Improving the Detection of Potential Cases of Familial Hypercholesterolemia: Could Machine Learning Be Part of the Solution?

BACKGROUND: Familial hypercholesterolemia (FH), while highly prevalent, is a significantly underdiagnosed monogenic disorder. Improved detection could reduce the large number of cardiovascular events attributable to poor case finding. We aimed to assess whether machine learning algorithms outperform clinical diagnostic criteria (signs, history, and biomarkers) and the recommended screening criteria in the United Kingdom in identifying individuals with FH-causing variants, presenting a scalable screening criteria for general populations. METHODS AND RESULTS: Analysis included UK Biobank participants with whole exome sequencing, classifying them as having FH when (likely) pathogenic variants were detected in their LDLR, APOB, or PCSK9 genes. Data were stratified into 3 data sets for (1) feature importance analysis; (2) deriving state-of-the-art statistical and machine learning models; (3) evaluating models' predictive performance against clinical diagnostic and screening criteria: Dutch Lipid Clinic Network, Simon Broome, Make Early Diagnosis to Prevent Early Death, and Familial Case Ascertainment Tool. One thousand and three of 454 710 participants were classified as having FH. A Stacking Ensemble model yielded the best predictive performance (sensitivity, 74.93%; precision, 0.61%; accuracy, 72.80%, area under the receiver operating characteristic curve, 79.12%) and outperformed clinical diagnostic criteria and the recommended screening criteria in identifying FH variant carriers within the validation data set (figures for Familial Case Ascertainment Tool, the best baseline model, were 69.55%, 0.44%, 65.43%, and 71.12%, respectively). Our model decreased the number needed to screen compared with the Familial Case Ascertainment Tool (164 versus 227). CONCLUSIONS: Our machine learning-derived model provides a higher pretest probability of identifying individuals with a molecular diagnosis of FH compared with current approaches. This provides a promising, cost-effective scalable tool for implementation into electronic health records to prioritize potential FH cases for genetic confirmation.

Unravelling genetic architecture of circulatory amino acid levels, and their effect on risk of complex disorders.

Variations in serum amino acid levels are linked to a multitude of complex disorders. We report the largest genome-wide association study (GWAS) on nine serum amino acids in the UK Biobank participants (117 944, European descent). We identified 34 genomic loci for circulatory levels of alanine, 48 loci for glutamine, 44 loci for glycine, 16 loci for histidine, 11 loci for isoleucine, 19 loci for leucine, 9 loci for phenylalanine, 32 loci for tyrosine and 20 loci for valine. Our gene-based analysis mapped 46-293 genes associated with serum amino acids, including MIP, GLS2, SLC gene family, GCKR, LMO1, CPS1 and COBLL1.The gene-property analysis across 30 tissues highlighted enriched expression of the identified genes in liver tissues for all studied amino acids, except for isoleucine and valine, in muscle tissues for serum alanine and glycine, in adrenal gland tissues for serum isoleucine and leucine, and in pancreatic tissues for serum phenylalanine. Mendelian randomization (MR) phenome-wide association study analysis and subsequent two-sample MR analysis provided evidence that every standard deviation increase in valine is associated with 35% higher risk of type 2 diabetes and elevated levels of serum alanine and branched-chain amino acids with higher levels of total cholesterol, triglyceride and low-density lipoprotein, and lower levels of high-density lipoprotein. In contrast to reports by observational studies, MR analysis did not support a causal association between studied amino acids and coronary artery disease, Alzheimer's disease, breast cancer or prostate cancer. In conclusion, we explored the genetic architecture of serum amino acids and provided evidence supporting a causal role of amino acids in cardiometabolic health.

Postdiagnosis body fatness, recreational physical activity, dietary factors and breast cancer prognosis: Global Cancer Update Programme (CUP Global) summary of evidence grading.

Based on the Global Cancer Update Programme, formally known as the World Cancer Research Fund/American Institute for Cancer Research Continuous Update Project, we performed systematic reviews and meta-analyses to investigate the association of postdiagnosis body fatness, physical activity and dietary factors with breast cancer prognosis. We searched PubMed and Embase for randomised controlled trials and longitudinal observational studies from inception to 31 October 2021. We calculated summary relative risks (RRs) and 95% confidence intervals (CIs) using random-effects meta-analyses. An independent Expert Panel graded the quality of evidence according to predefined criteria. The evidence on postdiagnosis body fatness and higher all-cause mortality (RR per 5 kg/m2 in body mass index: 1.07, 95% CI: 1.05-1.10), breast cancer-specific mortality (RR: 1.10, 95% CI: 1.06-1.14) and second primary breast cancer (RR: 1.14, 95% CI: 1.04-1.26) was graded as strong (likelihood of causality: probable). The evidence for body fatness and breast cancer recurrence and other nonbreast cancer-related mortality was graded as limited (likelihood of causality: limited-suggestive). The evidence on recreational physical activity and lower risk of all-cause (RR per 10 metabolic equivalent of task-hour/week: 0.85, 95% CI: 0.78-0.92) and breast cancer-specific mortality (RR: 0.86, 95% CI: 0.77-0.96) was judged as limited-suggestive. Data on dietary factors was limited, and no conclusions could be reached except for healthy dietary patterns, isoflavone and dietary fibre intake and serum 25(OH)D concentrations that were graded with limited-suggestive evidence for lower risk of the examined outcomes. Our results encourage the development of lifestyle recommendations for breast cancer patients to avoid obesity and be physically active.

Postdiagnosis body fatness, weight change and breast cancer prognosis: Global Cancer Update Program (CUP global) systematic literature review and meta-analysis.

Previous evidence on postdiagnosis body fatness and mortality after breast cancer was graded as limited-suggestive. To evaluate the evidence on body mass index (BMI), waist circumference, waist-hip-ratio and weight change in relation to breast cancer prognosis, an updated systematic review was conducted. PubMed and Embase were searched for relevant studies published up to 31 October, 2021. Random-effects meta-analyses were conducted to estimate summary relative risks (RRs). The evidence was judged by an independent Expert Panel using pre-defined grading criteria. One randomized controlled trial and 225 observational studies were reviewed (220 publications). There was strong evidence (likelihood of causality: probable) that higher postdiagnosis BMI was associated with increased all-cause mortality (64 studies, 32 507 deaths), breast cancer-specific mortality (39 studies, 14 106 deaths) and second primary breast cancer (11 studies, 5248 events). The respective summary RRs and 95% confidence intervals per 5 kg/m2 BMI were 1.07 (1.05-1.10), 1.10 (1.06-1.14) and 1.14 (1.04-1.26), with high between-study heterogeneity (I2  = 56%, 60%, 66%), but generally consistent positive associations. Positive associations were also observed for waist circumference, waist-hip-ratio and all-cause and breast cancer-specific mortality. There was limited-suggestive evidence that postdiagnosis BMI was associated with higher risk of recurrence, nonbreast cancer deaths and cardiovascular deaths. The evidence for postdiagnosis (unexplained) weight or BMI change and all outcomes was graded as limited-no conclusion. The RCT showed potential beneficial effect of intentional weight loss on disease-free-survival, but more intervention trials and well-designed observational studies in diverse populations are needed to elucidate the impact of body composition and their changes on breast cancer outcomes.

Postdiagnosis recreational physical activity and breast cancer prognosis: Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis.

It is important to clarify the associations between modifiable lifestyle factors such as physical activity and breast cancer prognosis to enable the development of evidence-based survivorship recommendations. We performed a systematic review and meta-analyses to summarise the evidence on the relationship between postbreast cancer diagnosis physical activity and mortality, recurrence and second primary cancers. We searched PubMed and Embase through 31st October 2021 and included 20 observational studies and three follow-up observational analyses of patients enrolled in clinical trials. In linear dose-response meta-analysis of the observational studies, each 10-unit increase in metabolic equivalent of task (MET)-h/week higher recreational physical activity was associated with 15% and 14% lower risk of all-cause (95% confidence interval [CI]: 8%-22%, studies = 12, deaths = 3670) and breast cancer-specific mortality (95% CI: 4%-23%, studies = 11, deaths = 1632), respectively. Recreational physical activity was not associated with breast cancer recurrence (HR = 0.97, 95% CI: 0.91-1.05, studies = 6, deaths = 1705). Nonlinear dose-response meta-analyses indicated 48% lower all-cause and 38% lower breast cancer-specific mortality with increasing recreational physical activity up to 20 MET-h/week, but little further reduction in risk at higher levels. Predefined subgroup analyses across strata of body mass index, hormone receptors, adjustment for confounders, number of deaths, menopause and physical activity intensities were consistent in direction and magnitude to the main analyses. Considering the methodological limitations of the included studies, the independent Expert Panel concluded 'limited-suggestive' likelihood of causality for an association between recreational physical activity and lower risk of all-cause and breast cancer-specific mortality.

Postdiagnosis dietary factors, supplement use and breast cancer prognosis: Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis.

Little is known about how diet might influence breast cancer prognosis. The current systematic reviews and meta-analyses summarise the evidence on postdiagnosis dietary factors and breast cancer outcomes from randomised controlled trials and longitudinal observational studies. PubMed and Embase were searched through 31st October 2021. Random-effects linear dose-response meta-analysis was conducted when at least three studies with sufficient information were available. The quality of the evidence was evaluated by an independent Expert Panel. We identified 108 publications. No meta-analysis was conducted for dietary patterns, vegetables, wholegrains, fish, meat, and supplements due to few studies, often with insufficient data. Meta-analysis was only possible for all-cause mortality with dairy, isoflavone, carbohydrate, dietary fibre, alcohol intake and serum 25-hydroxyvitamin D (25(OH)D), and for breast cancer-specific mortality with fruit, dairy, carbohydrate, protein, dietary fat, fibre, alcohol intake and serum 25(OH)D. The results, with few exceptions, were generally null. There was limited-suggestive evidence that predefined dietary patterns may reduce the risk of all-cause and other causes of death; that isoflavone intake reduces the risk of all-cause mortality (relative risk (RR) per 2 mg/day: 0.96, 95% confidence interval (CI): 0.92-1.02), breast cancer-specific mortality (RR for high vs low: 0.83, 95% CI: 0.64-1.07), and recurrence (RR for high vs low: 0.75, 95% CI: 0.61-0.92); that dietary fibre intake decreases all-cause mortality (RR per 10 g/day: 0.87, 95% CI: 0.80-0.94); and that serum 25(OH)D is inversely associated with all-cause and breast cancer-specific mortality (RR per 10 nmol/L: 0.93, 95% CI: 0.89-0.97 and 0.94, 95% CI: 0.90-0.99, respectively). The remaining associations were graded as limited-no conclusion.

Physical Activity and Health-Related Quality of Life in Women With Breast Cancer: A Meta-Analysis.

BACKGROUND: Physical activity (PA) is associated with improved health-related quality of life (HRQoL) among women with breast cancer; however, uncertainty remains regarding PA types and dose (frequency, duration, intensity) and various HRQoL measures. A systematic review and meta-analysis of randomized controlled trials was conducted to clarify whether specific types and doses of physical activity was related to global and specific domains of HRQoL, as part of the Global Cancer Update Programme, formerly known as the World Cancer Research Fund-American Institute for Cancer Research Continuous Update Project. METHODS: PubMed and CENTRAL databases were searched up to August 31, 2019. Weighted mean differences (WMDs) in HRQoL scores were estimated using random effects models. An independent expert panel graded the evidence. RESULTS: A total of 79 randomized controlled trials (14 554 breast cancer patients) were included. PA interventions resulted in higher global HRQoL as measured by the Functional Assessment of Cancer Therapy-Breast (WMD = 5.94, 95% confidence intervals [CI] = 2.64 to 9.24; I2 = 59%, n = 12), Functional Assessment of Cancer Therapy-General (WMD = 4.53, 95% CI = 1.94 to 7.13; I2 = 72%, n = 18), and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (WMD = 6.78, 95% CI = 2.61 to 10.95; I2 = 76.3%, n = 17). The likelihood of causality was considered probable that PA improves HRQoL in breast cancer survivors. Effects were weaker for physical function and mental and emotional health. Evidence regarding dose and type of PA remains insufficient for firm conclusions. CONCLUSION: PA results in improved global HRQoL in breast cancer survivors with weaker effects observed for physical function and mental and emotional health. Additional research is needed to define the impact of types and doses of activity on various domains of HRQoL.

World Cancer Research Fund International: Continuous Update Project-systematic literature review and meta-analysis of observational cohort studies on physical activity, sedentary behavior, adiposity, and weight change and breast cancer risk.

PURPOSE: The purpose of the present study was to systematically review the complex associations between energy balance-related factors and breast cancer risk, for which previous evidence has suggested different associations in the life course of women and by hormone receptor (HR) status of the tumor. METHODS: Relevant publications on adulthood physical activity, sedentary behavior, body mass index (BMI), waist and hip circumferences, waist-to-hip ratio, and weight change and pre- and postmenopausal breast cancer risk were identified in PubMed up to 30 April 2017. Random-effects meta-analyses were conducted to summarize the relative risks across studies. RESULTS: One hundred and twenty-six observational cohort studies comprising over 22,900 premenopausal and 103,000 postmenopausal breast cancer cases were meta-analyzed. Higher physical activity was inversely associated with both pre- and postmenopausal breast cancers, whereas increased sitting time was positively associated with postmenopausal breast cancer. Although higher early adult BMI (ages 18-30 years) was inversely associated with pre- and postmenopausal breast cancers, adult weight gain and greater body adiposity increased breast cancer risk in postmenopausal women, and the increased risk was evident for HR+ but not HR- breast cancers, and among never but not current users of postmenopausal hormones. The evidence was less consistent in premenopausal women. There were no associations with adult weight gain, inverse associations with adult BMI (study baseline) and hip circumference, and non-significant associations with waist circumference and waist-to-hip ratio that were reverted to positive associations on average in studies accounting for BMI. No significant associations were observed for HR-defined premenopausal breast cancers. CONCLUSION: Better understanding on the impact of these factors on pre- and postmenopausal breast cancers and their subtypes along the life course is needed.

Height and body fatness and colorectal cancer risk: an update of the WCRF-AICR systematic review of published prospective studies.

PURPOSE: There is no published dose-response meta-analysis on the association between height and colorectal cancer risk (CRC) by sex and anatomical sub-site. We conducted a meta-analysis of prospective studies on the association between height and CRC risk with subgroup analysis and updated evidence on the association between body fatness and CRC risk. METHODS: PubMed and several other databases were searched up to November 2016. A random effects model was used to calculate dose-response summary relative risks (RR's). RESULTS: 47 studies were included in the meta-analyses including 50,936 cases among 7,393,510 participants. The findings support the existing evidence regarding a positive association of height, general and abdominal body fatness and CRC risk. The summary RR were 1.04 [95% (CI)1.02-1.05, I² = 91%] per 5 cm increase in height, 1.02 [95% (CI)1.01-1.02, I² = 0%] per 5 kg increase in weight, 1.06 [95% (CI)1.04-1.07, I² = 83%] per 5 kg/m2 increase in BMI, 1.02 [95% (CI)1.02-1.03, I² = 4%] per 10 cm increase in waist circumference, 1.03 [95% (CI)1.01-1.05, I² = 16%] per 0.1 unit increase in waist to hip ratio. The significant association for height and CRC risk was similar in men and women. The significant association for BMI and CRC risk was stronger in men than in women. CONCLUSION: The positive association between height and risk of CRC suggests that life factors during childhood and early adulthood might play a role in CRC aetiology. Higher general and abdominal body fatness during adulthood are risk factors of CRC and these associations are stronger in men than in women.

Carbohydrates, glycemic index, glycemic load, and breast cancer risk: a systematic review and dose-response meta-analysis of prospective studies.

Context: The investigation of dose-response associations between carbohydrate intake, glycemic index, glycemic load, and risk of breast cancer stratified by menopausal status, hormone receptor status, and body mass index (BMI) remains inconclusive. Objective: A systematic review and dose-response meta-analyses was conducted to investigate these associations. Data Sources: As part of the World Cancer Research Fund/American Institute for Cancer Research Continuous Update Project, PubMed was searched up to May 2015 for relevant studies on these associations. Study Selection: Prospective studies reporting associations between carbohydrate intake, glycemic index, or glycemic load and breast cancer risk were included. Data Extraction: Two investigators independently extracted data from included studies. Results: Random-effects models were used to summarize relative risks (RRs) and 95%CIs. Heterogeneity between subgroups, including menopausal status, hormone receptor status, and BMI was explored using meta-regression. Nineteen publications were included. The summary RRs (95%CIs) for breast cancer were 1.04 (1.00-1.07) per 10 units/d for glycemic index, 1.01 (0.98-1.04) per 50 units/d for glycemic load, and 1.00 (0.96-1.05) per 50 g/d for carbohydrate intake. For glycemic index, the association appeared slightly stronger among postmenopausal women (summary RR per 10 units/d, 1.06; 95%CI, 1.02-1.10) than among premenopausal women, though the difference was not statistically significant (Pheterogeneity = 0.15). Glycemic load and carbohydrate intake were positively associated with breast cancer among postmenopausal women with estrogen-negative tumors (summary RR for glycemic load, 1.28; 95%CI, 1.08-1.52; and summary RR for carbohydrates, 1.13; 95%CI, 1.02-1.25). No differences in BMI were detected. Conclusions: Menopausal and hormone receptor status, but not BMI, might be potential influencing factors for the associations between carbohydrate intake, glycemic index, glycemic load, and breast cancer.

Blood concentrations of carotenoids and retinol and lung cancer risk: an update of the WCRF-AICR systematic review of published prospective studies.

Carotenoids and retinol are considered biomarkers of fruits and vegetables intake, and are of much interest because of their anti-inflammatory and antioxidant properties; however, there is inconsistent evidence regarding their protective effects against lung cancer. We conducted a meta-analysis of prospective studies of blood concentrations of carotenoids and retinol, and lung cancer risk. We identified relevant prospective studies published up to December 2014 by searching the PubMed and several other databases. We calculated summary estimates of lung cancer risk for the highest compared with lowest carotenoid and retinol concentrations and dose-response meta-analyses using random effects models. We used fractional polynomial models to assess potential nonlinear relationships. Seventeen prospective studies (18 publications) including 3603 cases and 458,434 participants were included in the meta-analysis. Blood concentrations of α-carotene, ß-carotene, total carotenoids, and retinol were significantly inversely associated with lung cancer risk or mortality. The summary relative risk were 0.66 (95% confidence interval [CI]: 0.55-0.80) per 5 µg/100 mL of α-carotene (studies [n] = 5), 0.84 (95% CI: 0.76-0.94) per 20 µg/100 mL of ß-carotene (n = 9), 0.66 (95% CI: 0.54-0.81) per 100 µg/100 mL of total carotenoids (n = 4), and 0.81 (95% CI: 0.73-0.90) per 70 µg/100 mL of retinol (n = 8). In stratified analysis by sex, the significant inverse associations for ß-carotene and retinol were observed only in men and not in women. Nonlinear associations were observed for ß-carotene, ß-cryptoxanthin, and lycopene, with stronger associations observed at lower concentrations. There were not enough data to conduct stratified analyses by smoking. In conclusion, higher blood concentrations of several carotenoids and retinol are associated with reduced lung cancer risk. Further studies in never and former smokers are needed to rule out confounding by smoking.

An update of the WCRF/AICR systematic literature review on esophageal and gastric cancers and citrus fruits intake.

PURPOSE: The 2007 World Cancer Research Fund/American Institute for Cancer Research expert report concluded that foods containing vitamin C probably protect against esophageal cancer and fruits probably protect against gastric cancer. Most of the previous evidence was from case-control studies, which may be affected by recall and selection biases. More recently, several cohort studies have examined these associations. We conducted a systematic literature review of prospective studies on citrus fruits intake and risk of esophageal and gastric cancers. METHODS: PubMed was searched for studies published until 1 March 2016. We calculated summary relative risks and 95 % confidence intervals (95 % CI) using random-effects models. RESULTS: With each 100 g/day increase of citrus fruits intake, a marginally significant decreased risk of esophageal cancer was observed (summary RR 0.86, 95 % CI 0.74-1.00, 1,057 cases, six studies). The associations were similar for squamous cell carcinoma (RR 0.87, 95 % CI 0.69-1.08, three studies) and esophageal adenocarcinoma (RR 0.93, 95 % CI 0.78-1.11, three studies). For gastric cancer, the nonsignificant inverse association was observed for gastric cardia cancer (RR 0.75, 95 % CI 0.55-1.01, three studies), but not for gastric non-cardia cancer (RR 1.02, 95 % CI 0.90-1.16, four studies). Consistent summary inverse associations were observed when comparing the highest with lowest intake, with statistically significant associations for esophageal (RR 0.77, 95 % CI 0.64-0.91, seven studies) and gastric cardia cancers (RR 0.62, 95 % CI 0.39-0.99, three studies). CONCLUSIONS: Citrus fruits may decrease the risk of esophageal and gastric cardia cancers, but further studies are needed.

WCRF-AICR continuous update project: Systematic literature review of prospective studies on circulating 25-hydroxyvitamin D and kidney cancer risk.

As part of the World Cancer Research Fund/American Institute for Cancer Research (WCRF-AICR) Continuous Update project we performed a systematic review of prospective studies with data for both measured or predicted 25(OH)D concentration and kidney cancer risk. PubMed was searched from inception until 1st December 2014 using WCRF/AICR search criteria. The search identified 4 papers suitable for inclusion, reporting data from three prospective cohort studies, one nested case-control study and the Vitamin D Pooling Project of Rarer Cancers (8 nested case-control studies). Summary effect sizes could not be computed due to incompatibility between studies. All studies except the Pooling Project suggested a reduced risk of kidney cancer by 19-40% with higher or adequate vitamin D status,. However, these estimates only reached statistical significance in one cohort (Copenhagen City Heart Study; CCHS, HR=0.75 (0.58 to 0.96)). In the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a significant reduction in risk by 18% was seen when using combined matched and non-matched controls OR=0.82 (0.68, 0.99), but not when using only matched controls (OR=0.81 (0.65, 1.00). Pooled (but not single cohort) data for predicted 25(OH)D from the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS) showed a statistically significant reduction in risk by 37% (HR=0.63 (0.44, 0.91)). There is no clear explanation for the inconsistency of results between studies, but reasons may include prevalence of smoking or other study population characteristics. Methods for assessing circulating 25(OH)D levels and control for confounders including seasonality or hypertension do not seem explanatory.

Fruits, vegetables, and bladder cancer risk: a systematic review and meta-analysis.

Smoking is estimated to cause about half of all bladder cancer cases. Case-control studies have provided evidence of an inverse association between fruit and vegetable intake and bladder cancer risk. As part of the World Cancer Research/American Institute for Cancer Research Continuous Update Project, we conducted a systematic review and meta-analysis of prospective studies to assess the dose-response relationship between fruit and vegetables and incidence and mortality of bladder cancer. We searched PubMed up to December 2013 for relevant prospective studies. We conducted highest compared with lowest meta-analyses and dose-response meta-analyses using random effects models to estimate summary relative risks (RRs) and 95% confidence intervals (CIs), and used restricted cubic splines to examine possible nonlinear associations. Fifteen prospective studies were included in the review. The summary RR for an increase of 1 serving/day (80 g) were 0.97 (95% CI: 0.95-0.99) I(2)  = 0%, eight studies for fruits and vegetables, 0.97 (95% CI: 0.94-1.00, I(2)  = 10%, 10 studies) for vegetables and 0.98 (95% CI: 0.96-1.00, I(2)  = 0%, 12 studies) for fruits. Results were similar in men and women and in current, former and nonsmokers. Amongst fruits and vegetables subgroups, for citrus fruits the summary RR for the highest compared with the lowest intake was 0.87 (95% CI: 0.76-0.99, I(2)  = 0%, eight studies) and for cruciferous vegetables there was evidence of a nonlinear relationship (P = 0.001). The current evidence from cohort studies is not consistent with a role for fruits and vegetables in preventing bladder cancer.

Anthropometric factors and ovarian cancer risk: a systematic review and nonlinear dose-response meta-analysis of prospective studies.

In the World Cancer Research Fund/American Institute for Cancer Research report from 2007 the evidence relating body fatness to ovarian cancer risk was considered inconclusive, while the evidence supported a probably causal relationship between adult attained height and increased risk. Several additional cohort studies have since been published, and therefore we conducted an updated meta-analysis of the evidence as part of the Continuous Update Project. We searched PubMed and several other databases up to 20th of August 2014. Summary relative risks (RRs) were calculated using a random effects model. The summary relative risk for a 5-U increment in BMI was 1.07 (95% CI: 1.03-1.11, I(2) = 54%, n = 28 studies). There was evidence of a nonlinear association, pnonlinearity < 0.0001, with risk increasing significantly from BMI∼28 and above. The summary RR per 5 U increase in BMI in early adulthood was 1.12 (95% CI: 1.05-1.20, I(2) = 0%, pheterogeneity = 0.54, n = 6), per 5 kg increase in body weight was 1.03 (95% CI: 1.02-1.05, I(2) = 0%, n = 4) and per 10 cm increase in waist circumference was 1.06 (95% CI: 1.00-1.12, I(2) = 0%, n = 6). No association was found for weight gain, hip circumference or waist-to-hip ratio. The summary RR per 10 cm increase in height was 1.16 (95% CI: 1.11-1.21, I(2) = 32%, n = 16). In conclusion, greater body fatness as measured by body mass index and weight are positively associated risk of ovarian cancer, and in addition, greater height is associated with increased risk. Further studies are needed to clarify whether abdominal fatness and weight gain is associated with risk.