Protein-truncating and rare missense variants in ATM and CHEK2 and associations with cancer in UK Biobank whole-exome sequence data.

BACKGROUND: Deleterious germline variants in ATM and CHEK2 have been associated with a moderately increased risk of breast cancer. Risks for other cancers remain unclear. METHODS: Cancer associations for coding variants in ATM and CHEK2 were evaluated using whole-exome sequence data from UK Biobank linked to cancer registration data (348 488 participants), and analysed both as a retrospective case-control and a prospective cohort study. Odds ratios, hazard ratios, and combined relative risks (RRs) were estimated by cancer type and gene. Separate analyses were performed for protein-truncating variants (PTVs) and rare missense variants (rMSVs; allele frequency <0.1%). RESULTS: PTVs in ATM were associated with increased risks of nine cancers at p<0.001 (pancreas, oesophagus, lung, melanoma, breast, ovary, prostate, bladder, lymphoid leukaemia (LL)), and three at p<0.05 (colon, diffuse non-Hodgkin's lymphoma (DNHL), rectosigmoid junction). Carriers of rMSVs had increased risks of four cancers (p<0.05: stomach, pancreas, prostate, Hodgkin's disease (HD)). RRs were highest for breast, prostate, and any cancer where rMSVs lay in the FAT or PIK domains, and had a Combined Annotation Dependent Depletion score in the highest quintile.PTVs in CHEK2 were associated with three cancers at p<0.001 (breast, prostate, HD) and six at p<0.05 (oesophagus, melanoma, ovary, kidney, DNHL, myeloid leukaemia). Carriers of rMSVs had increased risks of five cancers (p<0.001: breast, prostate, LL; p<0.05: melanoma, multiple myeloma). CONCLUSION: PTVs in ATM and CHEK2 are associated with a wide range of cancers, with the highest RR for pancreatic cancer in ATM PTV carriers. These findings can inform genetic counselling of carriers.

Circulating vitamin D and breast cancer risk: an international pooling project of 17 cohorts.

Laboratory and animal research support a protective role for vitamin D in breast carcinogenesis, but epidemiologic studies have been inconclusive. To examine comprehensively the relationship of circulating 25-hydroxyvitamin D [25(OH)D] to subsequent breast cancer incidence, we harmonized and pooled participant-level data from 10 U.S. and 7 European prospective cohorts. Included were 10,484 invasive breast cancer cases and 12,953 matched controls. Median age (interdecile range) was 57 (42-68) years at blood collection and 63 (49-75) years at breast cancer diagnosis. Prediagnostic circulating 25(OH)D was either newly measured using a widely accepted immunoassay and laboratory or, if previously measured by the cohort, calibrated to this assay to permit using a common metric. Study-specific relative risks (RRs) for season-standardized 25(OH)D concentrations were estimated by conditional logistic regression and combined by random-effects models. Circulating 25(OH)D increased from a median of 22.6 nmol/L in consortium-wide decile 1 to 93.2 nmol/L in decile 10. Breast cancer risk in each decile was not statistically significantly different from risk in decile 5 in models adjusted for breast cancer risk factors, and no trend was apparent (P-trend = 0.64). Compared to women with sufficient 25(OH)D based on Institute of Medicine guidelines (50- < 62.5 nmol/L), RRs were not statistically significantly different at either low concentrations (< 20 nmol/L, 3% of controls) or high concentrations (100- < 125 nmol/L, 3% of controls; ≥ 125 nmol/L, 0.7% of controls). RR per 25 nmol/L increase in 25(OH)D was 0.99 [95% confidence intervaI (CI) 0.95-1.03]. Associations remained null across subgroups, including those defined by body mass index, physical activity, latitude, and season of blood collection. Although none of the associations by tumor characteristics reached statistical significance, suggestive inverse associations were seen for distant and triple negative tumors. Circulating 25(OH)D, comparably measured in 17 international cohorts and season-standardized, was not related to subsequent incidence of invasive breast cancer over a broad range in vitamin D status.

Clinical workload in UK primary care: a retrospective analysis of 100 million consultations in England, 2007-14.

BACKGROUND: Primary care is the main source of health care in many health systems, including the UK National Health Service (NHS), but few objective data exist for the volume and nature of primary care activity. With rising concerns that NHS primary care workload has increased substantially, we aimed to assess the direct clinical workload of general practitioners (GPs) and practice nurses in primary care in the UK. METHODS: We did a retrospective analysis of GP and nurse consultations of non-temporary patients registered at 398 English general practices between April, 2007, and March, 2014. We used data from electronic health records routinely entered in the Clinical Practice Research Datalink, and linked CPRD data to national datasets. Trends in age-standardised and sex-standardised consultation rates were modelled with joinpoint regression analysis. FINDINGS: The dataset comprised 101,818,352 consultations and 20,626,297 person-years of observation. The crude annual consultation rate per person increased by 10·51%, from 4·67 in 2007-08, to 5·16 in 2013-14. Consultation rates were highest in infants (age 0-4 years) and elderly people (≥85 years), and were higher for female patients than for male patients of all ages. The greatest increases in age-standardised and sex-standardised rates were in GPs, with a rise of 12·36% per 10,000 person-years, compared with 0·9% for practice nurses. GP telephone consultation rates doubled, compared with a 5·20% rise in surgery consultations, which accounted for 90% of all consultations. The mean duration of GP surgery consultations increased by 6·7%, from 8·65 min (95% CI 8·64-8·65) to 9·22 min (9·22-9·23), and overall workload increased by 16%. INTERPRETATION: Our findings show a substantial increase in practice consultation rates, average consultation duration, and total patient-facing clinical workload in English general practice. These results suggest that English primary care as currently delivered could be reaching saturation point. Notably, our data only explore direct clinical workload and not indirect activities and professional duties, which have probably also increased. This and additional research questions, including the outcomes of workload changes on other sectors of health care, need urgent answers for primary care provision internationally. FUNDING: Department of Health Policy Research Programme.

Factors associated with consultation rates in general practice in England, 2013-2014: a cross-sectional study.

BACKGROUND: Workload in general practice has risen during the last decade, but the factors associated with this increase are unclear. AIM: To examine factors associated with consultation rates in general practice. DESIGN AND SETTING: A cross-sectional study examining a sample of 304 937 patients registered at 316 English practices between 2013 and 2014, drawn from the Clinical Practice Research Datalink. METHOD: Age, sex, ethnicity, smoking status, and deprivation measures were linked with practice-level data on staffing, rurality, training practice status, and Quality and Outcomes Framework performance. Multilevel analyses of patient consultation rates were conducted. RESULTS: Consultations were grouped into three types: all (GP or nurse), GP, and nurse. Non-smokers consulted less than current smokers (all: rate ratio [RR] = 0.88, 95% CI = 0.87 to 0.89; GP: RR = 0.88, 95% CI = 0.87 to 0.89; nurse: RR = 0.91, 95% CI = 0.90 to 0.92). Consultation rates were higher for those in the most deprived quintile compared with the least deprived quintile (all: RR = 1.18, 95% CI = 1.16 to 1.19; GP: RR = 1.17, 95% CI = 1.15 to 1.19; nurse: RR = 1.13, 95% CI = 1.11 to 1.15). For all three consultation types, consultation rates increased with age and female sex, and varied by ethnicity. Rates in practices with >8 and ≤19 full-time equivalent (FTE) GPs were higher compared with those with ≤2 FTE GPs (all: RR = 1.26, 95% CI = 1.06 to 1.49; GP: RR = 1.36, 95% CI = 1.19 to 1.56). CONCLUSION: The analyses show consistent trends in factors related to consultation rates in general practice across three types of consultation. These data can be used to inform the development of more sophisticated staffing models, and resource allocation formulae.

Patient-level and practice-level factors associated with consultation duration: a cross-sectional analysis of over one million consultations in English primary care.

OBJECTIVES: Consultation duration has previously been shown to be associated with patient, practitioner and practice characteristics. However, previous studies were conducted outside the UK, considered only small numbers of general practitioner (GP) consultations or focused primarily on practitioner-level characteristics. We aimed to determine the patient-level and practice-level factors associated with duration of GP and nurse consultations in UK primary care. DESIGN AND SETTING: Cross-sectional data were obtained from English general practices contributing to the Clinical Practice Research Datalink (CPRD) linked to data on patient deprivation and practice staffing, rurality and Quality and Outcomes Framework (QOF) achievement. PARTICIPANTS: 218 304 patients, from 316 English general practices, consulting from 1 April 2013 to 31 March 2014. ANALYSIS: Multilevel mixed-effects models described the association between consultation duration and patient-level and practice-level factors (patient age, gender, smoking status, ethnic group, deprivation and practice rurality, number of full-time equivalent GPs/nurses, list size, consultation rate, quintile of overall QOF achievement and training status). RESULTS: Mean duration of face-to-face GP consultations was 9.24 min and 5.32 min for telephone consultations. Nurse face-to-face and telephone consultations lasted 9.70 and 5.73 min on average, respectively. Longer GP consultation duration was associated with female patient gender, practice training status and older patient age. Shorter duration was associated with higher deprivation and consultation rate. Longer nurse consultation duration was associated with male patient gender, older patient age and ever smoking; and shorter duration with higher consultation rate. Observed differences in duration were small (eg, GP consultations with female patients compared with male patients were 8 s longer on average). CONCLUSIONS: Small observed differences in consultation duration indicate that patients are treated similarly regardless of background. Increased consultation duration may be beneficial for older or comorbid patients, but the benefits and costs of increased consultation duration require further study.

The falling rates of hospital admission, case fatality, and population-based mortality for subarachnoid hemorrhage in England, 1999-2010.

OBJECTIVE In this study, the authors examined trends in population-based hospital admission rates, patient-level case fatality rates (CFRs), and population-based mortality rates for nontraumatic (spontaneous) subarachnoid hemorrhage (SAH) in England. METHODS Population-based admission and mortality data (59,599 people admitted to a hospital with SAH, 1999-2010; 37,836 people whose death certificates mentioned SAH, 1995-2010) were analyzed. RESULTS Hospital admission rates for SAH per million population declined by 18.3%, from 100.4 (95% CI 97.6-103.1) in 1999 to 82.0 (95% CI 79.7-84.4) in 2010. CFRs at less than 30 days per 100 patients decreased by 18.2%, from 29.7 (95% CI 28.5-31.0) in 1999 to 24.3 (95% CI 23.2-25.5) in 2010. Population-based mortality rates per million population, where SAH was recorded as underlying cause of death on the death certificate, declined by 39.8%, from 41.2 (95% CI 39.5-43.0) in 1999 to 24.8 (95% CI 23.6-26.1) in 2010. CONCLUSIONS Population-based hospital admission rates, patient-level CFRs, and population-based mortality rates all declined between 1999 and 2010. Part of the decline in mortality rates for SAH is likely to be attributable to a decline in incidence. It is also, in part, attributable to increased survival after SAH. The available data do not allow us to compare the effects of different treatment methods for SAH on case fatality and mortality. During the period of study, mortality rates declined by almost 40%, and it is likely that there are a number of factors contributing to this substantial improvement in outcomes for SAH patients in England.

Breast cancer mortality trends in England and the assessment of the effectiveness of mammography screening: population-based study.

OBJECTIVE: To investigate whether mortality statistics show an effect of mammographic screening on population-based breast cancer mortality in England. DESIGN: Joinpoint regression analyses, and other analyses, of population-based mortality data. SETTING: Analysis of mortality rates in the Oxford region, UK (1979-2009) because, unlike the rest of England, all causes of death mentioned on each death certificate for its residents (not just the underlying cause) are available prior to commencement of the English National Breast Screening Programme (NHSBSP). In addition, analysis of English national breast cancer mortality rates (1971-2009). PARTICIPANTS: Women who died from breast cancer in the Oxford region (1979--2009) and England (1971--2009) MAIN OUTCOME MEASURES: Age-specific mortality rates, and age-standardized mortality rates. Joinpoint regression analysis was used to estimate years ('joinpoints') in which trends changed, and annual percentage change between joinpoints, with confidence intervals. RESULTS: In the Oxford region, trends for breast cancer mortality based on underlying cause and on mentions were very similar. For all ages combined, mortality rates peaked for both underlying cause and mentions in 1985 and then started to decline, prior to the introduction of the NHSBSP in 1988. Between 1979 and 2009, for mortality measured as underlying cause, rates declined by -2.1% (95% CI -2.7 to -1.4) per year for women aged 40-49 years (unscreened), and by the same percentage per year (-2.1% [-2.4 to -1.7]) for women aged 50-64 years (screened). In England, the first estimated changes in trend occurred prior to the introduction of screening, or before screening was likely to have had an effect (between 1982 and 1989). Thereafter, the downward trend was greatest in women aged under 40 years: -2.0% per year (-2.8 to -1.2) in 1988-2001 and -5.0% per year (-6.7 to -3.3) in 2001-2009. There was no evidence that declines in mortality rates were consistently greater in women in age groups and cohorts that had been screened at all, or screened several times, than in other (unscreened) women, in the same time periods. Conclusions Mortality statistics do not show an effect of mammographic screening on population-based breast cancer mortality in England.