Imperial College London

Dr David C Muller

Faculty of MedicineSchool of Public Health

Lecturer in Cancer Epidemiology and Biostatistics
 
 
 
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Contact

 

+44 (0)20 7594 0856david.muller

 
 
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Location

 

VC2Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

82 results found

Christakoudi S, Tsilidis KK, Muller DC, Freisling H, Weiderpass E, Overvad K, Söderberg S, Häggström C, Pischon T, Dahm CC, Zhang J, Tjønneland A, Halkjær J, MacDonald C, Boutron-Ruault M-C, Mancini FR, Kühn T, Kaaks R, Schulze MB, Trichopoulou A, Karakatsani A, Peppa E, Masala G, Pala V, Panico S, Tumino R, Sacerdote C, Quirós JR, Agudo A, Sánchez M-J, Cirera L, Barricarte-Gurrea A, Amiano P, Memarian E, Sonestedt E, Bueno-de-Mesquita B, May AM, Khaw K-T, Wareham NJ, Tong TYN, Huybrechts I, Noh H, Aglago EK, Ellingjord-Dale M, Ward HA, Aune D, Riboli Eet al., 2020, ABSI (A Body Shape Index) achieves better mortality risk stratification than alternative indices of abdominal obesity: results from a large European cohort, Scientific Reports, Vol: 10, ISSN: 2045-2322

Abdominal and general adiposity are independently associated with mortality, but there is no consensus on how best to assess abdominal adiposity. We compared the ability of alternative waist indices to complement body mass index (BMI) when assessing all-cause mortality. We used data from 352,985 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) and Cox proportional hazards models adjusted for other risk factors. During a mean follow-up of 16.1 years, 38,178 participants died. Combining in one model BMI and a strongly correlated waist index altered the association patterns with mortality, to a predominantly negative association for BMI and a stronger positive association for the waist index, while combining BMI with the uncorrelated A Body Shape Index (ABSI) preserved the association patterns. Sex-specific cohort-wide quartiles of waist indices correlated with BMI could not separate high-risk from low-risk individuals within underweight (BMI<18.5 kg/m2) or obese (BMI≥30 kg/m2) categories, while the highest quartile of ABSI separated 18%-39% of the individuals within each BMI category, which had 22%-55% higher risk of death. In conclusion, only a waist index independent of BMI by design, such as ABSI, complements BMI and enables efficient risk stratification, which could facilitate personalisation of screening, treatment and monitoring.

Journal article

Thomas M, Sakoda LC, Hoffmeister M, Rosenthal EA, Lee JK, van Duijnhoven FJB, Platz EA, Wu AH, Dampier CH, de la Chapelle A, Wolk A, Joshi AD, Burnett-Hartman A, Gsur A, Lindblom A, Castells A, Win AK, Namjou B, Van Guelpen B, Tangen CM, He Q, Li CI, Schafmayer C, Joshu CE, Ulrich CM, Bishop DT, Buchanan DD, Schaid D, Drew DA, Muller DC, Duggan D, Crosslin DR, Albanes D, Giovannucci EL, Larson E, Qu F, Mentch F, Giles GG, Hakonarson H, Hampel H, Stanaway IB, Figueiredo JC, Huyghe JR, Minnier J, Chang-Claude J, Hampe J, Harley JB, Visvanathan K, Curtis KR, Offit K, Li L, Le Marchand L, Vodickova L, Gunter MJ, Jenkins MA, Slattery ML, Lemire M, Woods MO, Song M, Murphy N, Lindor NM, Dikilitas O, Pharoah PDP, Campbell PT, Newcomb PA, Milne RL, MacInnis RJ, Castellví-Bel S, Ogino S, Berndt SI, Bézieau S, Thibodeau SN, Gallinger SJ, Zaidi SH, Harrison TA, Keku TO, Hudson TJ, Vymetalkova V, Moreno V, Martín V, Arndt V, Wei W-Q, Chung W, Su Y-R, Hayes RB, White E, Vodicka P, Casey G, Gruber SB, Schoen RE, Chan AT, Potter JD, Brenner H, Jarvik GP, Corley DA, Peters U, Hsu Let al., 2020, Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk., Am J Hum Genet, Vol: 107, Pages: 432-444

Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but mig

Journal article

Loveday C, Sud A, Jones ME, Broggio J, Scott S, Gronthound F, Torr B, Garrett A, Nicol DL, Jhanji S, Boyce SA, Williams M, Barry C, Riboli E, Kipps E, McFerran E, Muller DC, Lyratzopoulos G, Lawler M, Abulafi M, Houlston RS, Turnbull Cet al., 2020, Prioritisation by FIT to mitigate the impact of delays in the 2-week wait colorectal cancer referral pathway during the COVID-19 pandemic: a UK modelling study, Gut, ISSN: 0017-5749

OBJECTIVE: To evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent from the COVID-19 pandemic. DESIGN: We modelled the reduction in CRC survival and life years lost resultant from per-patient delays of 2-6 months in the 2WW pathway. We stratified by age group, individual-level benefit in CRC survival versus age-specific nosocomial COVID-19-related fatality per referred patient undergoing colonoscopy. We modelled mitigation strategies using thresholds of FIT triage of 2, 10 and 150 µg Hb/g to prioritise 2WW referrals for colonoscopy. To construct the underlying models, we employed 10-year net CRC survival for England 2008-2017, 2WW pathway CRC case and referral volumes and per-day-delay HRs generated from observational studies of diagnosis-to-treatment interval. RESULTS: Delay of 2/4/6 months across all 11 266 patients with CRC diagnosed per typical year via the 2WW pathway were estimated to result in 653/1419/2250 attributable deaths and loss of 9214/20 315/32 799 life years. Risk-benefit from urgent investigatory referral is particularly sensitive to nosocomial COVID-19 rates for patients aged >60. Prioritisation out of delay for the 18% of symptomatic referrals with FIT >10 µg Hb/g would avoid 89% of these deaths attributable to presentational/diagnostic delay while reducing immediate requirement for colonoscopy by >80%. CONCLUSIONS: Delays in the pathway to CRC diagnosis and treatment have potential to cause significant mortality and loss of life years. FIT triage of symptomatic patients in primary care could streamline access to colonoscopy, reduce delays for true-positive CRC cases and reduce nosocomial COVID-19 mortality in older true-negative 2WW referrals. However, this strategy offers benefit only in short-term rationalisation of limited endoscopy services: the a

Journal article

Sud A, Torr B, Jones M, Broggio J, Scott S, Loveday C, Garrett A, Gronthoud F, Nicol D, Jhanji S, Boyce S, Williams M, Riboli E, Muller D, Kipps E, Larkin J, Navani N, Swanton C, Lyratzopoulos G, McFerran E, Lawler M, Houlston R, Turnbull Cet al., 2020, Effect of delays in the UK two-week wait cancer referral pathway during the COVID-19 pandemic on cancer survival: a modelling study, The Lancet Oncology, Vol: 21, Pages: 1035-1044, ISSN: 1213-9432

Background: During the COVID-19 lockdown, referrals via the 2 Week Wait (2WW) urgent pathway for suspected cancer in England are reported to have dropped by up to 84%. We aimed to examine the impact on cancer survival of different scenarios of lockdown accumulated-backlog. We also aimed to examine by tumour-referral-group and age, survival benefit per referred patient considering survival decrement from delayed referral versus risk of death from nosocomial SARS-CoV-2 infection.Methods: To construct the underlying models, we used age- and stage-stratified 10 year cancer survival estimates for England 2007-2017 for 20 common tumour-types. We applied per-day hazard ratios for cancer progression generated from observational studies of delay to-treatment. We quantified the annual numbers of cancers diagnosed via the 2WW-pathway using the 2WW age- and stage-specific breakdowns. From these, for per-patient delays of 1- 6 months, we estimated aggregate number of lives lost and life-years lost in England. Using referral-to-diagnosis conversion rates and COVID-19 case fatality rates, we also estimated the survival increment per patient referred. Findings: Per month across England in 2013-2016, on average 6,281 patients with Stage 1- 3 cancer were diagnosed via the 2WW pathway of whom 1,691 would be predicted to die within 10 years from their disease. We estimated 2WW-pathway presentational-delay from three months of lockdown will result in total in 181/361/542 attributable additional deaths (if % reduction in referrals was 25/50/75% respectively). Limited diagnostic capacity to address the backlog may result in additional delays: 401/811/1,231 attributable additional deaths are estimated if additional diagnostic capacity is delayed until months 3-8 post-lockdown. 2-month delay in 2WW investigatory referral results in average loss of life-years per-referred-patient of between 0 and 0.7, depending on age and tumour-type. Interpretation: Prompt provision of additional capacity f

Journal article

Elliott P, Muller DC, Schneider-Luftman D, Pazoki R, Evangelou E, Dehghan A, Neal B, Tzoulaki Iet al., 2020, Estimated 24-hour urinary sodium excretion and incident cardiovascular disease and mortality among 398 628 individuals in UK biobank., Hypertension, Vol: 76, Pages: 1-9, ISSN: 0194-911X

We report on an analysis to explore the association between estimated 24-hour urinary sodium excretion (surrogate for sodium intake) and incident cardiovascular disease (CVD) and mortality. Data were obtained from 398 628 UK Biobank prospective cohort study participants (40-69 years) recruited between 2006 and 2010, with no history of CVD, renal disease, diabetes mellitus or cancer, and cardiovascular events and mortality recorded during follow-up. Hazard ratios between 24-hour sodium excretion were estimated from spot urinary sodium concentrations across incident CVD and its components and all-cause and cause-specific mortality. In restricted cubic splines analyses, there was little evidence for an association between estimated 24-hour sodium excretion and CVD, coronary heart disease, or stroke; hazard ratios for CVD (95% CIs) for the 15th and 85th percentiles (2.5 and 4.2 g/day, respectively) compared with the 50th percentile of estimated sodium excretion (3.2 g/day) were 1.05 (1.01-1.10) and 0.96 (0.92-1.00), respectively. An inverse association was observed with heart failure, but that was no longer apparent in sensitivity analysis. A J-shaped association was observed between estimated sodium excretion and mortality. Our findings do not support a J-shaped association of estimated sodium excretion with CVD, although such an association was apparent for all-cause and cause-specific mortality across a wide range of diseases. Reasons for these differences are unclear; methodological limitations, including the use of estimating equations based on spot urinary data, need to be considered in interpreting our findings.

Journal article

Maric T, Kanu C, Muller DC, Tzoulaki I, Johnson MR, Savvidou MDet al., 2020, Fetal growth and fetoplacental circulation in pregnancies following bariatric surgery: a prospective study, Publisher: WILEY, Pages: 839-846, ISSN: 1470-0328

Conference paper

Ji X, Mukherjee S, Landi MT, Bosse Y, Joubert P, Zhu D, Gorlov I, Xiao X, Han Y, Gorlova O, Hung RJ, Brhane Y, Carreras-Torres R, Christiani DC, Caporaso N, Johansson M, Liu G, Bojesen SE, Le Marchand L, Albanes D, Bickeböller H, Aldrich MC, Bush WS, Tardon A, Rennert G, Chen C, Byun J, Dragnev KH, Field JK, Kiemeney LF, Lazarus P, Zienolddiny S, Lam S, Schabath MB, Andrew AS, Bertazzi PA, Pesatori AC, Diao N, Su L, Song L, Zhang R, Leighl N, Johansen JS, Mellemgaard A, Saliba W, Haiman C, Wilkens L, Fernandez-Somoano A, Fernandez-Tardon G, Heijden EHFMVD, Kim JH, Davies MPA, Marcus MW, Brunnström H, Manjer J, Melander O, Muller DC, Overvad K, Trichopoulou A, Tumino R, Goodman GE, Cox A, Taylor F, Woll P, Wichmann E, Muley T, Risch A, Rosenberger A, Grankvist K, Johansson M, Shepherd F, Tsao M-S, Arnold SM, Haura EB, Bolca C, Holcatova I, Janout V, Kontic M, Lissowska J, Mukeria A, Ognjanovic S, Orlowski TM, Scelo G, Swiatkowska B, Zaridze D, Bakke P, Skaug V, Butler LM, Offit K, Srinivasan P, Bandlamudi C, Hellmann MD, Solit DB, Robson ME, Rudin CM, Stadler ZK, Taylor BS, Berger MF, Houlston R, McLaughlin J, Stevens V, Nickle DC, Obeidat M, Timens W, Artigas MS, Shete S, Brenner H, Chanock S, Brennan P, McKay JD, Amos CIet al., 2020, Protein-altering germline mutations implicate novel genes related to lung cancer development., Nature Communications, Vol: 11, Pages: 1-14, ISSN: 2041-1723

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10-15) and replication (adjusted OR = 2.93, P = 2.22 × 10-3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10-22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.

Journal article

Clasen J, Heath AK, Scelo G, Muller DCet al., 2020, Components of one-carbon metabolism and renal cell carcinoma: A systematic review and meta-analysis, European Journal of Nutrition, ISSN: 0044-264X

PurposeLittle is known about the aetiology of renal cell carcinoma (RCC). Components of one-carbon (1C) metabolism, which are required for nucleotide synthesis and methylation reactions, may be related to risk of RCC but existing evidence is inconclusive. We conducted a systematic review and independent exposure-specific meta-analyses of dietary intake and circulating biomarkers of 1C metabolites and RCC risk.MethodsMedline and Embase databases were searched for observational studies investigating RCC or kidney cancer incidence or mortality in relation to components of 1C metabolism and 12 eligible articles were included in the meta-analyses. We used Bayesian meta-analyses to estimate summary relative risks (RRs) and 95% credible intervals (CrIs) comparing the highest versus lowest categories as well as the between-study heterogeneity.ResultsWe did not find convincing evidence of an association between any exposure (riboflavin, vitamin B6, folate, vitamin B12, methionine, homocysteine, choline, or betaine) and RCC risk. However, vitamin B6 biomarker status did have a protective (RR = 0.62) but imprecise (95% CrI 0.39–1.14) effect estimate and folate intake had a notable association as well (RR = 0.85, 95% CrI 0.71–1.01).ConclusionThere was a lack of precision due largely to the low number of studies. Further investigation is warranted, especially for folate and vitamin B6, which had consistent suggestive evidence of a protective effect for both dietary intake and biomarker status. A unique strength of this review is the use of Bayesian meta-analyses which allowed for robust estimation of between-study heterogeneity.

Journal article

Elliott J, Bodinier B, Bond TA, Chadeau-Hyam M, Evangelou E, Moons KGM, Dehghan A, Muller DC, Elliott P, Tzoulaki Iet al., 2020, Predictive Accuracy of a Polygenic Risk Score-Enhanced Prediction Model vs a Clinical Risk Score for Coronary Artery Disease, JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, Vol: 323, Pages: 636-645, ISSN: 0098-7484

Journal article

Sanikini H, Muller DC, Sophiea M, Rinaldi S, Agudo A, Duell EJ, Weiderpass E, Overvad K, Tjønneland A, Halkjaer J, Boutron-Ruault M-C, Carbonnel F, Cervenka I, Boeing H, Kaaks R, Kühn T, Trichopoulou A, Martimianaki G, Karakatsani A, Pala V, Palli D, Mattiello A, Tumino R, Sacerdote C, Skeie G, Rylander C, López MDC, Sánchez M-J, Ardanaz E, Regnér S, Stocks T, Bueno-de-Mesquita B, Vermeulen RCH, Aune D, Tong TYN, Kliemann N, Murphy N, Chadeau-Hyam M, Gunter MJ, Cross AJet al., 2020, Anthropometric and reproductive factors and risk of esophageal and gastric cancer by subtype and subsite: results from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, International Journal of Cancer, Vol: 146, Pages: 929-942, ISSN: 0020-7136

Obesity has been associated with upper gastrointestinal cancers; however, there are limited prospective data on associations by subtype/subsite. Obesity can impact hormonal factors, which have been hypothesized to play a role in these cancers. We investigated anthropometric and reproductive factors in relation to esophageal and gastric cancer by subtype and subsite for 476,160 participants from the European Prospective Investigation into Cancer and Nutrition cohort. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox models. During a mean follow‐up of 14 years, 220 esophageal adenocarcinomas (EA), 195 esophageal squamous cell carcinomas, 243 gastric cardia (GC) and 373 gastric noncardia (GNC) cancers were diagnosed. Body mass index (BMI) was associated with EA in men (BMI ≥30 vs. 18.5–25 kg/m2: HR = 1.94, 95% CI: 1.25–3.03) and women (HR = 2.66, 95% CI: 1.15–6.19); however, adjustment for waist‐to‐hip ratio (WHR) attenuated these associations. After mutual adjustment for BMI and HC, respectively, WHR and waist circumference (WC) were associated with EA in men (HR = 3.47, 95% CI: 1.99–6.06 for WHR >0.96 vs. <0.91; HR = 2.67, 95% CI: 1.52–4.72 for WC >98 vs. <90 cm) and women (HR = 4.40, 95% CI: 1.35–14.33 for WHR >0.82 vs. <0.76; HR = 5.67, 95% CI: 1.76–18.26 for WC >84 vs. <74 cm). WHR was also positively associated with GC in women, and WC was positively associated with GC in men. Inverse associations were observed between parity and EA (HR = 0.38, 95% CI: 0.14–0.99; >2 vs. 0) and age at first pregnancy and GNC (HR = 0.54, 95% CI: 0.32–0.91; >26 vs. <22 years); whereas bilateral ovariectomy was positively associated with GNC (HR = 1.87, 95% CI: 1.04–3.36). These findings support a role for hormonal pathways in upper gastrointestinal cancers.

Journal article

Heath A, Muller D, van den Brandt P, Papadimitriou N, Critselis E, Gunter M, Vineis P, Weiderpass E, Fagherazzi G, Boeing H, Ferrari P, Olsen A, Tjønneland A, Arveux P, Boutron-Ruault M-C, Romana Mancini F, Kühn T, Turzanski-Fortner R, Schulze M, Karakatsani A, Thriskos P, Trichopoulou A, Masala G, Contiero P, Ricceri F, Panico S, Bueno-de-Mesquita B, Bakker M, van Gils C, Standahl Olsen K, Skeie G, Lasheras C, Agudo A, Rodríguez-Barranco M, Sánchez M-J, Amiano P, Chirlaque M-D, Barricarte A, Drake I, Ericson U, Johansson I, Winkvist A, Key T, Freisling H, His M, Huybrechts I, Christakoudi S, Ellingjord-Dale M, Riboli E, Tsilidis K, Tzoulaki Iet al., 2020, Nutrient-wide association study of 92 foods and nutrients and breast cancer risk, Breast Cancer Research, Vol: 22, ISSN: 1465-542X

Background: Several dietary factors have been reported to be associated with risk of breast cancer, but to date unequivocal evidence only exists for alcohol consumption. We sought to systematically assess the association between intake of 92 foods and nutrients and breast cancer risk using a nutrient-wide association study. Methods: Using data from 272,098 women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, we assessed dietary intake of 92 foods and nutrients estimated by dietary questionnaires. Cox regression was used to quantify the association between each food/nutrient and risk of breast cancer. A false discovery rate (FDR) of 0.05 was used to select the set of foods and nutrients to be replicated in the independent Netherlands Cohort Study (NLCS). Results: Six foods and nutrients were identified as associated with risk of breast cancer in the EPIC study (10,979 cases). Higher intake of alcohol overall was associated with a higher risk of breast cancer (hazard ratio (HR) for a 1 SD increment in intake = 1.05, 95% CI 1.03–1.07), as was beer/cider intake and wine intake (HRs per 1 SD increment = 1.05, 95% CI 1.03–1.06 and 1.04, 95% CI 1.02–1.06, respectively), whereas higher intakes of fibre, apple/pear, and carbohydrates were associated with a lower risk of breast cancer (HRs per 1 SD increment = 0.96, 95% CI 0.94–0.98; 0.96, 95% CI 0.94–0.99; and 0.96, 95% CI 0.95–0.98, respectively). When evaluated in the NLCS (2368 cases), estimates for each of these foods and nutrients were similar in magnitude and direction, with the exception of beer/cider intake, which was not associated with risk in the NLCS Conclusions: Our findings confirm a positive association of alcohol consumption andsuggest an inverse association of dietary fibre and possibly fruit intake with breast cancer risk.

Journal article

Freisling H, Viallon V, Lennon H, Bagnardi V, Ricci C, Butterworth AS, Sweeting M, Muller D, Romieu I, Bazelle P, Kvaskoff M, Arveux P, Severi G, Bamia C, Kühn T, Kaaks R, Bergmann M, Boeing H, Tjønneland A, Olsen A, Overvad K, Dahm CC, Menéndez V, Agudo A, Sánchez M-J, Amiano P, Santiuste C, Gurrea AB, Tong TYN, Schmidt JA, Tzoulaki I, Tsilidis KK, Ward H, Palli D, Agnoli C, Tumino R, Ricceri F, Panico S, Picavet HSJ, Bakker M, Monninkhof E, Nilsson P, Manjer J, Rolandsson O, Thysell E, Weiderpass E, Jenab M, Riboli E, Vineis P, Danesh J, Wareham NJ, Gunter MJ, Ferrari Pet al., 2020, Lifestyle factors and risk of multimorbidity of cancer and cardiometabolic diseases: a multinational cohort study, BMC Medicine, Vol: 18, Pages: 5-5, ISSN: 1741-7015

BACKGROUND: Although lifestyle factors have been studied in relation to individual non-communicable diseases (NCDs), their association with development of a subsequent NCD, defined as multimorbidity, has been scarcely investigated. The aim of this study was to investigate associations between five lifestyle factors and incident multimorbidity of cancer and cardiometabolic diseases. METHODS: In this prospective cohort study, 291,778 participants (64% women) from seven European countries, mostly aged 43 to 58 years and free of cancer, cardiovascular disease (CVD), and type 2 diabetes (T2D) at recruitment, were included. Incident multimorbidity of cancer and cardiometabolic diseases was defined as developing subsequently two diseases including first cancer at any site, CVD, and T2D in an individual. Multi-state modelling based on Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (95% CI) of developing cancer, CVD, or T2D, and subsequent transitions to multimorbidity, in relation to body mass index (BMI), smoking status, alcohol intake, physical activity, adherence to the Mediterranean diet, and their combination as a healthy lifestyle index (HLI) score. Cumulative incidence functions (CIFs) were estimated to compute 10-year absolute risks for transitions from healthy to cancer at any site, CVD (both fatal and non-fatal), or T2D, and to subsequent multimorbidity after each of the three NCDs. RESULTS: During a median follow-up of 11 years, 1910 men and 1334 women developed multimorbidity of cancer and cardiometabolic diseases. A higher HLI, reflecting healthy lifestyles, was strongly inversely associated with multimorbidity, with hazard ratios per 3-unit increment of 0.75 (95% CI, 0.71 to 0.81), 0.84 (0.79 to 0.90), and 0.82 (0.77 to 0.88) after cancer, CVD, and T2D, respectively. After T2D, the 10-year absolute risks of multimorbidity were 40% and 25% for men and women, respectively, with unhealthy lifestyle, and 30% and 18

Journal article

Sasamoto N, Babic A, Rosner BA, Fortner RT, Vitonis AF, Yamamoto H, Fichorova RN, Titus LJ, Tjonneland A, Hansen L, Kvaskoff M, Fournier A, Mancini FR, Boeing H, Trichopoulou A, Peppa E, Karakatsani A, Palli D, Grioni S, Mattiello A, Tumino R, Fiano V, Onland-Moret NC, Weiderpass E, Gram IT, Quiros JR, Lujan-Barroso L, Sanchez M-J, Colorado-Yohar S, Barricarte A, Amiano P, Idahl A, Lundin E, Sartor H, Khaw K-T, Key TJ, Muller D, Riboli E, Gunter M, Dossus L, Trabert B, Wentzensen N, Kaaks R, Cramer DW, Tworoger SS, Terry KLet al., 2019, Development and validation of circulating CA125 prediction models in postmenopausal women, Journal of Ovarian Research, Vol: 12, Pages: 1-12, ISSN: 1757-2215

BackgroundCancer Antigen 125 (CA125) is currently the best available ovarian cancer screening biomarker. However, CA125 has been limited by low sensitivity and specificity in part due to normal variation between individuals. Personal characteristics that influence CA125 could be used to improve its performance as screening biomarker.MethodsWe developed and validated linear and dichotomous (≥35 U/mL) circulating CA125 prediction models in postmenopausal women without ovarian cancer who participated in one of five large population-based studies: Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, n = 26,981), European Prospective Investigation into Cancer and Nutrition (EPIC, n = 861), the Nurses’ Health Studies (NHS/NHSII, n = 81), and the New England Case Control Study (NEC, n = 923). The prediction models were developed using stepwise regression in PLCO and validated in EPIC, NHS/NHSII and NEC.ResultThe linear CA125 prediction model, which included age, race, body mass index (BMI), smoking status and duration, parity, hysterectomy, age at menopause, and duration of hormone therapy (HT), explained 5% of the total variance of CA125. The correlation between measured and predicted CA125 was comparable in PLCO testing dataset (r = 0.18) and external validation datasets (r = 0.14). The dichotomous CA125 prediction model included age, race, BMI, smoking status and duration, hysterectomy, time since menopause, and duration of HT with AUC of 0.64 in PLCO and 0.80 in validation dataset.ConclusionsThe linear prediction model explained a small portion of the total variability of CA125, suggesting the need to identify novel predictors of CA125. The dichotomous prediction model showed moderate discriminatory performance which validated well in independent dataset. Our dichotomous model could be valuable in identifying healthy women who may have elevated CA125 lev

Journal article

Papadimitriou N, Muller D, van den Brandt PA, Geybels M, Patel CJ, Gunter MJ, Lopez DS, Key TJ, Perez-Cornago A, Ferrari P, Vineis P, Weiderpass E, Boeing H, Agudo A, Sanchez M-J, Overvad K, Kuehn T, Fortner RT, Palli D, Drake I, Bjartell A, Santiuste C, Bueno-de-Mesquita BH, Krogh V, Tjonneland A, Lauritzen DF, Gurrea AB, Quiros JR, Stattin P, Trichopoulou A, Martimianaki G, Karakatsani A, Thysell E, Johansson I, Ricceri F, Tumino R, Larranaga N, Khaw KT, Riboli E, Tzoulaki I, Tsilidis KKet al., 2019, A nutrient-wide association study for risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition and the Netherlands Cohort Study, European Journal of Nutrition, ISSN: 0044-264X

PurposeThe evidence from the literature regarding the association of dietary factors and risk of prostate cancer is inconclusive.MethodsA nutrient-wide association study was conducted to systematically and comprehensively evaluate the associations between 92 foods or nutrients and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox proportional hazard regression models adjusted for total energy intake, smoking status, body mass index, physical activity, diabetes and education were used to estimate hazard ratios and 95% confidence intervals for standardized dietary intakes. As in genome-wide association studies, correction for multiple comparisons was applied using the false discovery rate (FDR < 5%) method and suggested results were replicated in an independent cohort, the Netherlands Cohort Study (NLCS).ResultsA total of 5916 and 3842 incident cases of prostate cancer were diagnosed during a mean follow-up of 14 and 20 years in EPIC and NLCS, respectively. None of the dietary factors was associated with the risk of total prostate cancer in EPIC (minimum FDR-corrected P, 0.37). Null associations were also observed by disease stage, grade and fatality, except for positive associations observed for intake of dry cakes/biscuits with low-grade and butter with aggressive prostate cancer, respectively, out of which the intake of dry cakes/biscuits was replicated in the NLCS.ConclusionsOur findings provide little support for an association for the majority of the 92 examined dietary factors and risk of prostate cancer. The association of dry cakes/biscuits with low-grade prostate cancer warrants further replication given the scarcity in the literature.

Journal article

Mullee A, Romaguera D, Pearson-Stuttard J, Viallon V, Stepien M, Freisling H, Fagherazzi G, Mancini FR, Boutron-Ruault M-C, Kühn T, Kaaks R, Boeing H, Aleksandrova K, Tjønneland A, Halkjær J, Overvad K, Weiderpass E, Skeie G, Parr CL, Quirós JR, Agudo A, Sánchez M-J, Amiano P, Cirera L, Ardanaz E, Khaw K-T, Tong TYN, Schmidt JA, Trichopoulou A, Martimianaki G, Karakatsani A, Palli D, Agnoli C, Tumino R, Sacerdote C, Panico S, Bueno-de-Mesquita B, Verschuren WMM, Boer JMA, Vermeulen R, Ramne S, Sonestedt E, van Guelpen B, Holgersson PL, Tsilidis KK, Heath AK, Muller D, Riboli E, Gunter MJ, Murphy Net al., 2019, Association between soft drink consumption and mortality in 10 European countries., JAMA Internal Medicine, ISSN: 2168-6106

Importance: Soft drinks are frequently consumed, but whether this consumption is associated with mortality risk is unknown and has been understudied in European populations to date. Objective: To examine the association between total, sugar-sweetened, and artificially sweetened soft drink consumption and subsequent total and cause-specific mortality. Design, Setting, and Participants: This population-based cohort study involved participants (n = 451 743 of the full cohort) in the European Prospective Investigation into Cancer and Nutrition (EPIC), an ongoing, large multinational cohort of people from 10 European countries (Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden, and the United Kingdom), with participants recruited between January 1, 1992, and December 31, 2000. Excluded participants were those who reported cancer, heart disease, stroke, or diabetes at baseline; those with implausible dietary intake data; and those with missing soft drink consumption or follow-up information. Data analyses were performed from February 1, 2018, to October 1, 2018. Exposure: Consumption of total, sugar-sweetened, and artificially sweetened soft drinks. Main Outcomes and Measures: Total mortality and cause-specific mortality. Hazard ratios (HRs) and 95% CIs were estimated using multivariable Cox proportional hazards regression models adjusted for other mortality risk factors. Results: In total, 521 330 individuals were enrolled. Of this total, 451 743 (86.7%) were included in the study, with a mean (SD) age of 50.8 (9.8) years and with 321 081 women (71.1%). During a mean (range) follow-up of 16.4 (11.1 in Greece to 19.2 in France) years, 41 693 deaths occurred. Higher all-cause mortality was found among participants who consumed 2 or more glasses per day (vs consumers of <1 glass per month) of total soft drinks (hazard ratio [HR], 1.17; 95% CI, 1.11-1.22; P < .001), sugar-sweetened soft drinks (HR, 1.08;

Journal article

Ward HA, Whitman J, Muller DC, Johansson M, Jakszyn P, Weiderpass E, Palli D, Fanidi A, Vermeulen R, Tjønneland A, Hansen L, Dahm CC, Overvad K, Severi G, Boutron-Ruault M-C, Affret A, Kaaks R, Fortner R, Boeing H, Trichopoulou A, La Vecchia C, Kotanidou A, Berrino F, Krogh V, Tumino R, Ricceri F, Panico S, Bueno-de-Mesquita HB, Peeters PH, Nøst TH, Sandanger TM, Quirós JR, Agudo A, Rodríguez-Barranco M, Larrañaga N, Huerta JM, Ardanaz E, Drake I, Brunnström H, Johansson M, Grankvist K, Travis RC, Freisling H, Stepien M, Merritt MA, Riboli E, Cross AJet al., 2019, Haem iron intake and risk of lung cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, European Journal of Clinical Nutrition, Vol: 73, Pages: 1122-1132, ISSN: 1476-5640

BACKGROUND: Epidemiological studies suggest that haem iron, which is found predominantly in red meat and increases endogenous formation of carcinogenic N-nitroso compounds, may be positively associated with lung cancer. The objective was to examine the relationship between haem iron intake and lung cancer risk using detailed smoking history data and serum cotinine to control for potential confounding. METHODS: In the European Prospective Investigation into Cancer and Nutrition (EPIC), 416,746 individuals from 10 countries completed demographic and dietary questionnaires at recruitment. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident lung cancer (n = 3731) risk relative to haem iron, non-haem iron, and total dietary iron intake. A corresponding analysis was conducted among a nested subset of 800 lung cancer cases and 1489 matched controls for whom serum cotinine was available. RESULTS: Haem iron was associated with lung cancer risk, including after adjustment for details of smoking history (time since quitting, number of cigarettes per day): as a continuous variable (HR per 0.3 mg/1000 kcal 1.03, 95% CI 1.00-1.07), and in the highest versus lowest quintile (HR 1.16, 95% CI 1.02-1.32; trend across quintiles: P = 0.035). In contrast, non-haem iron intake was related inversely with lung cancer risk; however, this association attenuated after adjustment for smoking history. Additional adjustment for serum cotinine did not considerably alter the associations detected in the nested case-control subset. CONCLUSIONS: Greater haem iron intake may be modestly associated with lung cancer risk.

Journal article

Laskar RS, Muller DC, Li P, Machiela MJ, Ye Y, Gaborieau V, Foll M, Hofmann JN, Colli L, Sampson JN, Wang Z, Bacq-Daian D, Boland A, Abedi-Ardekani B, Durand G, Le Calvez-Kelm F, Robinot N, Blanche H, Prokhortchouk E, Skryabin KG, Burdett L, Yeager M, Radojevic-Skodric S, Savic S, Foretova L, Holcatova I, Janout V, Mates D, Rascu S, Mukeria A, Zaridze D, Bencko V, Cybulski C, Fabianova E, Jinga V, Lissowska J, Lubinski J, Navratilova M, Rudnai P, Świątkowska B, Benhamou S, Cancel-Tassin G, Cussenot O, Trichopoulou A, Riboli E, Overvad K, Panico S, Ljungberg B, Sitaram RT, Giles GG, Milne RL, Severi G, Bruinsma F, Fletcher T, Koppova K, Larsson SC, Wolk A, Banks RE, Selby PJ, Easton DF, Pharoah P, Andreotti G, Beane Freeman LE, Koutros S, Albanes D, Männistö S, Weinstein S, Clark PE, Edwards TL, Lipworth L, Carol H, Freedman ML, Pomerantz MM, Cho E, Kraft P, Preston MA, Wilson KM, Michael Gaziano J, Sesso HD, Black A, Freedman ND, Huang W-Y, Anema JG, Kahnoski RJ, Lane BR, Noyes SL, Petillo D, Teh BT, Peters U, White E, Anderson GL, Johnson L, Luo J, Chow W-H, Moore LE, Choueiri TK, Wood C, Johansson M, McKay JD, Brown KM, Rothman N, Lathrop MG, Deleuze J-F, Wu X, Brennan P, Chanock SJ, Purdue MP, Scelo Get al., 2019, Sex specific associations in genome wide association analysis of renal cell carcinoma, European Journal of Human Genetics, Vol: 27, Pages: 1589-1598, ISSN: 1018-4813

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.

Journal article

Sasamoto N, Babic A, Rosner BA, Fortner RT, Vitonis AF, Yamamoto H, Fichorova RN, Tjønneland A, Hansen L, Overvad K, Kvaskoff M, Fournier A, Mancini FR, Boeing H, Trichopoulou A, Peppa E, Karakatsani A, Palli D, Pala V, Mattiello A, Tumino R, Grasso C, Onland-Moret NC, Weiderpass E, Quirós JR, Lujan-Barroso L, Rodríguez-Barranco M, Colorado-Yohar S, Barricarte A, Dorronsoro M, Idahl A, Lundin E, Sartor H, Khaw K-T, Key TJ, Muller D, Riboli E, Gunter M, Dossus L, Kaaks R, Cramer DW, Tworoger SS, Terry KLet al., 2019, Predicting circulating CA125 levels among healthy premenopausal women, Cancer Epidemiology, Biomarkers and Prevention, Vol: 28, Pages: 1076-1085, ISSN: 1055-9965

Background: CA125 is the most promising ovarian cancer screening biomarker to date. Multiple studies reported CA125 levels vary by personal characteristics, which could inform personalized CA125 thresholds. However, this has not been well described in premenopausal women. Methods: We evaluated predictors of CA125 levels among 815 premenopausal women from the New England Case Control Study (NEC). We developed linear and dichotomous (≥ 35 U/ mL) CA125 prediction models and externally validated an abridged model restricting to available predictors among 473 premenopausal women in the European Prospective Investigation into Cancer and Nutrition Study (EPIC).Results: The final linear CA125 prediction model included age, race, tubal ligation, endometriosis, menstrual phase at blood draw, and fibroids, which explained 7% of the total variance of CA125. The correlation between observed and predicted CA125 levels based on the abridged model (including age, race, and menstrual phase at blood draw) had similar correlation coefficients in NEC(r=0.22) and in EPIC(r=0.22). The dichotomous CA125 prediction model included age, tubal ligation, endometriosis, prior personal cancer diagnosis, family history of ovarian cancer, number of miscarriages, menstrual phase at blood draw and smoking status with AUC of 0.83. The abridged dichotomous model (including age, number of miscarriages, menstrual phase at blood draw, and smoking status) showed similar AUCs in NEC(0.73) and in EPIC(0.78).Conclusions: We identified a combination of factors associated with CA125 levels in premenopausal women.Impact: Our model could be valuable in identifying healthy women likely to have elevated CA125 and consequently improve its specificity for ovarian cancer screening.

Journal article

Espina C, Bauld L, Bonanni B, Brenner H, Brown K, Dillner J, Kampman E, Nilbert M, Vineis P, Weijenberg MP, Cox A, de Kok TM, Fecht D, Mitrou G, Muller DC, Serrano D, Steindorf K, Storm H, Thorat MA, van Duijnhoven F, Weiderpass E, Schüz Jet al., 2019, The essential role of prevention in reducing the cancer burden in Europe: A commentary from Cancer Prevention Europe, Tumori Journal, ISSN: 2038-2529

Journal article

Elliott P, Aresu M, Gao H, Vergnaud A-C, Heard A, McRobie D, Spear J, Singh D, Kongsgård HW, Mbema C, Muller DCet al., 2019, Use of TETRA personal radios and sickness absence in the Airwave Health Monitoring Study of the British police forces, Environmental Research, Vol: 175, Pages: 148-155, ISSN: 0013-9351

BackgroundTerrestrial Trunked Radio (TETRA) is used for radiocommunications among the British police forces.ObjectivesTo investigate association of personal radio use and sickness absence among police officers and staff from the Airwave Health Monitoring Study.MethodsParticipant-level sickness absence records for 26 forces were linked with personal radio use for 32,102 participants. We used multivariable logistic regression to analyse TETRA usage in year prior to enrolment and sickness absence (lasting more than 7 or 28 consecutive days) in the following year and a zero-inflated negative binomial model for analyses of number of sickness absence episodes of any duration (‘spells’) over the same period. In secondary analyses, we looked at an extended period of observation among a sub-cohort with linked data over time, using Cox proportional hazards regression.ResultsMedian personal radio use (year prior to enrolment) was 29.7 min per month (interquartile range 7.5, 64.7) among users. In the year following enrolment there were 25,655 sickness absence spells among 15,248 participants. There were similar risks of sickness absence lasting more than seven days among users and non-users, although among users risk was higher with greater use, odds ratio = 1.04 (95% confidence interval [CI] 1.02 to 1.06) per doubling of radio use. There was no association for sickness absence of more than 28 days. For sickness absence spells, risk was lower among users than non-users (incidence rate ratio = 0.91; 95% CI 0.75 to 1.11), again with higher risk among users for greater radio use. There was no association between radio use and sickness absence in secondary analyses.DiscussionThere were similar or lower risks of sickness absence in TETRA radio users compared with non-users. Among users, the higher risk of sickness absence with greater radio use may reflect working pattern differences among police personnel rather than effects of radiofrequency exposure.

Journal article

Honda K, Katzke VA, Husing A, Okaya S, Shoji H, Onidani K, Olsen A, Tjonneland A, Overvad K, Weiderpass E, Vineis P, Muller DC, Tsilidis KK, Palli D, Pala V, Tumino R, Naccarati A, Panico S, Aleksandrova K, Boeing H, Bueno-de-Mesquita HB, Peeters PH, Trichopoulou A, Lagiou P, Khab K-T, Wareham NJ, Travis RC, Merino S, Duell EJ, Rodríguez-Barranco M, Chirlaque MD, Barricarte A, Rebours V, Boutron-Ruault M-C, Romana Mancini F, Brennan P, Scelo G, Manjer J, Sund M, Ohlund D, Canzian F, Kaaks Ret al., 2019, CA19-9 and Apolipoprotein-A2 isoforms as detection markers for pancreatic cancer - a prospective evaluation, International Journal of Cancer, Vol: 144, Pages: 1877-1887, ISSN: 0020-7136

Recently, we identified unique processing patterns of apolipoprotein A2 (ApoA2) in patients with pancreatic cancer. This study provides a first prospective evaluation of an ApoA2 isoform (“ApoA2-ATQ/AT”), alone and in combination with carbohydrate antigen 19-9 (CA19-9), as an early detection biomarker for pancreatic cancer.We performed ELISA measurements of CA19-9 and ApoA2-ATQ/AT in 156 patients with pancreatic cancer and 217 matched controls within the European EPIC cohort, using plasma samples collected up to 60 months prior to diagnosis. The detection discrimination statistics were calculated for risk scores by strata of lag-time.For CA19-9, in univariate marker analyses, C-statistics to distinguish future pancreatic cancer patients from cancer-free individuals were 0.80 for plasma taken ≤6 months before diagnosis, and 0.71 for >6-18 months; for ApoA2-ATQ/AT, C-statistics were 0.62, and 0.65, respectively. Joint models based on ApoA2-ATQ/AT plus CA19-9 significantly improved discrimination within >6-18 months (C = 0.74 vs. 0.71 for CA19-9 alone, p = 0.022) and ≤18 months (C = 0.75 vs. 0.74, p = 0.022). At 98% specificity, and for lag times of ≤6, >6-18 or ≤18 months, sensitivities were 57%, 36% and 43% for CA19-9 combined with ApoA2-ATQ/AT, respectively, vs. 50%, 29% and 36% for CA19-9 alone. Compared to CA19-9 alone, the combination of CA19-9 and ApoA2-ATQ/AT may improve detection of pancreatic cancer up to 18 months prior to diagnosis under usual care, and may provide a useful first measure for pancreatic cancer detection prior to imaging.

Journal article

Smith T, Muller D, Moons K, Cross A, Johansson M, Ferrari P, Fagherazzi G, Peeters P, Severi G, Husing A, Kaaks R, Tjonneland A, Olsen A, Overvad K, Bonet C, Rodriguez-Barranco M, Huerta JM, Barricarte Gurrea A, Bradbury K, Trichopoulou A, Bamia C, Orfanos P, Palli D, Pala V, Vineis P, Bueno-de-Mesquita B, Ohlsson B, Harlid S, Van Guelpen B, Skeie G, Weiderpass E, Jenab M, Murphy N, Riboli E, Gunter M, Aleksandrova K, Tzoulaki Iet al., 2019, Comparison of prognostic models to predict the occurrence of colorectal cancer in asymptomatic individuals: A systematic literature review and external validation in the EPIC and UK Biobank prospective cohort studies, Gut, Vol: 68, Pages: 672-683, ISSN: 0017-5749

ObjectiveTo systematically identify and validate published colorectal cancer risk prediction models that do not require invasive testing in two large population-based prospective cohorts.DesignModels were identified through an update of a published systematic review and validated in the European Prospective Investigation into Cancer and Nutrition (EPIC) and the UK Biobank. The performance of the models to predict the occurrence of colorectal cancer within 5 or 10 years after study enrolment was assessed by discrimination (C-statistic) and calibration (plots of observed versus predicted probability).ResultsThe systematic review and its update identified 16 models from 8 publications (8 colorectal, 5 colon and 3 rectal). The number of participants included in each model validation ranged from 41,587 to 396,515, and the number of cases from 115 to 1,781. Eligible and ineligible participants across the models were largely comparable. Calibration of the models, where assessable, was very good and further improved by recalibration. The C-statistics of the models were largely similar between validation cohorts with the highest values achieved being 0.70 (95%CI 0.68-0.72) in the UK Biobank and 0.71 (0.67-0.74) in EPIC. ConclusionSeveral of these non-invasive models exhibited good calibration and discrimination within both external validation populations and are therefore potentially suitable candidates for the facilitation of risk stratification in population-based colorectal screening programmes. Future work should both evaluate this potential, through modelling and impact studies, and ascertain if further enhancement in their performance can be obtained.

Journal article

Li Y, Xiao X, Bossé Y, Gorlova O, Gorlov I, Han Y, Byun J, Leighl N, Johansen JS, Barnett M, Chen C, Goodman G, Cox A, Taylor F, Woll P, Wichmann HE, Manz J, Muley T, Risch A, Rosenberger A, Han J, Siminovitch K, Arnold SM, Haura EB, Bolca C, Holcatova I, Janout V, Kontic M, Lissowska J, Mukeria A, Ognjanovic S, Orlowski TM, Scelo G, Swiatkowska B, Zaridze D, Bakke P, Skaug V, Zienolddiny S, Duell EJ, Butler LM, Houlston R, Artigas MS, Grankvist K, Johansson M, Shepherd FA, Marcus MW, Brunnström H, Manjer J, Melander O, Muller DC, Overvad K, Trichopoulou A, Tumino R, Liu G, Bojesen SE, Wu X, Le Marchand L, Albanes D, Bickeböller H, Aldrich MC, Bush WS, Tardon A, Rennert G, Teare MD, Field JK, Kiemeney LA, Lazarus P, Haugen A, Lam S, Schabath MB, Andrew AS, Bertazzi PA, Pesatori AC, Christiani DC, Caporaso N, Johansson M, McKay JD, Brennan P, Hung RJ, Amos CIet al., 2019, Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development, Oncotarget, Vol: 10, Pages: 1760-1774, ISSN: 1949-2553

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.

Journal article

Heath A, Kim I, Hodge A, English D, Muller Det al., 2019, Vitamin D status and mortality: A systematic review of observational studies, International Journal of Environmental Research and Public Health, Vol: 16, ISSN: 1660-4601

Epidemiological evidence suggests that vitamin D deficiency is associated with increased mortality, but it is unclear whether this is explained by reverse causation, and if there are specific causes of death for which vitamin D might be important. We conducted a systematic review of observational studies investigating associations between circulating 25-hydroxyvitamin D (25(OH)D) concentration and all-cause or cause-specific mortality in generally healthy populations. Relevant studies were identified using PubMed and EMBASE searches. After screening 722 unique records and removing those that were ineligible, 84 articles were included in this review. The vast majority of studies reported inverse associations between 25(OH)D concentration and all-cause mortality. This association appeared to be non-linear, with progressively lower mortality with increasing 25(OH)D up to a point, beyond which there was no further decrease. There is moderate evidence that vitamin D status is inversely associated with cancer mortality and death due to respiratory diseases, while for cardiovascular mortality, there is weak evidence of an association in observational studies, which is not supported by the data from intervention or Mendelian randomization studies. The relationship between vitamin D status and other causes of death remains uncertain due to limited data. Larger long-term studies are required to clarify these associations.

Journal article

Sen A, Papadimitriou N, Lagiou P, Perez-Cornago A, Travis RC, Key TJ, Murphy N, Gunter M, Freisling H, Tzoulaki I, Muller DC, Cross AJ, Lopez DS, Bergmann M, Boeing H, Bamia C, Kotanidou A, Karakatsani A, Tjønneland A, Kyrø C, Outzen M, Redondo M-L, Cayssials V, Chirlaque M-D, Barricarte A, Sánchez M-J, Larrañaga N, Tumino R, Grioni S, Palli D, Caini S, Sacerdote C, Bueno-de-Mesquita B, Kühn T, Kaaks R, Nilsson LM, Landberg R, Wallström P, Drake I, Bech BH, Overvad K, Aune D, Khaw K-T, Riboli E, Trichopoulos D, Trichopoulou A, Tsilidis KKet al., 2019, Coffee and tea consumption and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition, International Journal of Cancer, Vol: 144, Pages: 240-250, ISSN: 0020-7136

The epidemiological evidence regarding the association of coffee and tea consumption with prostate cancer risk is inconclusive, and few cohort studies have assessed these associations by disease stage and grade. We examined the associations of coffee (total, caffeinated and decaffeinated) and tea intake with prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition. Among 142,196 men, 7,036 incident prostate cancer cases were diagnosed over 14 years of follow-up. Data on coffee and tea consumption were collected through validated country-specific food questionnaires at baseline. We used Cox proportional hazards regression models to compute hazard ratios (HRs) and 95% confidence intervals (CI). Models were stratified by center and age, and adjusted for anthropometric, lifestyle and dietary factors. Median coffee and tea intake were 375 mL/day and 106 mL/day, respectively, but large variations existed by country. Comparing the highest (median of 855 mL/day) versus lowest (median of 103 mL/day) consumers of coffee and tea (450 mL/day versus 12 mL/day) the HRs were 1.02 (95% CI, 0.94-1.09) and 0.98 (95% CI, 0.90-1.07) for risk of total prostate cancer, and 0.97 (95% CI, 0.79-1.21) and 0.89 (95% CI, 0.70-1.13) for risk of fatal disease, respectively. No evidence of association was seen for consumption of total, caffeinated or decaffeinated coffee or tea and risk of total prostate cancer or cancer by stage, grade or fatality in this large cohort. Further investigations are needed to clarify whether an association exists by different preparations or by concentrations and constituents of these beverages. This article is protected by copyright. All rights reserved.

Journal article

Muller DC, Larose TL, Hodge A, Guida F, Langhammer A, Grankvist K, Meyer K, Cai Q, Arslan AA, Zeleniuch-Jacquotte A, Albanes D, Giles GG, Sesso HD, Lee I-M, Gaziano JM, Yuan J-M, Hoffman Bolton J, Buring JE, Visvanathan K, Le Marchand L, Purdue MP, Caporaso NE, Midttun Ø, Ueland PM, Prentice RL, Weinstein SJ, Stevens VL, Zheng W, Blot WJ, Shu X-O, Zhang X, Xiang Y-B, Koh W-P, Hveem K, Thomson CA, Pettinger M, Engström G, Brunnström H, Milne RL, Stampfer MJ, Han J, Johansson M, Brennan P, Severi G, Johansson Met al., 2019, Circulating high sensitivity C reactive protein concentrations and risk of lung cancer: nested case-control study within Lung Cancer Cohort Consortium., BMJ, Vol: 364, Pages: k4981-k4981, ISSN: 0959-8138

OBJECTIVES: To conduct a comprehensive analysis of prospectively measured circulating high sensitivity C reactive protein (hsCRP) concentration and risk of lung cancer overall, by smoking status (never, former, and current smokers), and histological sub-type. DESIGN: Nested case-control study. SETTING: 20 population based cohort studies in Asia, Europe, Australia, and the United States. PARTICIPANTS: 5299 patients with incident lung cancer, with individually incidence density matched controls. EXPOSURE: Circulating hsCRP concentrations in prediagnostic serum or plasma samples. MAIN OUTCOME MEASURE: Incident lung cancer diagnosis. RESULTS: A positive association between circulating hsCRP concentration and the risk of lung cancer for current (odds ratio associated with a doubling in hsCRP concentration 1.09, 95% confidence interval 1.05 to 1.13) and former smokers (1.09, 1.04 to 1.14) was observed, but not for never smokers (P<0.01 for interaction). This association was strong and consistent across all histological subtypes, except for adenocarcinoma, which was not strongly associated with hsCRP concentration regardless of smoking status (odds ratio for adenocarcinoma overall 0.97, 95% confidence interval 0.94 to 1.01). The association between circulating hsCRP concentration and the risk of lung cancer was strongest in the first two years of follow-up for former and current smokers. Including hsCRP concentration in a risk model, in addition to smoking based variables, did not improve risk discrimination overall, but slightly improved discrimination for cancers diagnosed in the first two years of follow-up. CONCLUSIONS: Former and current smokers with higher circulating hsCRP concentrations had a higher risk of lung cancer overall. Circulating hsCRP concentration was not associated with the risk of lung adenocarcinoma. Circulating hsCRP concentration could be a prediagnostic marker of lung cancer rather than a causal risk factor.

Journal article

Johansson M, Carreras-Torres R, Scelo G, Purdue MP, Mariosa D, Muller DC, Timpson NJ, Haycock PC, Brown KM, Wang Z, Ye Y, Hofmann JN, Foll M, Gaborieau V, Machiela MJ, Colli LM, Li P, Garnier J-G, Blanche H, Boland A, Burdette L, Prokhortchouk E, Skryabin KG, Yeager M, Radojevic-Skodric S, Ognjanovic S, Foretova L, Holcatova I, Janout V, Mates D, Mukeriya A, Rascu S, Zaridze D, Bencko V, Cybulski C, Fabianova E, Jinga V, Lissowska J, Lubinski J, Navratilova M, Rudnai P, Benhamou S, Cancel-Tassin G, Cussenot O, Weiderpass E, Ljungberg B, Tumkur Sitaram R, Häggström C, Bruinsma F, Jordan SJ, Severi G, Winship I, Hveem K, Vatten LJ, Fletcher T, Larsson SC, Wolk A, Banks RE, Selby PJ, Easton DF, Andreotti G, Beane Freeman LE, Koutros S, Männistö S, Weinstein S, Clark PE, Edwards TL, Lipworth L, Gapstur SM, Stevens VL, Carol H, Freedman ML, Pomerantz MM, Cho E, Wilson KM, Gaziano JM, Sesso HD, Freedman ND, Parker AS, Eckel-Passow JE, Huang W-Y, Kahnoski RJ, Lane BR, Noyes SL, Petillo D, Teh BT, Peters U, White E, Anderson GL, Johnson L, Luo J, Buring J, Lee I-M, Chow W-H, Moore LE, Eisen T, Henrion M, Larkin J, Barman P, Leibovich BC, Choueiri TK, Lathrop GM, Deleuze J-F, Gunter M, McKay JD, Wu X, Houlston RS, Chanock SJ, Relton C, Richards JB, Martin RM, Davey Smith G, Brennan Pet al., 2019, The influence of obesity-related factors in the etiology of renal cell carcinoma - a mendelian randomization study, PLoS Medicine, Vol: 16, ISSN: 1549-1277

BackgroundSeveral obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.Methods and findingsGenetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.ConclusionsThis study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

Journal article

Gao H, Aresu M, Vergnaud AC, McRobie D, Spear J, Heard A, Kongsgard HW, Singh D, Muller DC, Elliott P, Wells Jet al., 2018, Personal radio use and cancer risks among 48,158 British police officers and staff from the Airwave Health Monitoring Study, British Journal of Cancer, Vol: 120, Pages: 375-378, ISSN: 0007-0920

BackgroundRadiofrequency electromagnetic fields (RF-EMF) from mobile phones have been classified as potentially carcinogenic. No study has investigated use of Terrestrial Trunked Radio (TETRA), a source of RF-EMF with wide occupational use, and cancer risks.MethodsWe investigated association of monthly personal radio use and risk of cancer using Cox proportional hazards regression among 48,518 police officers and staff of the Airwave Health Monitoring Study in Great Britain.ResultsDuring median follow-up of 5.9 years, 716 incident cancer cases were identified. Among users, the median of the average monthly duration of use in the year prior to enrolment was 30.5  min (inter-quartile range 8.1, 68.1). Overall, there was no association between personal radio use and risk of all cancers (hazard ratio [HR] = 0.98, 95% confidence interval [CI]: 0.93, 1.03). For head and neck cancers HR = 0.72 (95% CI: 0.30, 1.70) among personal radio users vs non-users, and among users it was 1.06 (95% CI: 0.91, 1.23) per doubling of minutes of personal radio use.ConclusionsWith the limited follow-up to date, we found no evidence of association of personal radio use with cancer risk. Continued follow-up of the cohort is warranted.

Journal article

Li K, Anderson G, Viallon V, Arveux P, Kvaskoff M, Fournier A, Krogh V, Tumino R, Sánchez MJ, Ardanaz E, Chirlaque MD, Agudo A, Muller DC, Smith T, Tzoulaki I, Key TJ, Bueno-De-Mesquita B, Trichopoulou A, Bamia C, Orfanos P, Kaaks R, Hüsing A, Fortner RT, Zeleniuch-Jacquotte A, Sund M, Dahm CC, Overvad K, Aune D, Weiderpass E, Romieu I, Riboli E, Gunter MJ, Dossus L, Prentice R, Ferrari Pet al., 2018, Risk prediction for estrogen receptor-specific breast cancers in two large prospective cohorts, Breast Cancer Research, Vol: 20, ISSN: 1465-5411

Background: Few published breast cancer (BC) risk prediction models consider the heterogeneity of predictor variables between estrogen-receptor positive (ER+) and negative (ER-) tumors. Using data from two large cohorts, we examined whether modeling this heterogeneity could improve prediction. Methods: We built two models, for ER+ (ModelER+) and ER- tumors (ModelER-), respectively, in 281,330 women (51% postmenopausal at recruitment) from the European Prospective Investigation into Cancer and Nutrition cohort. Discrimination (C-statistic) and calibration (the agreement between predicted and observed tumor risks) were assessed both internally and externally in 82,319 postmenopausal women from the Women's Health Initiative study. We performed decision curve analysis to compare ModelER+ and the Gail model (ModelGail) regarding their applicability in risk assessment for chemoprevention. Results: Parity, number of full-term pregnancies, age at first full-term pregnancy and body height were only associated with ER+ tumors. Menopausal status, age at menarche and at menopause, hormone replacement therapy, postmenopausal body mass index, and alcohol intake were homogeneously associated with ER+ and ER- tumors. Internal validation yielded a C-statistic of 0.64 for ModelER+ and 0.59 for ModelER-. External validation reduced the C-statistic of ModelER+ (0.59) and ModelGail (0.57). In external evaluation of calibration, ModelER+ outperformed the ModelGail: the former led to a 9% overestimation of the risk of ER+ tumors, while the latter yielded a 22% underestimation of the overall BC risk. Compared with the treat-all strategy, ModelER+ produced equal or higher net benefits irrespective of the benefit-to-harm ratio of chemoprevention, while ModelGail did not produce higher net benefits unless the benefit-to-harm ratio was below 50. The clinical applicability, i.e. the area defined by the net benefit curve and the treat-all and treat-none strategies, was 12.7 × 10- 6 for Mod

Journal article

Sandanger T, Nost T, Guida F, Rylander C, Campanella G, Muller D, van Dongen J, Boomsma D, Johansson M, Vineis P, Vermeulen R, Lund E, Chadeau Met al., 2018, DNA methylation and associated gene expression in blood prior to lung cancer diagnosis in the Norwegian Women and Cancer cohort, Scientific Reports, Vol: 8, ISSN: 2045-2322

The majority of lung cancer is caused by tobacco smoking, and lung cancer-relevant epigenetic markers have been identified in relation to smoking exposure. Still, smoking-related markers appear to mediate little of the effect of smoking on lung cancer. Thus in order to identify disease-relevant markers and enhance our understanding of pathways, a wide search is warranted. Through an epigenome-wide search within a case-control study (131 cases, 129 controls) nested in a Norwegian prospective cohort of women, we found 25 CpG sites associated with lung cancer. Twenty-three were classified as associated with smoking (LC-AwS), and two were classified as unassociated with smoking (LC-non-AwS), as they remained associated with lung cancer after stringent adjustment for smoking exposure using the comprehensive smoking index (CSI): cg10151248 (PC, CSI-adjusted odds ratio (OR) = 0.34 [0.23–0.52] per standard deviation change in methylation) and cg13482620 (B3GNTL1, CSI-adjusted OR = 0.33 [0.22–0.50]). Analysis among never smokers and a cohort of smoking-discordant twins confirmed the classification of the two LC-non-AwS CpG sites. Gene expression profiles demonstrated that the LC-AwS CpG sites had different enriched pathways than LC-non-AwS sites. In conclusion, using blood-derived DNA methylation and gene expression profiles from a prospective lung cancer case-control study in women, we identified 25 CpG lung cancer markers prior to diagnosis, two of which were LC-non-AwS markers and related to distinct pathways.

Journal article

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