routinely linked to health records. We undertook data linkage to describe the population on the register, their mental healthcare usage and to calculate age- and sex-specific incidence rates of mental health outcomes. We analysed records from the Aberdeen City Council Child Protection Register and for mental health prescribing and referrals to child and adolescent mental health services (CAMHS) for the NHS Grampian region between 1st January 2012 and 31st December 2022. We identified 1,498 individuals with a Child Protection Register registration, of which 70% were successfully matched to health records. 20% of registrations occurred before birth and the median age of registration was 3 years. 10.1% of children with a registration ever received a mental health prescription, 5.1% for treatment of attention deficit hyperactivity disorder and 1.7% for treatment of depression. 18.9% received a referral to specialist outpatient Child and Adolescent Mental Health Services. Age- and sex- standardised incidence rates for mental health prescribing and referrals are higher for children with a child protection registration compared to the general population. Children identified as being at significant risk of harm and involved with child protection services are at greater risk of seeking or receiving professional mental health support than their peers. Clinical services should investigate additional ways to support this population’s mental well-being as a priority. Efforts to reduce the exposure of children to potentially harmful environments at a societal level should also be pursued

Inequalities in children's mental health care : analysis of routinely collected data on prescribing and referrals to secondary care

© 2022. The Author(s).Peer reviewedPublisher PD

Complex interventions in midwifery care: Reflections on the design and evaluation of an algorithm for the diagnosis of labour

Randomised controlled trials are the ‘gold standard’ for evaluating the effectiveness of interventions in health-care settings. However, in midwifery care, many interventions are ‘complex’, comprising a number of different elements which may have an effect on the impact of the intervention in health-care settings. In this paper we reflect on our experience of designing and evaluating a complex intervention (a decision tool to assist with the diagnosis of labour in midwifery care), examining some of the issues that our study raises for future research in complex interventions

Inequalities in children’s mental health prescribing and referrals for specialist mental health services.

Objective 1 in 8 young people in the United Kingdom are estimated to have a diagnosable mental health condition. Prevalence is increasing over time, many are untreated, and need is not evenly distributed across the population. We aimed to investigate trends in children’s mental health prescribing and referrals to specialist outpatient services. Approach We linked individual-level healthcare administrative records on community prescribing and referrals to outpatient Child and Adolescent Mental Health Services (CAMHS). The study cohort included all children aged 2 through 17 in the NHS Grampian Health Board region from 2015 to 2021 (average annual population circa 100,000) with a mental health prescription or CAMHS referral. We measured prevalence of mental health prescribing and referrals to CAMHS over time. We investigated demographic and socioeconomic differences, including comparison of rates by age, sex, and residential area deprivation. We also investigated socioeconomic and demographic differences in referral acceptance and rejection. Results Prescriptions for mental health drugs have risen 40%: from 5,000 per month in 2015 to 7,000 in 2021. 75% of prescriptions to primary schoolers are to boys, mostly for attention deficit hyperactivity disorder medications. Prescriptions to girls rise during secondary school, mostly for anti-depressants. Prescribing rates are 2.6-fold higher in the most versus least deprived areas. Referrals to CAMHS have risen 20% over the study period, and the proportion of referrals rejected has increased from 18% to 31% – leaving the number of children accepted to specialist care stable. Boys are referred twice as often at younger ages, while girls’ referrals spike during puberty. Since 2015, boys have been referred less and rejected more, with girls now making up 61% of those treated. Referral rates are two-fold higher in the most versus least deprived areas. Conclusions Both mental health prescribing and referrals to CAMHS have increased in this population, but the CAMHS service size remained fixed. Presentation and treatment patterns vary dramatically by age and sex, and socioeconomic inequalities are clear and persistent

Structured group education programme and accompanying mHealth intervention to promote physical activity in women with a history of gestational diabetes : a randomised controlled trial

Aims: Assess effectiveness of a hybrid intervention targeting physical activity in women with prior gestational diabetes. Methods: Randomised controlled trial with parallel arms. 293 women (35.1 ± 5.1 years; 40% ethnic minority) recruited from two hospitals and randomised to routine care or hybrid lifestyle intervention comprising two group sessions and access to a mobile web app. Primary outcome was a change in objectively measured physical activity at 12 months. Secondary outcomes included self‐efficacy for exercise, quality of life and anxiety and depression. Linear regression compared outcome measures between groups. Results: 83% of intervention participants attended at least one group session, of who 66% registered to use the app. There was a non‐significant increase in physical activity at 12 months (between‐group difference of 0.95 mg [95% CI: −0.46 to 2.37]), equivalent to approximately 500 steps per day. Intervention participants reported higher self‐efficacy for exercise (0.54, 95% CI: 0.05 to 1.102; p = 0.029), lower anxiety (−0.91, 95% CI: −1.74 to −0.09; p = 0.031), and higher quality of life (0.05, 95% CI: 0.004 to 0.09; p = 0.032), compared to controls. Conclusions: The intervention improved confidence in exercise and quality of life. Further research is needed to improve participant engagement with physical activity interventions in multi‐ethnic populations with a history of gestational diabetes

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common