Publications by authors named "Sarah J Lewis"

108 Publications

Global processing provides malignancy evidence complementary to the information captured by humans or machines following detailed mammogram inspection.

Sci Rep 2021 Oct 11;11(1):20122. Epub 2021 Oct 11.

Discipline of Medical Imaging Sciences, Faculty of Medicine and Health, University of Sydney, 512/Block M, Cumberland Campus, Sydney, NSW, 2006, Australia.

The information captured by the gist signal, which refers to radiologists' first impression arising from an initial global image processing, is poorly understood. We examined whether the gist signal can provide complementary information to data captured by radiologists (experiment 1), or computer algorithms (experiment 2) based on detailed mammogram inspection. In the first experiment, 19 radiologists assessed a case set twice, once based on a half-second image presentation (i.e., gist signal) and once in the usual viewing condition. Their performances in two viewing conditions were compared using repeated measure correlation (rm-corr). The cancer cases (19 cases × 19 readers) exhibited non-significant trend with rm-corr = 0.012 (p = 0.82, CI: -0.09, 0.12). For normal cases (41 cases × 19 readers), a weak correlation of rm-corr = 0.238 (p < 0.001, CI: 0.17, 0.30) was found. In the second experiment, we combined the abnormality score from a state-of-the-art deep learning-based tool (DL) with the radiological gist signal using a support vector machine (SVM). To obtain the gist signal, 53 radiologists assessed images based on half-second image presentation. The SVM performance for each radiologist and an average reader, whose gist responses were the mean abnormality scores given by all 53 readers to each image was assessed using leave-one-out cross-validation. For the average reader, the AUC for gist, DL, and the SVM, were 0.76 (CI: 0.62-0.86), 0.79 (CI: 0.63-0.89), and 0.88 (CI: 0.79-0.94). For all readers with a gist AUC significantly better than chance-level, the SVM outperformed DL. The gist signal provided malignancy evidence with no or weak associations with the information captured by humans in normal radiologic reporting, which involves detailed mammogram inspection. Adding gist signal to a state-of-the-art deep learning-based tool improved its performance for the breast cancer detection.
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http://dx.doi.org/10.1038/s41598-021-99582-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505651PMC
October 2021

Mercury and Prenatal Growth: A Systematic Review.

Int J Environ Res Public Health 2021 07 3;18(13). Epub 2021 Jul 3.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.

The intrauterine environment is critical for healthy prenatal growth and affects neonatal survival and later health. Mercury is a toxic metal which can freely cross the placenta and disrupt a wide range of cellular processes. Many observational studies have investigated mercury exposure and prenatal growth, but no prior review has synthesised this evidence. Four relevant publication databases (Embase, MEDLINE/PubMed, PsycINFO, and Scopus) were systematically searched to identify studies of prenatal mercury exposure and birth weight, birth length, or head circumference. Study quality was assessed using the NIH Quality Assessment Tool, and results synthesised in a narrative review. Twenty-seven studies met the review criteria, these were in 17 countries and used 8 types of mercury biomarker. Studies of birth weight (total = 27) involving populations with high levels of mercury exposure, non-linear methods, or identified as high quality were more likely to report an association with mercury, but overall results were inconsistent. Most studies reported no strong evidence of association between mercury and birth length (n = 14) or head circumference (n = 14). Overall, our review did not identify strong evidence that mercury exposure leads to impaired prenatal growth, although there was some evidence of a negative association of mercury with birth weight.
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http://dx.doi.org/10.3390/ijerph18137140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297189PMC
July 2021

Improving radiologist's ability in identifying particular abnormal lesions on mammograms through training test set with immediate feedback.

Sci Rep 2021 05 10;11(1):9899. Epub 2021 May 10.

Faculty of Medicine and Health, The University of Sydney, Level 7 - D18, Susan Wakil Health Building, Sydney, NSW, 2006, Australia.

It has been shown that there are differences in diagnostic accuracy of cancer detection on mammograms, from below 50% in developing countries to over 80% in developed world. One previous study reported that radiologists from a population in Asia displayed a low mammographic cancer detection of 48% compared with over 80% in developed countries, and more importantly, that most lesions missed by these radiologists were spiculated masses or stellate lesions. The aim of this study was to explore the performance of radiologists after undertaking a training test set which had been designed to improve the capability in detecting a specific type of cancers on mammograms. Twenty-five radiologists read two sets of 60 mammograms in a standardized mammogram reading room. The first test set focused on stellate or spiculated masses. When radiologists completed the first set, the system displayed immediate feedback to the readers comparing their performances in each case with the truth of cancer cases and cancer types so that the readers could identify individual-based errors. Later radiologists were asked to read the second set of mammograms which contained different types of cancers including stellate/spiculated masses, asymmetric density, calcification, discrete mass and architectural distortion. Case sensitivity, lesion sensitivity, specificity, receiver operating characteristics (ROC) and Jackknife alternative free-response receiver operating characteristics (JAFROC) were calculated for each participant and their diagnostic accuracy was compared between two sessions. Results showed significant improvement among radiologists in case sensitivity (+ 11.4%; P < 0.05), lesion sensitivity (+ 18.7%; P < 0.01) and JAFROC (+ 11%; P < 0.01) in the second set compared with the first set. The increase in diagnostic accuracy was also recorded in the detection of stellate/spiculated mass (+ 20.6%; P < 0.05). This indicated that the performance of radiologists in detecting malignant lesions on mammograms can be improved if an appropriate training intervention is applied after the readers' weakness and strength are identified.
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http://dx.doi.org/10.1038/s41598-021-89214-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110801PMC
May 2021

Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study.

Am J Clin Nutr 2021 06;113(6):1490-1502

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited.

Objectives: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR).

Methods: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.

Results: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk.

Conclusions: These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.
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http://dx.doi.org/10.1093/ajcn/nqab003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168352PMC
June 2021

Causal Effects of Lifetime Smoking on Breast and Colorectal Cancer Risk: Mendelian Randomization Study.

Cancer Epidemiol Biomarkers Prev 2021 05 2;30(5):953-964. Epub 2021 Mar 2.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background: Observational evidence has shown that smoking is a risk factor for breast and colorectal cancer. We used Mendelian randomization (MR) to examine causal associations between smoking and risks of breast and colorectal cancer.

Methods: Genome-Wide Association Study summary data were used to identify genetic variants associated with lifetime amount of smoking ( = 126 variants) and ever having smoked regularly ( = 112 variants). Using two-sample MR, we examined these variants in relation to incident breast (122,977 cases/105,974 controls) and colorectal cancer (52,775 cases/45,940 controls).

Results: In inverse-variance weighted models, a genetic predisposition to higher lifetime amount of smoking was positively associated with breast cancer risk [OR per 1-SD increment: 1.13; 95% confidence interval (CI): 1.00-1.26; = 0.04]; although heterogeneity was observed. Similar associations were found for estrogen receptor-positive and estrogen receptor-negative tumors. Higher lifetime amount of smoking was positively associated with colorectal cancer (OR per 1-SD increment, 1.21; 95% CI, 1.04-1.40; = 0.01), colon cancer (OR, 1.31; 95% CI, 1.11-1.55; < 0.01), and rectal cancer (OR, 1.36; 95% CI, 1.07-1.73; = 0.01). Ever having smoked regularly was not associated with risks of breast (OR, 1.01; 95% CI, 0.90-1.14; = 0.85) or colorectal cancer (OR, 0.97; 95% CI, 0.86-1.10; = 0.68).

Conclusions: These findings are consistent with prior observational evidence and support a causal role of higher lifetime smoking amount in the development of breast and colorectal cancer.

Impact: The results from this comprehensive MR analysis indicate that lifetime smoking is a causal risk factor for these common malignancies.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611442PMC
May 2021

Closing schools is not evidence based and harms children.

BMJ 2021 02 23;372:n521. Epub 2021 Feb 23.

Institute of Population Health Sciences, Newcastle University, Newcastle upon Tyne, UK.

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http://dx.doi.org/10.1136/bmj.n521DOI Listing
February 2021

Coffee consumption and risk of breast cancer: A Mendelian randomization study.

PLoS One 2021 19;16(1):e0236904. Epub 2021 Jan 19.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.

Background: Observational studies have reported either null or weak protective associations for coffee consumption and risk of breast cancer.

Methods: We conducted a two-sample Mendelian randomization (MR) analysis to evaluate the relationship between coffee consumption and breast cancer risk using 33 single-nucleotide polymorphisms (SNPs) associated with coffee consumption from a genome-wide association (GWA) study on 212,119 female UK Biobank participants of White British ancestry. Risk estimates for breast cancer were retrieved from publicly available GWA summary statistics from the Breast Cancer Association Consortium (BCAC) on 122,977 cases (of which 69,501 were estrogen receptor (ER)-positive, 21,468 ER-negative) and 105,974 controls of European ancestry. Random-effects inverse variance weighted (IVW) MR analyses were performed along with several sensitivity analyses to assess the impact of potential MR assumption violations.

Results: One cup per day increase in genetically predicted coffee consumption in women was not associated with risk of total (IVW random-effects; odds ratio (OR): 0.91, 95% confidence intervals (CI): 0.80-1.02, P: 0.12, P for instrument heterogeneity: 7.17e-13), ER-positive (OR = 0.90, 95% CI: 0.79-1.02, P: 0.09) and ER-negative breast cancer (OR: 0.88, 95% CI: 0.75-1.03, P: 0.12). Null associations were also found in the sensitivity analyses using MR-Egger (total breast cancer; OR: 1.00, 95% CI: 0.80-1.25), weighted median (OR: 0.97, 95% CI: 0.89-1.05) and weighted mode (OR: 1.00, CI: 0.93-1.07).

Conclusions: The results of this large MR study do not support an association of genetically predicted coffee consumption on breast cancer risk, but we cannot rule out existence of a weak association.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236904PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815134PMC
April 2021

Genetically predicted circulating concentrations of micronutrients and risk of breast cancer: A Mendelian randomization study.

Int J Cancer 2021 02 25;148(3):646-653. Epub 2020 Aug 25.

Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.

The epidemiological literature reports inconsistent associations between consumption or circulating concentrations of micronutrients and breast cancer risk. We investigated associations between genetically predicted concentrations of 11 micronutrients (beta-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B , vitamin B and zinc) and breast cancer risk using Mendelian randomization (MR). A two-sample MR study was conducted using 122 977 women with breast cancer and 105 974 controls from the Breast Cancer Association Consortium. MR analyses were conducted using the inverse variance-weighted approach, and sensitivity analyses were conducted to assess the impact of potential violations of MR assumptions. A value of 1 SD (SD: 0.08 mmol/L) higher genetically predicted concentration of magnesium was associated with a 17% (odds ratio [OR]: 1.17, 95% confidence interval [CI]: 1.10-1.25, P value = 9.1 × 10 ) and 20% (OR: 1.20, 95% CI: 1.08-1.34, P value = 3.2 × 10 ) higher risk of overall and ER breast cancer, respectively. An inverse association was observed for a SD (0.5 mg/dL) higher genetically predicted phosphorus concentration and ER breast cancer (OR: 0.84, 95% CI: 0.72-0.98, P value = .03). There was little evidence that any other nutrient was associated with breast cancer. The results for magnesium were robust under all sensitivity analyses and survived correction for multiple comparisons. Higher circulating concentrations of magnesium and potentially phosphorus may affect breast cancer risk. Further work is required to replicate these findings and investigate underlying mechanisms.
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http://dx.doi.org/10.1002/ijc.33246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268064PMC
February 2021

Reader characteristics and mammogram features associated with breast imaging reporting scores.

Br J Radiol 2020 Oct 5;93(1114):20200363. Epub 2020 Aug 5.

Discipline of Medical Imaging Sciences, Faculty of Medicine and Health. The University of Sydney 75 East street, Lidcombe, New South Wales, Australia 2141.

Objectives: This study aims to explore the reading performances of radiologists in detecting cancers on mammograms using Tabar Breast Imaging Reporting and Data System (BIRADS) classification and identify factors related to breast imaging reporting scores.

Methods: 117 readings of five different mammogram test sets with each set containing 20 cancer and 40 normal cases were performed by Australian radiologists. Each radiologist evaluated the mammograms using the BIRADS lexicon with category 1 - negative, category 2 - benign findings, category 3 - equivocal findings (Recall), category 4 - suspicious findings (Recall), and category 5 - highly suggestive of malignant findings (Recall). Performance metrics (true positive, false positive, true negative, and false negative) were calculated for each radiologist and the distribution of reporting categories was analyzed in reader-based and case-based groups. The association of reader characteristics and case features among categories was examined using Mann-Whitney U and Kruskal-Wallis tests.

Results: 38% of cancer-containing mammograms were reported with category 3 which decreased to 32.3% with category 4 and 16.2% with category 5 while 16.6 and 10.3% of cancer cases were marked with categories 1 and 2. Female readers had less false-negative rates when using categories 1 and 2 for cancer cases than male readers ( < 0.01). A similar pattern as gender category was also found in Breast Screen readers and readers completed breast reading fellowships compared with non-Breast Screen and non-fellowship readers ( < 0.05). Radiologists with low number of cases read per week were more likely to record the cancer cases with category 4 while the ones with high number of cases were with category 3 ( < 0.01). Discrete mass and asymmetric density were the two types of abnormalities reported mostly as equivocal findings with category 3 (47-50%; = 0.005) while spiculated mass or stellate lesions were mostly selected as highly suggestive of malignancy with category 5 (26%, = 0.001).

Conclusions: Most radiologists used category 3 when reporting cancer mammograms. Gender, working for BreastScreen, fellowship completion, and number of cases read per week were factors associated with scoring selection. Radiologists reported higher Tabar BIRADS category for specific types of abnormalities on mammograms than others.

Advances In Knowledge: The study identified factors associated with the decision of radiologists in assigning a BIRADS Tabar score for mammograms with abnormality. These findings will be useful for individual training programs to improve the confidence of radiologists in recognizing abnormal lesions on screening mammograms.
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http://dx.doi.org/10.1259/bjr.20200363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548374PMC
October 2020

Evaluating shared genetic influences on nonsyndromic cleft lip/palate and oropharyngeal neoplasms.

Genet Epidemiol 2020 11 24;44(8):924-933. Epub 2020 Jul 24.

Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, UK.

It has been hypothesised that nonsyndromic cleft lip/palate (nsCL/P) and cancer may share aetiological risk factors. Population studies have found inconsistent evidence for increased incidence of cancer in nsCL/P cases, but several genes (e.g., CDH1, AXIN2) have been implicated in the aetiologies of both phenotypes. We aimed to evaluate shared genetic aetiology between nsCL/P and oral cavity/oropharyngeal cancers (OC/OPC), which affect similar anatomical regions. Using a primary sample of 5,048 OC/OPC cases and 5,450 controls of European ancestry and a replication sample of 750 cases and 336,319 controls from UK Biobank, we estimate genetic overlap using nsCL/P polygenic risk scores (PRS) with Mendelian randomization analyses performed to evaluate potential causal mechanisms. In the primary sample, we found strong evidence for an association between a nsCL/P PRS and increased odds of OC/OPC (per standard deviation increase in score, odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.04, 1.13; p = .000053). Although confidence intervals overlapped with the primary estimate, we did not find confirmatory evidence of an association between the PRS and OC/OPC in UK Biobank (OR 1.02; 95% CI: 0.95, 1.10; p = .55). Mendelian randomization analyses provided evidence that major nsCL/P risk variants are unlikely to influence OC/OPC. Our findings suggest possible shared genetic influences on nsCL/P and OC/OPC.
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http://dx.doi.org/10.1002/gepi.22343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240308PMC
November 2020

A Mendelian randomization study of the causal association between anxiety phenotypes and schizophrenia.

Am J Med Genet B Neuropsychiatr Genet 2020 09 24;183(6):360-369. Epub 2020 Jun 24.

Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Schizophrenia shows a genetic correlation with both anxiety disorder and neuroticism, a trait strongly associated with anxiety. However, genetic correlations do not discern causality from genetic confounding. We therefore aimed to investigate whether anxiety-related phenotypes lie on the causal pathway to schizophrenia using Mendelian randomization (MR). Four MR methods, each with different assumptions regarding instrument validity, were used to investigate casual associations of anxiety and neuroticism related phenotypes on schizophrenia, and vice versa: inverse variance weighted (IVW), weighted median, weighted mode, and, when appropriate, MR Egger regression. MR provided evidence of a causal effect of neuroticism on schizophrenia (IVW odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.12-1.59), but only weak evidence of a causal effect of anxiety on schizophrenia (IVW OR: 1.10, 95% CI: 1.01-1.19). There was also evidence of a causal association from schizophrenia liability to anxiety disorder (IVW OR: 1.28, 95% CI: 1.18-1.39) and worry (IVW beta: 0.05, 95% CI: 0.03-0.07), but effect estimates from schizophrenia to neuroticism were inconsistent in the main analysis. The evidence of neuroticism increasing schizophrenia risk provided by our results supports future efforts to evaluate neuroticism- or anxiety-based therapies to prevent onset of psychotic disorders.
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http://dx.doi.org/10.1002/ajmg.b.32808DOI Listing
September 2020

Cleft lip/palate and educational attainment: cause, consequence or correlation? A Mendelian randomization study.

Int J Epidemiol 2020 08;49(4):1282-1293

MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Background: Previous studies have found that children born with a non-syndromic orofacial cleft have lower-than-average educational attainment. Differences could be due to a genetic predisposition to low intelligence and academic performance, factors arising due to the cleft phenotype (such as social stigmatization, impaired speech/language development) or confounding by the prenatal environment. A clearer understanding of this mechanism will inform interventions to improve educational attainment in individuals born with a cleft, which could substantially improve their quality of life. We assessed evidence for the hypothesis that common variant genetic liability to non-syndromic cleft lip with or without cleft palate (nsCL/P) influences educational attainment.

Methods: We performed a genome-wide association study (GWAS) meta-analysis of nsCL/P with 1692 nsCL/P cases and 4259 parental and unrelated controls. Using GWAS summary statistics, we performed Linkage Disequilibrium (LD)-score regression to estimate the genetic correlation between nsCL/P, educational attainment (GWAS n = 766 345) and intelligence (GWAS n = 257 828). We used two-sample Mendelian randomization to evaluate the causal effects of genetic liability to nsCL/P on educational attainment and intelligence.

Results: There was limited evidence for shared genetic aetiology or causal relationships between nsCL/P and educational attainment [genetic correlation (rg) -0.05, 95% confidence interval (CI) -0.12 to 0.01, P 0.13; MR estimate (βMR) -0.002, 95% CI -0.009 to 0.006, P 0.679) or intelligence (rg -0.04, 95% CI -0.13 to 0.04, P 0.34; βMR -0.009, 95% CI -0.02 to 0.002, P 0.11).

Conclusions: Common variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This is an important first step towards understanding the aetiology of low educational attainment in this group.
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http://dx.doi.org/10.1093/ije/dyaa047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660147PMC
August 2020

Association Between Genetically Proxied Inhibition of HMG-CoA Reductase and Epithelial Ovarian Cancer.

JAMA 2020 02;323(7):646-655

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.

Importance: Preclinical and epidemiological studies indicate a potential chemopreventive role of statins in epithelial ovarian cancer risk.

Objective: To evaluate the association of genetically proxied inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (ie, genetic variants related to lower function of HMG-CoA reductase, target of statins) with epithelial ovarian cancer among the general population and in BRCA1/2 mutation carriers.

Design, Setting, And Participants: Single-nucleotide polymorphisms (SNPs) in HMGCR, NPC1L1, and PCSK9 associated with low-density lipoprotein (LDL) cholesterol in a genome-wide association study (GWAS) meta-analysis (N ≤196 475) were used to proxy therapeutic inhibition of HMG-CoA reductase, Niemann-Pick C1-Like 1 (NPC1L1) and proprotein convertase subtilisin/kexin type 9 (PCSK9), respectively. Summary statistics were obtained for these SNPs from a GWAS meta-analysis of case-control analyses of invasive epithelial ovarian cancer in the Ovarian Cancer Association Consortium (OCAC; N = 63 347) and from a GWAS meta-analysis of retrospective cohort analyses of epithelial ovarian cancer among BRCA1/2 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA; N = 31 448). Across the 2 consortia, participants were enrolled between 1973 and 2014 and followed up through 2015. OCAC participants came from 14 countries and CIMBA participants came from 25 countries. SNPs were combined into multi-allelic models and mendelian randomization estimates representing lifelong inhibition of targets were generated using inverse-variance weighted random-effects models.

Exposures: Primary exposure was genetically proxied inhibition of HMG-CoA reductase and secondary exposures were genetically proxied inhibition of NPC1L1 and PCSK9 and genetically proxied circulating LDL cholesterol levels.

Main Outcomes And Measures: Overall and histotype-specific invasive epithelial ovarian cancer (general population) and epithelial ovarian cancer (BRCA1/2 mutation carriers), measured as ovarian cancer odds (general population) and hazard ratio (BRCA1/2 mutation carriers).

Results: The OCAC sample included 22 406 women with invasive epithelial ovarian cancer and 40 941 control individuals and the CIMBA sample included 3887 women with epithelial ovarian cancer and 27 561 control individuals. Median ages for the cohorts ranged from 41.5 to 59.0 years and all participants were of European ancestry. In the primary analysis, genetically proxied HMG-CoA reductase inhibition equivalent to a 1-mmol/L (38.7-mg/dL) reduction in LDL cholesterol was associated with lower odds of epithelial ovarian cancer (odds ratio [OR], 0.60 [95% CI, 0.43-0.83]; P = .002). In BRCA1/2 mutation carriers, genetically proxied HMG-CoA reductase inhibition was associated with lower ovarian cancer risk (hazard ratio, 0.69 [95% CI, 0.51-0.93]; P = .01). In secondary analyses, there were no significant associations of genetically proxied inhibition of NPC1L1 (OR, 0.97 [95% CI, 0.53-1.75]; P = .91), PCSK9 (OR, 0.98 [95% CI, 0.85-1.13]; P = .80), or circulating LDL cholesterol (OR, 0.98 [95% CI, 0.91-1.05]; P = .55) with epithelial ovarian cancer.

Conclusions And Relevance: Genetically proxied inhibition of HMG-CoA reductase was significantly associated with lower odds of epithelial ovarian cancer. However, these findings do not indicate risk reduction from medications that inhibit HMG-CoA reductase; further research is needed to understand whether there is a similar association with such medications.
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http://dx.doi.org/10.1001/jama.2020.0150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042851PMC
February 2020

Allergy, asthma, and the risk of breast and prostate cancer: a Mendelian randomization study.

Cancer Causes Control 2020 Mar 31;31(3):273-282. Epub 2020 Jan 31.

Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Purpose: The relationship of allergic diseases, such as asthma, hay fever, and eczema, with cancer is under debate. Observational studies have reported conflicting findings, but such studies are susceptible to confounding and reverse causation. Understanding the potential role of allergy in carcinogenesis may shed new light on the biological mechanisms underpinning intrinsic immunity and cancer.

Methods: We conducted a Mendelian randomization study, using germline genetic variants as instrumental variables, to determine the causal relevance of allergic disease and on two most common malignancies: breast cancer and prostate cancer. We used the summary statistics from the largest ever genome-wide association studies conducted on allergic disease (n = 180,129), asthma (n = 14,085), breast (n = 122,977), and prostate cancer (n = 79,148) and calculated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer for allergic disease.

Results: We did not observe any evidence to support a causal association between allergic disease and risk of breast cancer overall [OR 1.00 (95% CI 0.96-1.04), p = 0.95] or by subtype (estrogen receptor (ER)+ [0.99 (0.95-1.04), p = 0.71], ER- [1.05 (0.99-1.10), p = 0.11]). We also did not find any evidence for an association with prostate cancer [1.00 (0.94-1.05), p = 0.93] or advanced subtype [0.97 (0.90-1.05), p = 0.46]. Sensitivity analyses did not reveal directional pleiotropy.

Conclusion: Our study does not support a causal effect of allergic disease on the risk of breast or prostate cancer. Future studies may be conducted to focus on understanding the causal role of allergic disease in cancer prognosis or drug responses (e.g., immunotherapy).
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http://dx.doi.org/10.1007/s10552-020-01271-7DOI Listing
March 2020

Physical activity and risks of breast and colorectal cancer: a Mendelian randomisation analysis.

Nat Commun 2020 01 30;11(1):597. Epub 2020 Jan 30.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.
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http://dx.doi.org/10.1038/s41467-020-14389-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992637PMC
January 2020

Evidence of detrimental effects of prenatal alcohol exposure on offspring birthweight and neurodevelopment from a systematic review of quasi-experimental studies.

Int J Epidemiol 2021 01;49(6):1972-1995

MRC Integrative Epidemiology Unit, Department of Population Health Sciences, University of Bristol, Bristol, UK.

Background: Systematic reviews of prenatal alcohol exposure effects generally only include conventional observational studies. However, estimates from such studies are prone to confounding and other biases.

Objectives: To systematically review the evidence on the effects of prenatal alcohol exposure from randomized controlled trials (RCTs) and observational designs using alternative analytical approaches to improve causal inference.

Search Strategy: Medline, Embase, Web of Science, PsychINFO from inception to 21 June 2018. Manual searches of reference lists of retrieved papers.

Selection Criteria: RCTs of interventions to stop/reduce drinking in pregnancy and observational studies using alternative analytical methods (quasi-experimental studies e.g. Mendelian randomization and natural experiments, negative control comparisons) to determine the causal effects of prenatal alcohol exposure on pregnancy and longer-term offspring outcomes in human studies.

Data Collection And Analysis: One reviewer extracted data and another checked extracted data. Risk of bias was assessed using customized risk of bias tools. A narrative synthesis of findings was carried out and a meta-analysis for one outcome.

Main Results: Twenty-three studies were included, representing five types of study design, including 1 RCT, 9 Mendelian randomization and 7 natural experiment studies, and reporting on over 30 outcomes. One study design-outcome combination included enough independent results to meta-analyse. Based on evidence from several studies, we found a likely causal detrimental role of prenatal alcohol exposure on cognitive outcomes, and weaker evidence for a role in low birthweight.

Conclusion: None of the included studies was judged to be at low risk of bias in all domains, results should therefore be interpreted with caution.

Systematic Review Registration: This study is registered with PROSPERO, registration number CRD42015015941.
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http://dx.doi.org/10.1093/ije/dyz272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825937PMC
January 2021

Appraising causal relationships of dietary, nutritional and physical-activity exposures with overall and aggressive prostate cancer: two-sample Mendelian-randomization study based on 79 148 prostate-cancer cases and 61 106 controls.

Int J Epidemiol 2020 04;49(2):587-596

MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Bristol, UK.

Background: Prostate cancer is the second most common male cancer worldwide, but there is substantial geographical variation, suggesting a potential role for modifiable risk factors in prostate carcinogenesis.

Methods: We identified previously reported prostate cancer risk factors from the World Cancer Research Fund (WCRF)'s systematic appraisal of the global evidence (2018). We assessed whether each identified risk factor was causally associated with risk of overall (79 148 cases and 61 106 controls) or aggressive (15 167 cases and 58 308 controls) prostate cancer using Mendelian randomization (MR) based on genome-wide association-study summary statistics from the PRACTICAL and GAME-ON/ELLIPSE consortia. We assessed evidence for replication in UK Biobank (7844 prostate-cancer cases and 204 001 controls).

Results: WCRF identified 57 potential risk factors, of which 22 could be instrumented for MR analyses using single nucleotide polymorphisms. For overall prostate cancer, we identified evidence compatible with causality for the following risk factors (odds ratio [OR] per standard deviation increase; 95% confidence interval): accelerometer-measured physical activity, OR = 0.49 (0.33-0.72; P = 0.0003); serum iron, OR = 0.92 (0.86-0.98; P = 0.007); body mass index (BMI), OR = 0.90 (0.84-0.97; P = 0.003); and monounsaturated fat, OR = 1.11 (1.02-1.20; P = 0.02). Findings in our replication analyses in UK Biobank were compatible with our main analyses (albeit with wide confidence intervals). In MR analysis, height was positively associated with aggressive-prostate-cancer risk: OR = 1.07 (1.01-1.15; P = 0.03).

Conclusions: The results for physical activity, serum iron, BMI, monounsaturated fat and height are compatible with causality for prostate cancer. The results suggest that interventions aimed at increasing physical activity may reduce prostate-cancer risk, although interventions to change other risk factors may have negative consequences on other diseases.
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http://dx.doi.org/10.1093/ije/dyz235DOI Listing
April 2020

Genetic evidence for assortative mating on alcohol consumption in the UK Biobank.

Nat Commun 2019 11 19;10(1):5039. Epub 2019 Nov 19.

Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, UK.

Alcohol use is correlated within spouse-pairs, but it is difficult to disentangle effects of alcohol consumption on mate-selection from social factors or the shared spousal environment. We hypothesised that genetic variants related to alcohol consumption may, via their effect on alcohol behaviour, influence mate selection. Here, we find strong evidence that an individual's self-reported alcohol consumption and their genotype at rs1229984, a missense variant in ADH1B, are associated with their partner's self-reported alcohol use. Applying Mendelian randomization, we estimate that a unit increase in an individual's weekly alcohol consumption increases partner's alcohol consumption by 0.26 units (95% C.I. 0.15, 0.38; P = 8.20 × 10). Furthermore, we find evidence of spousal genotypic concordance for rs1229984, suggesting that spousal concordance for alcohol consumption existed prior to cohabitation. Although the SNP is strongly associated with ancestry, our results suggest some concordance independent of population stratification. Our findings suggest that alcohol behaviour directly influences mate selection.
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http://dx.doi.org/10.1038/s41467-019-12424-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864067PMC
November 2019

Artificial Intelligence in medical imaging practice: looking to the future.

J Med Radiat Sci 2019 Dec 10;66(4):292-295. Epub 2019 Nov 10.

Discipline of Medical Imaging Science, The University of Sydney, Lidcombe, New South Wales, Australia.

Artificial intelligence (AI) is heralded as the most disruptive technology to health services in the 21 century. Many commentary articles published in the general public and health domains recognise that medical imaging is at the forefront of these changes due to our large digital data footprint. Radiomics is transforming medical images into mineable high-dimensional data to optimise clinical decision-making; however, some would argue that AI could infiltrate workplaces with very few ethical checks and balances. In this commentary article, we describe how AI is beginning to change medical imaging services and the innovations that are on the horizon. We explore how AI and its various forms, including machine learning, will challenge the way medical imaging is delivered from workflow, image acquisition, image registration to interpretation. Diagnostic radiographers will need to learn to work alongside our 'virtual colleagues', and we argue that there are vital changes to entry and advanced curricula together with national professional capabilities to ensure machine-learning tools are used in the safest and most effective manner for our patients.
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http://dx.doi.org/10.1002/jmrs.369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920680PMC
December 2019

Appraising the role of previously reported risk factors in epithelial ovarian cancer risk: A Mendelian randomization analysis.

PLoS Med 2019 08 7;16(8):e1002893. Epub 2019 Aug 7.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.

Background: Various risk factors have been associated with epithelial ovarian cancer risk in observational epidemiological studies. However, the causal nature of the risk factors reported, and thus their suitability as effective intervention targets, is unclear given the susceptibility of conventional observational designs to residual confounding and reverse causation. Mendelian randomization (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observational studies. We used MR to evaluate the association of 12 previously reported risk factors (reproductive, anthropometric, clinical, lifestyle, and molecular factors) with risk of invasive epithelial ovarian cancer, invasive epithelial ovarian cancer histotypes, and low malignant potential tumours.

Methods And Findings: Genetic instruments to proxy 12 risk factors were constructed by identifying single nucleotide polymorphisms (SNPs) that were robustly (P < 5 × 10-8) and independently associated with each respective risk factor in previously reported genome-wide association studies. These risk factors included genetic liability to 3 factors (endometriosis, polycystic ovary syndrome, type 2 diabetes) scaled to reflect a 50% higher odds liability to disease. We obtained summary statistics for the association of these SNPs with risk of overall and histotype-specific invasive epithelial ovarian cancer (22,406 cases; 40,941 controls) and low malignant potential tumours (3,103 cases; 40,941 controls) from the Ovarian Cancer Association Consortium (OCAC). The OCAC dataset comprises 63 genotyping project/case-control sets with participants of European ancestry recruited from 14 countries (US, Australia, Belarus, Germany, Belgium, Denmark, Finland, Norway, Canada, Poland, UK, Spain, Netherlands, and Sweden). SNPs were combined into multi-allelic inverse-variance-weighted fixed or random effects models to generate effect estimates and 95% confidence intervals (CIs). Three complementary sensitivity analyses were performed to examine violations of MR assumptions: MR-Egger regression and weighted median and mode estimators. A Bonferroni-corrected P value threshold was used to establish strong evidence (P < 0.0042) and suggestive evidence (0.0042 < P < 0.05) for associations. In MR analyses, there was strong or suggestive evidence that 2 of the 12 risk factors were associated with invasive epithelial ovarian cancer and 8 of the 12 were associated with 1 or more invasive epithelial ovarian cancer histotypes. There was strong evidence that genetic liability to endometriosis was associated with an increased risk of invasive epithelial ovarian cancer (odds ratio [OR] per 50% higher odds liability: 1.10, 95% CI 1.06-1.15; P = 6.94 × 10-7) and suggestive evidence that lifetime smoking exposure was associated with an increased risk of invasive epithelial ovarian cancer (OR per unit increase in smoking score: 1.36, 95% CI 1.04-1.78; P = 0.02). In analyses examining histotypes and low malignant potential tumours, the strongest associations found were between height and clear cell carcinoma (OR per SD increase: 1.36, 95% CI 1.15-1.61; P = 0.0003); age at natural menopause and endometrioid carcinoma (OR per year later onset: 1.09, 95% CI 1.02-1.16; P = 0.007); and genetic liability to polycystic ovary syndrome and endometrioid carcinoma (OR per 50% higher odds liability: 0.89, 95% CI 0.82-0.96; P = 0.002). There was little evidence for an association of genetic liability to type 2 diabetes, parity, or circulating levels of 25-hydroxyvitamin D and sex hormone binding globulin with ovarian cancer or its subtypes. The primary limitations of this analysis include the modest statistical power for analyses of risk factors in relation to some less common ovarian cancer histotypes (low grade serous, mucinous, and clear cell carcinomas), the inability to directly examine the association of some ovarian cancer risk factors that did not have robust genetic variants available to serve as proxies (e.g., oral contraceptive use, hormone replacement therapy), and the assumption of linear relationships between risk factors and ovarian cancer risk.

Conclusions: Our comprehensive examination of possible aetiological drivers of ovarian carcinogenesis using germline genetic variants to proxy risk factors supports a role for few of these factors in invasive epithelial ovarian cancer overall and suggests distinct aetiologies across histotypes. The identification of novel risk factors remains an important priority for the prevention of epithelial ovarian cancer.
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http://dx.doi.org/10.1371/journal.pmed.1002893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685606PMC
August 2019

Sex hormone binding globulin and risk of breast cancer: a Mendelian randomization study.

Int J Epidemiol 2019 06;48(3):807-816

Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.

Background: There are observational data suggesting an inverse association between circulating concentrations of sex hormone binding globulin (SHBG) and risk of postmenopausal breast cancer. However, causality is uncertain and few studies have investigated this association by tumour receptor status. We aimed to investigate these associations under the causal framework of Mendelian randomization (MR).

Methods: We used summary association estimates extracted from published genome-wide association study (GWAS) meta-analyses for SHBG and breast cancer, to perform two-sample MR analyses. Summary statistics were available for 122 977 overall breast cancer cases, of which 69 501 were estrogen receptor positive (ER+ve) and 21 468 were ER-ve, and 105 974 controls. To control for potential horizontal pleiotropy acting via body mass index (BMI), we performed multivariable inverse-variance weighted (IVW) MR as the main analysis, with the robustness of this approach further tested in sensitivity analyses.

Results: The multivariable IVW MR analysis indicated a lower risk of overall (odds ratio [OR]: 0.94; 95% confidence interval [CI]: 0.90, 0.98; P: 0.006) and ER+ve (OR: 0.92; 95% CI: 0.87, 0.97; P: 0.003) breast cancer, and a higher risk of ER-ve disease (OR: 1.09; 95% CI: 1.00, 1.18; P: 0.047) per 25 nmol/L higher SHBG levels. Sensitivity analyses were consistent with the findings of the main analysis.

Conclusions: We corroborated the previous literature evidence coming from observational studies for a potentially causal inverse association between SHBG concentrations and risk of ER+ve breast cancer, but our findings also suggested a potential novel positive association with ER-ve disease that warrants further investigation, given the low prior probability of being true.
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http://dx.doi.org/10.1093/ije/dyz107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659370PMC
June 2019

Prenatal alcohol exposure and facial morphology in a UK cohort.

Drug Alcohol Depend 2019 04 5;197:42-47. Epub 2019 Feb 5.

MRC Integrative Epidemiology Unit, Population Health Sciences, Oakfield House, Oakfield Grove, University of Bristol, BS8 2BN, UK; Bristol Dental School, University of Bristol, UK. Electronic address:

Background: High levels of prenatal alcohol exposure are known to cause an array of adverse outcomes including fetal alcohol syndrome (FAS); however, the effects of low to moderate exposure are less-well characterized. Previous findings suggest that differences in normal-range facial morphology may be a marker for alcohol exposure and related adverse effects.

Methods: In the Avon Longitudinal Study of Parents and Children, we tested for an association between maternal alcohol consumption and six FAS-related facial phenotypes in their offspring, using both self-report questionnaires and the maternal genotype at rs1229984 in ADH1B as measures of maternal alcohol consumption.

Results: In both self-reported alcohol consumption (N = 4233) and rs1229984 genotype (N = 3139) analyses, we found no strong statistical evidence for an association between maternal alcohol consumption and facial phenotypes tested. The directions of effect estimates were compatible with the known effects of heavy alcohol exposure, but confidence intervals were largely centered around zero.

Conclusions: There is no strong evidence, in a sample representative of the general population, for an effect of prenatal alcohol exposure on normal-range variation in facial morphology.
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http://dx.doi.org/10.1016/j.drugalcdep.2018.11.031DOI Listing
April 2019

Does testosterone mediate the relationship between vitamin D and prostate cancer? A systematic review and meta-analysis protocol.

Syst Rev 2019 02 12;8(1):52. Epub 2019 Feb 12.

Bristol Medicine School, Population Health Sciences, University of Bristol, Bristol, England.

Background: Evidence from studies on prostate cancer progression have identified vitamin D to be a potentially important nutrient. However, the World Cancer Research Fund and American Institute for Cancer Research have reported the quality of this evidence to be limited and warrant further investigation. We plan to use the recently developed WCRF International/University of Bristol mechanistic systematic review framework to determine whether the observed association between vitamin D and prostate cancer exists through a plausible biological pathway.

Methods: This protocol sets out how we will perform a systematic review of the literature in human and animal studies. We will search the electronic databases MEDLINE, EMBASE, PubMed, and BIOSIS Citation Index without restrictions on year of publication or language. We will extract data from observational and experimental studies examining two inter-linked pathways in the relationship between vitamin D and prostate cancer progression: (1) vitamin D and testosterone, and (2) testosterone and prostate cancer progression. We focus on testosterone as its actions form a potentially novel intermediate mechanism that was identified via our online literature mining tools. The outcomes of interest include incidence or prevalence of prostate cancer, measures of prostate cancer progression (including biochemical recurrence, local, or distal metastases), and prostate cancer-specific mortality. We will assess study quality and the level of certainty of the evidence. We will analyse data where possible, using meta-analysis with forest plots or albatross plots; otherwise, a narrative synthesis will be performed.

Discussion: To our knowledge, this will be the first systematic synthesis of the evidence underpinning the vitamin D-testosterone-prostate cancer mechanistic pathway. The results of the review may inform future research, intervention trials, and public health messages.
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http://dx.doi.org/10.1186/s13643-018-0908-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371501PMC
February 2019

Evidence for DNA methylation mediating genetic liability to non-syndromic cleft lip/palate.

Epigenomics 2019 02 14;11(2):133-145. Epub 2019 Jan 14.

MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, BS8 2BN, UK.

Aim: To determine if nonsyndromic cleft lip with or without cleft palate (nsCL/P) genetic risk variants influence liability to nsCL/P through gene regulation pathways, such as those involving DNA methylation.

Materials & Methods: nsCL/P genetic summary data and methylation data from four studies were used in conjunction with Mendelian randomization and joint likelihood mapping to investigate potential mediation of nsCL/P genetic variants.

Results & Conclusion: Evidence was found at VAX1 (10q25.3), LOC146880 (17q23.3) and NTN1 (17p13.1), that liability to nsCL/P and variation in DNA methylation might be driven by the same genetic variant, suggesting that genetic variation at these loci may increase liability to nsCL/P by influencing DNA methylation. Follow-up analyses using different tissues and gene expression data provided further insight into possible biological mechanisms.
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http://dx.doi.org/10.2217/epi-2018-0091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462847PMC
February 2019

Circulating vitamin D concentrations and risk of breast and prostate cancer: a Mendelian randomization study.

Int J Epidemiol 2019 10;48(5):1416-1424

Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Ioannina, Greece.

Background: Observational studies have suggested an association between circulating vitamin D concentrations [25(OH)D] and risk of breast and prostate cancer, which was not supported by a recent Mendelian randomization (MR) analysis comprising 15 748 breast and 22 898 prostate-cancer cases. Demonstrating causality has proven challenging and one common limitation of MR studies is insufficient power.

Methods: We aimed to determine whether circulating concentrations of vitamin D are causally associated with the risk of breast and prostate cancer, by using summary-level data from the largest ever genome-wide association studies conducted on vitamin D (N = 73 699), breast cancer (Ncase = 122 977) and prostate cancer (Ncase = 79 148). We constructed a stronger instrument using six common genetic variants (compared with the previous four variants) and applied several two-sample MR methods.

Results: We found no evidence to support a causal association between 25(OH)D and risk of breast cancer [OR per 25 nmol/L increase, 1.02 (95% confidence interval: 0.97-1.08), P = 0.47], oestrogen receptor (ER)+ [1.00 (0.94-1.07), P = 0.99] or ER- [1.02 (0.90-1.16), P = 0.75] subsets, prostate cancer [1.00 (0.93-1.07), P = 0.99] or the advanced subtype [1.02 (0.90-1.16), P = 0.72] using the inverse-variance-weighted method. Sensitivity analyses did not reveal any sign of directional pleiotropy.

Conclusions: Despite its almost five-fold augmented sample size and substantially improved statistical power, our MR analysis does not support a causal effect of circulating 25(OH)D concentrations on breast- or prostate-cancer risk. However, we can still not exclude a modest or non-linear effect of vitamin D. Future studies may be designed to understand the effect of vitamin D in subpopulations with a profound deficiency.
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http://dx.doi.org/10.1093/ije/dyy284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934026PMC
October 2019

Radiation Therapy Patient Education Review and a Case Study Using the Virtual Environment for Radiotherapy Training System.

J Med Imaging Radiat Sci 2018 03 13;49(1):106-117. Epub 2017 Sep 13.

Faculty of Health Sciences, The University of Sydney, Lidcombe, New South Wales, Australia.

Introduction: The emergence of modern learning environments for radiation therapy (RT) education offers innovative opportunities for RT patients. This article presents a descriptive review of the current state of practice for two recently available tools, the "Virtual Environment for Radiotherapy Training" (VERT) and the "Patient Education And Radiotherapy Learning" (PEARL) systems. Subsequently, a case study summarizes the instructional design and development of an RT breast cancer patient education program, with the intention of providing a blueprint for further patient education initiatives that incorporate VERT.

Methods: A total of 278 articles were identified for the descriptive review, using academic databases and a grey literature search. After screening for descriptive accounts of patient education interventions using VERT or PEARL, five full articles were retrieved and coded using a data extraction protocol. This information was used to inform the subsequent development of a breast cancer education program using a three-step development model, encompassing (1) consultation process and literature review; (2) program content and instructional process; and (3) program evaluation plan. The VERT integration process within the second stage is the focus of the case study presented.

Results: The literature search found that methods for the design, delivery, and evaluation of the education programs varied across studies. Positive impacts of VERT and PEARL in patient education have been demonstrated. The development of the 1-hour education program was based on comprehensive, evidence-based learner literature and was designed with the intention of specifically engaging learners with the three-dimensional VERT system. In particular, the VERT integration process aimed to exploit VERT's range of visualization features and draw upon the multidisciplinary nature of radiation cancer care.

Discussion: VERT and PEARL offer innovative education opportunities and have been justly recognized as valuable tools for RT patient education. When aligned to an educational framework, rich visual displays offered by VERT and PEARL have the potential to support patient education programs and exploit the advantages of a virtual RT environment. With the increasing accessibility of these tools, the data presented in this article offer information for educators interested in development and evaluation of future patient education programs. Feasibility and economic aspects need to be addressed within local departments, and further research is required to ascertain specific capability of VERT and PEARL in supporting psychological and health-related patient outcomes.
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http://dx.doi.org/10.1016/j.jmir.2017.07.005DOI Listing
March 2018

Mendelian randomization does not support serum calcium in prostate cancer risk.

Cancer Causes Control 2018 Nov 10;29(11):1073-1080. Epub 2018 Oct 10.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Purpose: Observational studies suggest that dietary and serum calcium are risk factors for prostate cancer. However, such studies suffer from residual confounding (due to unmeasured or imprecisely measured confounders), undermining causal inference. Mendelian randomization uses randomly assigned (hence unconfounded and pre-disease onset) germline genetic variation to proxy for phenotypes and strengthen causal inference in observational studies. We tested the hypothesis that serum calcium is associated with an increased risk of overall and advanced prostate cancer.

Methods: A genetic instrument was constructed using five single-nucleotide polymorphisms robustly associated with serum calcium in a genome-wide association study (n ≤ 61,079). This instrument was then used to test the effect of a 0.5 mg/dL increase (1 standard deviation, SD) in serum calcium on risk of prostate cancer in 72,729 men in the PRACTICAL (Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome) Consortium (44,825 cases, 27,904 controls) and risk of advanced prostate cancer in 33,498 men (6,263 cases, 27,235 controls).

Results: We found weak evidence for a protective effect of serum calcium on prostate cancer risk (odds ratio [OR] per 0.5 mg/dL increase in calcium: 0.83, 95% CI 0.63-1.08; p = 0.12). We did not find strong evidence for an effect of serum calcium on advanced prostate cancer (OR per 0.5 mg/dL increase in calcium: 0.98, 95% CI 0.57-1.70; p = 0.93).

Conclusions: Our Mendelian randomization analysis does not support the hypothesis that serum calcium increases risk of overall or advanced prostate cancer.
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http://dx.doi.org/10.1007/s10552-018-1081-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245088PMC
November 2018

Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology.

PLoS Genet 2018 08 1;14(8):e1007501. Epub 2018 Aug 1.

Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, United Kingdom.

There is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used polygenic risk scores (PRS) to test for genetic overlap between nsCL/P and seven biologically relevant facial phenotypes. Where evidence was found of genetic overlap, we used bidirectional Mendelian randomization (MR) to test the hypothesis that genetic liability to nsCL/P is causally related to implicated facial phenotypes. Across 5,804 individuals of European ancestry from two studies, we found strong evidence, using PRS, of genetic overlap between nsCL/P and philtrum width; a 1 S.D. increase in nsCL/P PRS was associated with a 0.10 mm decrease in philtrum width (95% C.I. 0.054, 0.146; P = 2x10-5). Follow-up MR analyses supported a causal relationship; genetic variants for nsCL/P homogeneously cause decreased philtrum width. In addition to the primary analysis, we also identified two novel risk loci for philtrum width at 5q22.2 and 7p15.2 in our Genome-wide Association Study (GWAS) of 6,136 individuals. Our results support a liability threshold model of inheritance for nsCL/P, related to abnormalities in development of the philtrum.
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http://dx.doi.org/10.1371/journal.pgen.1007501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089455PMC
August 2018

Causal Inference in Cancer Epidemiology: What Is the Role of Mendelian Randomization?

Cancer Epidemiol Biomarkers Prev 2018 09 25;27(9):995-1010. Epub 2018 Jun 25.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.

Observational epidemiologic studies are prone to confounding, measurement error, and reverse causation, undermining robust causal inference. Mendelian randomization (MR) uses genetic variants to proxy modifiable exposures to generate more reliable estimates of the causal effects of these exposures on diseases and their outcomes. MR has seen widespread adoption within cardio-metabolic epidemiology, but also holds much promise for identifying possible interventions for cancer prevention and treatment. However, some methodologic challenges in the implementation of MR are particularly pertinent when applying this method to cancer etiology and prognosis, including reverse causation arising from disease latency and selection bias in studies of cancer progression. These issues must be carefully considered to ensure appropriate design, analysis, and interpretation of such studies. In this review, we provide an overview of the key principles and assumptions of MR, focusing on applications of this method to the study of cancer etiology and prognosis. We summarize recent studies in the cancer literature that have adopted a MR framework to highlight strengths of this approach compared with conventional epidemiological studies. Finally, limitations of MR and recent methodologic developments to address them are discussed, along with the translational opportunities they present to inform public health and clinical interventions in cancer. .
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http://dx.doi.org/10.1158/1055-9965.EPI-17-1177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522350PMC
September 2018

Radiologists can detect the 'gist' of breast cancer before any overt signs of cancer appear.

Sci Rep 2018 06 7;8(1):8717. Epub 2018 Jun 7.

Department of Psychology, University of York, Heslington, York, UK.

Radiologists can detect abnormality in mammograms at above-chance levels after a momentary glimpse of an image. The study investigated this instantaneous perception of an abnormality, known as a "gist" response, when 23 radiologists viewed prior mammograms of women that were reported as normal, but later diagnosed with breast cancer at subsequent screening. Five categories of cases were included: current cancer-containing mammograms, current mammograms of the normal breast contralateral to the cancer, prior mammograms of normal cases, prior mammograms with visible cancer signs in a breast from women who were initially reported as normal, but later diagnosed with breast cancer at subsequent screening in the same breast, and prior mammograms without any visible cancer signs from women labelled as initially normal but subsequently diagnosed with cancer. Our findings suggest that readers can distinguish patients who were diagnosed with cancer, from individuals without breast cancer (normal category), at above-chance levels based on a half-second glimpse of the mammogram even before any lesion becomes visible on the mammogram. Although 20 of the 23 radiologists demonstrated this ability, radiologists' abilities for perceiving the gist of the abnormal varied between the readers and appeared to be linked to expertise. These results could have implications for identifying women of higher than average risk of a future malignancy event, thus impacting upon tailored screening strategies.
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http://dx.doi.org/10.1038/s41598-018-26100-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992208PMC
June 2018
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