[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. METHODS: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. RESULTS: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE =0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. CONCLUSION: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
JNCI Journal of the National Cancer Institute 10/2015; 107(12). DOI:10.1093/jnci/djv279 · 12.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, men >50y, women 50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed signifi- cant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (!50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analy- sis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimor- phism of body shape.
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.
[Show abstract][Hide abstract] ABSTRACT: Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.
[Show abstract][Hide abstract] ABSTRACT: Background:
Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear.
We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control patients, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control patients.
The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5×10(-8).
Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.
Journal of the National Cancer Institute 08/2015; 107(11). DOI:10.1093/jnci/djv219 · 12.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Considerable resources are spent on research to establish what works to improve the nation’s health. If the findings from this research are used, better health outcomes can follow, but we know that these findings are not always used. In public health, evidence of what works may not ‘fit’ everywhere, making it difficult to know what to do locally. Research suggests that evidence use is a social and dynamic process, not a simple application of research findings. It is unclear whether it is easier to get evidence used via a legal contracting process or within unified organisational arrangements with shared responsibilities.
To work in cocreation with research participants to investigate how research is utilised and knowledge mobilised in the commissioning and planning of public health services to reduce alcohol-related harms.
Design, setting and participants
Two in-depth, largely qualitative, cross-comparison case studies were undertaken to compare real-time research utilisation in commissioning across a purchaser–provider split (England) and in joint planning under unified organisational arrangements (Scotland) to reduce alcohol-related harms. Using an overarching realist approach and working in cocreation, case study partners (stakeholders in the process) picked the topic and helped to interpret the findings. In Scotland, the topic picked was licensing; in England, it was reducing maternal alcohol consumption.
Sixty-nine interviews, two focus groups, 14 observations of decision-making meetings, two local feedback workshops (
= 23 and
= 15) and one national workshop (
= 10) were undertaken. A questionnaire (
= 73) using a Behaviourally Anchored Rating Scale was issued to test the transferability of the 10 main findings. Given the small numbers, care must be taken in interpreting the findings.
Not all practitioners have the time, skills or interest to work in cocreation, but when there was collaboration, much was learned. Evidence included professional and tacit knowledge, and anecdotes, as well as findings from rigorous research designs. It was difficult to identify evidence in use and decisions were sometimes progressed in informal ways and in places we did not get to see. There are few formal evidence entry points. Evidence (prevalence and trends in public health issues) enters the process and is embedded in strategic documents to set priorities, but local data were collected in both sites to provide actionable messages (sometimes replicating the evidence base).
Two mid-range theories explain the findings. If evidence has
(relates to ‘here and now’ as opposed to ‘there and then’) and
(short, presented verbally or visually and with emotional appeal) it is more likely to be used in both settings. A second mid-range theory explains how differing tensions pull and compete as feasible and acceptable local solutions are pursued across stakeholders. Answering what works depends on answering for whom and where simultaneously to find workable (if temporary) ‘blends’. Gaining this agreement across stakeholders appeared more difficult across the purchaser–provider split, because opportunities to interact were curtailed; however, more research is needed.
This study was funded by the Health Services and Delivery Research programme of the National Institute for Health Research.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:
Caffeine has been shown to prevent ultraviolet radiation-induced carcinogenesis and to inhibit growth of melanoma cells in experimental studies. We evaluated the association among caffeine intake, coffee consumption, and melanoma risk among three large cohort studies.
The analysis used data from 89,220 women in the Nurses' Health Study II (1991-2009), 74,666 women in the Nurses' Health Study (1980-2008), and 39,424 men in the Health Professionals Follow-up Study (1986-2008). We used Cox proportional hazards models to estimate the hazard ratios (HR) with 95% confidence intervals (CIs) of melanoma associated with dietary intakes.
We documented 2,254 melanoma cases over 4 million person-years of follow-up. After adjustment for other risk factors, higher total caffeine intake was associated with a lower risk of melanoma (≥393 mg/day vs. <60 mg/day: HR = 0.78, 95% CI = 0.64, 0.96; Ptrend = 0.048). The association was more apparent in women (≥393 mg/day vs. <60 mg/day: HR = 0.70, 95% CI = 0.58, 0.85; Ptrend = 0.001) than in men (HR = 0.94, 95% CI = 0.75, 1.2; Ptrend = 0.81), and more apparent for melanomas occurring on body sites with higher continuous sun exposure (head, neck, and extremities; ≥393 mg/day vs. <60 mg/day: HR = 0.71, 95% CI = 0.59, 0.86; Ptrend = 0.001) than for melanomas occurring on body sites with lower continuous sun exposure (trunk including shoulder, back, hip, abdomen, and chest; HR = 0.90, 95% CI = 0.70, 1.2; Ptrend = 0.60). This pattern of association was similar to that for caffeinated coffee consumption, whereas no association was found for decaffeinated coffee consumption and melanoma risk.
Increasing caffeine intake and caffeinated coffee consumption is associated with decreased risk of cutaneous malignant melanomas.
[Show abstract][Hide abstract] ABSTRACT: Health systems have entered a third era embracing whole systems thinking and posing complex policy and management challenges. Understanding how such systems work and agreeing what needs to be put in place to enable them to undergo effective and sustainable change are more pressing issues than ever for policy-makers. The theory-policy-practice-gap and its four dimensions, as articulated by Chinitz and Rodwin, is acknowledged. It is suggested that insights derived from political science can both enrich our understanding of the gap and suggest what changes are needed to tackle the complex challenges facing health systems.
International Journal of Health Policy and Management (IJHPM) 06/2015; 4(6):391-394. DOI:10.15171/ijhpm.2015.62
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium.
A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect.
Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease.
Although no variants reached genome-wide significance (P <5 x 10(-8)), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels.
Breast Cancer Research 04/2015; 17(1). DOI:10.1186/s13058-015-0570-7 · 5.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose
– The purpose of this paper is to examine a bold and ambitious scheme known as the North East transformation system (NETS). The principal aim of the NETS is the achievement of a step-change in the quality of health services delivered to people living in the North East region of England. The paper charts the origins of the NETS and its early journey before describing what happened to it when the UK coalition government published its proposals for unexpected major structural change in the NHS. This had a profound impact on the leadership and direction of the NETS and resulted in it taking a different direction from that intended.
– The research design took the form of a mixed methods, longitudinal 3.5-year study aimed at exploring transformational change in terms of content, context, process and outcomes. The sample of study sites comprised 14 NHS trusts in the North East region chosen to provide geographical coverage of the area and to reflect the scale, scope and variety of the bodies that formed part of the NETS programme. The qualitative component of the research, which the paper draws upon, included 68 semi-structured interviews, observational studies and focus groups. Data analysis made use of both deductive and inductive frameworks. The deductive framework adopted was Pettigrew et al.’s “receptive contexts for change” and four of the eight factors stood out as especially important and form the basis of the paper.
– The fate of the NETS was shaped and influenced by the eight factors comprising the Pettigrew et al. receptive contexts for change framework but four factors in particular stood out as being especially significant: environmental pressure, quality and coherence of policy, key people leading change, supportive organisational culture. Perhaps the most significant lesson from the NETS is that achieving whole systems change is particularly vulnerable to the vicissitudes of politics especially where that system, like the UK NHS, is itself subject to those very same pressures. Yet, despite having an enormous influence on health policy, the political context is frequently avoided in research or not regarded as instrumental in determining the outcomes in respect of transformational change.
– The chief limitation is the credibility and authenticity of the interviews captured at particular points in time. These formed the datebase for subsequent analysis. The authors sought to guard against possible bias by supplementing interviews with observational studies and focus groups as well as running two dissemination events at which emerging findings from the study were subjected to independent external scrutiny and comment. These events provided a form of validation for the key study findings.
– The research findings demonstrate the importance of context for the likely outcome and success of complex transformational change initiatives. These require time to become embedded and demonstrate results especially when focused on changing culture and behaviour. But, in practice, allowing sufficient time during which the organisation may remain sufficiently stable to allow the change intervention to run its course and become embedded and sustainable is highly problematic. The consequence is that bold and ambitious efforts like the NETS are not given the space and stability to prove themselves. Too often, politics and external environmental pressures intrude in ways that may prove dysfunctional and negative.
– Unless a different approach to transformational change and its leadership and management is adopted, then changing the NHS to enable it to appear more responsive to changing health care needs and expectations will remain a cause for concern. Ultimately the public will be the losers if the NHS remains insensitive to changing needs and expectations. The patient experience was at the centre of the NETS programme.
– The study is original insofar as no other has sought to evaluate the NETS independently and over a reasonable time period. The research design, based on a mixed-methods approach, is unusual in evaluations of this nature. The study’s conclusions are not so original but their value lies in largely confirming and reinforcing the findings from other studies. It perhaps goes further in stressing the impact of politics on health policy and the negative consequences of constant organisational change on attempts to achieve deep change in the way the NHS is organised and led.
Journal of Health Organisation and Management 03/2015; 29(1):10-24. DOI:10.1108/JHOM-01-2014-0019 · 0.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We are transforming the educational strategy at the Harvard T. H. Chan School of Public Health guided by 5 principles: (1) development of T-shaped competencies (breadth across fields, depth in primary fields), (2) flexible and modular design accommodating different needs through the lifecycle, (3) greater experiential learning, (4) 3 levels of education (informative, formative, and transformative learning), and (5) integrated instructional design (online, in person, and in the field). We aim to create an arc of education resulting in continuous learning. We seek to bridge the research versus education dichotomy and create research-teaching congruence, adapting the values of peer review and quality assessment that we routinely accept for grant and article review to education.
American Journal of Public Health 03/2015; 105(S1):S109-S113. DOI:10.2105/AJPH.2014.302468 · 4.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 x 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
[Show abstract][Hide abstract] ABSTRACT: Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis
[Show abstract][Hide abstract] ABSTRACT: Background:
Since 1 April 2013, local authority (LA) health and well-being boards (HWBs) in England are required to publish a health and well-being strategy (HWS). HWSs should identify how population health needs are to be addressed. The extent to which this has been achieved is not known. We analysed HWSs to assess how LAs have interpreted statutory guidance, how evidence has been used within HWSs and the relationship of HWSs to Joint Strategic Needs Assessments (JSNAs).
Qualitative thematic content analysis of a random sample of one-third of upper tier LA HWSs in 2013-14.
Fifty out of 152 LAs were sampled and 47 HWSs analysed. Strategies varied in timescale, length and structure. The term 'evidence' was used most commonly referring to local need, rather than evidence of effectiveness. All, except two, referred to JSNAs.
HWSs are dominated by evidence of need and could be strengthened by greater use of evidence of effectiveness for public health interventions. Public health agencies and academics can support the development of effective HWSs by improving the accessibility of evidence and conducting research when evidence is absent. To strengthen HWSs' impact, the statutory guidance should clarify the distinction between evidence of need and evidence of effectiveness.
Journal of Public Health 10/2014; 37(3). DOI:10.1093/pubmed/fdu073 · 2.04 Impact Factor