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BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. METHODS: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. FINDINGS: Genetically elevated PUFA desaturase activity was associated (P

High-resolution angle- and spin-resolved photoemission spectroscopy reveals new features of the electronic structure of the ferromagnetic triple-layered ruthenate Sr$_4$Ru$_3$O$_{10}$. There are narrow spectral peaks $\sim$30 meV below the Fermi-level in two regions of the Brillouin zone: a hole-like band at the zone-center and a saddle-point van Hove singularity at the zone edge. Below T$_c$ each feature is almost completely spin-polarized, with opposite sign polarization and with strong Kondo-coherence-like temperature-dependent spectral weight variation suggestive of strong Hund's metal correlations. In addition, there are distinct Fermi surfaces for wide electron-like minority spin bands around the zone center and narrow hole-like majority spin Fermi surface contours around the zone corners. The origin of these features is in general agreement with density functional calculations, if they are shifted to reduce the exchange splitting, and scaled to take into account effects of correlation. Furthermore, the deduced narrow band origins from the tri-layer splitting of $d_{xz/yz}$ orbitals implies a layer-specific spin-polarization contribution from the narrow bands. Over a larger energy range, net spin-majority polarization of incoherent Ru $d$-bands is observed to extend down to the top of the oxygen bands, where additional narrow oxygen bands contribute to the magnetism with spin-minority polarization., Comment: 11 pages, 5 figures plus supplement 8 pages, 4 figures

Additional file 4. (Supplemental Figures): Supplementary figure 1. Correlation of MR-IVW estimates (betas) using the two different instrument definitions. Y axis represents the MR IVW estimates using the cis-eQTL and X axis represents the MR IVW estimates using the cis-pQTL instrument definition. Supplementary figure 2. Associations that showed MR evidence for both causality and colocalization (posterior probability>0.8) are plotted, within ��500 kb of the gene locus of the exposure cytokine.

Additional file 2. Supplementary Figure 1. A comparison of the area under the ROC curves (AUC) obtained for the models included in the sensitivity analyses (n = 384).

Additional file 1. Members from the PRACTICAL Consortium, CRUK, BPC3, CAPS and PEGASUS.

Additional file 1. Table S1. Proportion of missing data, N = 408; Table S2. Baseline descriptives of participants included in the complete case analysis (n = 225); Table S3. Association of DNA Methylation-Based predictors of Ageing with overall-survival based on imputed data (n = 408); Table S4. Results of the complete case cox regression analysis (n = 225); Table S5. Results of the sensitivity analyses, adjusting for units of alcohol consumed per week (Model 4); Table S6. The impact of including two epigenetic age acceleration measures on model fit and discrimination.

Additional file 3: Appendix S16. STROBE-MR checklist of recommended items to address in reports of Mendelian randomization studies.

Supplemental material, sj-docx-1-msc-10.1177_09691413221119238 for Screening asymptomatic men for prostate cancer: A comparison of international guidelines on prostate-specific antigen testing by Sherena D Jackson, May R de la Rue, Thomas PL Greenslade, Anna M John, Shahida Wahid, Richard M Martin, Naomi J Williams and Emma L Turner in Journal of Medical Screening

Additional file 3. Additional methods.

Additional file 1: Appendix S1. Supplementary methods. Appendix S2. List of unique molecular traits identified from literature search. Appendix S3. PubMed search terms for literature review. Table S4. Additional information on GWAS, including covariates adjusted for. Table S6. Results of female BMI sensitivity analysis MR. Table S7. Results of female-specific SNP fasting insulin sensitivity analysis MR. Table S8. Results of female-specific SNP BMI sensitivity mediation analysis. Table S9. Results of female-specific SNP fasting insulin mediation analysis. Table S10. Results of post-hoc power analysis for MR of all molecular traits on endometrial cancer risk, and BMI on all traits confirmed to have a causal effect on endometrial cancer. Table S11. Conditional F-statistics with different levels of genetic correlation for SHBG and bioavailable testosterone and BMI in multivariable Mendelian randomization analyses. Table S12. Conditional F-statistics for fasting insulin (adjusted for BMI) and BMI with differing thresholds used to construct fasting insulin. Table S13. Conditional F-statistics for multivariable Mendelian randomization of BMI and mediators on endometrial cancer risk. Table S14. Conditional F-statistics for further multivariable Mendelian randomization analyses. Table S15. Sample overlap between GWAS. Figure S17. Leave-one-out analysis for MR examining the effect of adult BMI on overall endometrial cancer risk. Table S18. Results from sensitivity analyses examining the influence of Winner’s curse on GWAS with overlapping samples. Table S19. Results from sensitivity analyses examining the influence of Winner’s curse on GWAS with overlapping samples in analyses determining the mediating role of traits in the relationship between BMI and endometrial cancer risk. Figure S20. Leave-one-out analysis for MR examining the effect of adult BMI on endometrioid endometrial cancer risk. Figure S21. Leave-one-out analysis for MR examining the effect of adult BMI on non-endometrioid endometrial cancer risk. Figure S22. Leave-one-out analysis for MR examining the effect of total testosterone level on endometrial cancer risk. Figure S23. Leave-one-out analysis for MR examining the effect of bioavailable testosterone level on endometrial cancer risk. Figure S24. Leave-one-out analysis for MR examining the effect of fasting insulin level on endometrial cancer risk. Figure S25. Leave-one-out analysis for MR examining the effect of SHBG level on endometrial cancer risk. Figure S26. Leave-one-out analysis for MR examining the effect of total serum cholesterol level on endometrial cancer risk. Table S27. Results of female-specific SNP CRP sensitivity analysis MR. Figure S28. Leave-one-out analysis for MR examining the effect of total testosterone level on endometrioid endometrial cancer risk. Figure S29. Leave-one-out analysis for MR examining the effect of bioavailable testosterone level on endometrioid endometrial cancer risk. Figure S30. Leave-one-out analysis for MR examining the effect of fasting insulin level on endometrioid endometrial cancer risk. Figure S31. Leave-one-out analysis for MR examining the effect of SHBG level on endometrioid endometrial cancer risk. Figure S32. Leave-one-out analysis for MR examining the effect of adult BMI on fasting insulin level. Figure S33. Leave-one-out analysis for MR examining the effect of adult BMI on SHBG level. Figure S34. Leave-one-out analysis for MR examining the effect of adult BMI on bioavailable testosterone level. Figure S35. Leave-one-out analysis for MR examining the effect of adult BMI on total serum cholesterol level. Figure S36. Leave-one-out analysis for MR examining the effect of adult BMI on C-reactive protein level. Table S37. Results of multivariable MR mediation analysis examining the effect of BMI and endometrial cancer with fasting insulin as a potential mediator with BMI-adjusted fasting insulin instrument and 100 SNPs from BMI instrument. Table S38. Results of sensitivity analysis examining the effect of only including 100 SNPs for the BMI instrument in MR analyses. Table S39. Results of multivariable MR mediation analysis examining the effect of BMI and endometrial cancer with fasting insulin as a potential mediator with 100 SNPs from BMI instrument. Table S40. Results of multivariable MR mediation analysis examining the effect of BMI and endometrial cancer with fasting insulin as a potential mediator with BMI-adjusted fasting insulin instrument. Table S41. Results of multivariable MR mediation analysis examining the effect of endometrial cancer with pairs of confirmed mediating molecular traits without BMI. Table S42. Results of multivariable MR mediation analysis examining the effect of BMI and endometrial cancer with all confirmed mediating molecular traits with BMI-adjusted fasting insulin. Table S43. Results of multivariable MR mediation analysis examining the effect of BMI and endometrial cancer with pairs of confirmed mediating molecular traits. Table S44. Results of multivariable MR mediation analysis examining the effect of BMI and endometrial cancer with all confirmed mediating molecular traits including fasting insulin adjusted for BMI with 100 SNPs from BMI instrument. Table S45. Results of multivariable MR mediation analysis examining the effect of BMI and endometrial cancer with pairs of confirmed mediating molecular traits with 100 SNPs from BMI instrument. Table S46. Results of multivariable MR mediation analysis examining the effect of endometrial cancer with all confirmed mediating molecular traits without BMI. Table S47. Results from sensitivity analyses examining the influence of Winner’s curse on GWAS with overlapping samples in analyses determining the interdependent effects of mediators of the relationship between BMI and endometrial cancer risk. Table S48. Results of HEIDI test-filtered low-density lipoprotein (LDL) cholesterol and overall endometrial cancer MR.

Studies have indicated that the presence and size of subclinical atherosclerotic plaques improve the prediction of atherosclerotic cardiovascular events (ASCVE) over and above that provided by conventional risk factors alone. However, the relative contribution of different ultrasonographic measurements and sites of measurements on the 10-year ASCVD risk is largely unknown.Our aims were to determine the relative performance of carotid intima-media thickness, plaque thickness, and plaque area in 10-year ASCVD prediction when added to conventional risk factors as well as whether the vascular territory of these measurements, carotid or common femoral bifurcation, and the number of bifurcations with plaque (NBP) influence prediction.We enrolled 985 adults (mean age: 58.1 ± 10.2 years) free of atherosclerotic cardiovascular disease. Conventional risk factors were recorded, and both carotid and common femoral bifurcations were scanned with ultrasonography. The primary endpoint was a composite of first-time fatal or nonfatal ASCVE.Over a mean ± SD follow-up of 13.2 ± 3.7 years, ASCVE occurred in 154 (15.6%) participants. By adding different plaque measurements to conventional risk factors in a Cox model, net reclassification improvement was 10.4% with maximum intima-media thickness, 9.5% with carotid plaque thickness, and 14.2% with carotid plaque area. It increased to 16.1%, 16.6%, and 16.6% (P 0.0001) by adding measurements from 4 bifurcations: NBP, total plaque thickness, and total plaque area, respectively.NBP, total plaque thickness, or total plaque area from both the carotid and common femoral bifurcations provides a better prediction of future ASCVE than measurements from a single site. The results need to be validated in an independent cohort.

BackgroundPolygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).Materials and method180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.Results166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.ConclusionsIncorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

Different strategies of maintenance therapy (sequential CT, intermittent CT, intermittent CT and MAbs, or de-escalation MAbs monotherapy) after first-line treatment are undertaken. Many randomized clinical trials (RCT), which evaluated these approaches, suffer from incorrect design, heterogenous primary endpoints, inadequate size, and other methodology flaws. Drawing any conclusions becomes challenging and recommendations are mainly vague. We evaluated those studies from another perspective, focusing on the design quality and the clinical benefit measure with a more objective and accurate methodology. These data allowed a clearer and more exact overview of the statement in maintenance treatment.

Purpose: Total neoadjuvant treatment (TNT) is a valid strategy for patients with high-risk locally advanced rectal cancer (LARC). Biomarkers of response to TNT are an unmet clinical need. We aimed to determine the value of circulating tumor DNA(ctDNA) to predict tumor response, recurrence, and survival in patients with LARC treated with TNT. Experimental Design: The GEMCAD 1402 was a phase II randomized, multicentric clinical trial that randomized 180 patients with LARC to modified schedule of fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) +/- aflibercept, followed by chemoradiation and surgery. Plasma samples were collected at baseline and after TNT within 48 hours before surgery (presurgery). An ultra-sensitive assay that integrates genomic and epigenomic cancer signatures was used to assess ctDNA status. ctDNA results were correlated with variables of local tumor response in the surgery sample, local/systemic recurrence, and survival. Results: A total of 144 paired plasma samples from 72 patients were included. ctDNA was detectable in 83% of patients at baseline and in 15% following TNT (presurgery). No association was found between ctDNA status and pathologic response. Detectable presurgery ctDNA was significantly associated with systemic recurrence, shorter disease-free survival (HR, 4; P = 0.033), and shorter overall survival (HR, 23; P < 0.0001). Conclusions: In patients with LARC treated with TNT, presurgery ctDNA detected minimal metastatic disease identifying patients at high risk of distant recurrence and death. This study sets the basis for prospective clinical trials that use liquid biopsy to personalize the therapeutic approach following TNT.

Additional file 1. Supplementary Material, Description of data: The supplementary material contains additional information concerning: 1. Risk thresholds; 2. Confounder measures and their derivation; 3.Deriving the adolescent cumulative risk exposure measure; 4. Deriving the latent classes; 5. Deriving the sample; 6. Comparison of imputation sample and those excluded from the analysis by key demographic variables; 7.Risk profiles for adolescence, percentage of sample and cumulative risk score for complete case and imputed samples; 8. Latent class trajectories; 9. Cross tabulations of cumulative risk score quartiles and proportion belonging to each of the latent classes; and 10. Associations between the adolescent cancer risk measure and socioeconomic status (SES) measures.

Additional file 3. Data sources. Description of data: contains both a table showing the sources of ALSPAC questionnaire and clinic data used in research and links to each questionnaire or data source.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

Additional file 2. STROBE Statement—Checklist of items that should be included in reports of cohort studies, Description of data: a table providing information regarding where each of the components of the report are located in the document.

BackgroundA polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening.MethodsUnited Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups.ResultsThe expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age.ConclusionsPHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS.ImpactPersonalized genetic risk assessments could inform prostate cancer screening decisions.

BackgroundA polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening.MethodsUnited Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups.ResultsThe expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age.ConclusionsPHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS.ImpactPersonalized genetic risk assessments could inform prostate cancer screening decisions.

Additional file 1: Supplementary Table 1: Baseline descriptive characteristics of included participants, stratified by HPV status. Supplementary Table 2: Multivariable Cox proportional hazards results for model 2 (clinical) and model 3 (respective phenotype). Supplementary Table 3: Baseline descriptive characteristics of participants included in the sensitivity analysis (n=248). Supplementary Table 4: Results of the sensitivity analysis restricted to participants with data available for BMI. Supplementary Table 5: A comparison of minimally adjusted and fully adjusted Cox proportional hazards models results, using the imputed dataset (n=408). Supplementary Table 6: Details of array type and sample size for studies used to derive DNAm scores in this analysis. Supplementary Table 7: Proportion of missing data (n=408).

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.

© 2018 The Author(s). Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa 1 .

© 2018 The Author(s). Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

Physical growth traits can be naturally represented by continuous functions. In a large dataset of infancy growth patterns, we develop a practical approach to infer statistical associations between growth-trajectories and IQ performance in early childhood. The main objective of this study is to show how to assess physical growth curves and detect if particular infancy growth patterns are associated with differences in IQ (Full-scale WASI scores) in later ages using a semi-parametric functional response model. Additionally, we investigate the association between different growth measurements in terms of their cross-correlation with each other, their correlation with later IQ, as well as their time-varying dynamics. This analysis framework can easily incorporate or learn population information in a non-parametric way, rendering the existence of prior population charts partially redundant.

PurposeColorectal cancer (CRC) brain metastases (BM) are an uncommon and late event. We aim to investigate the impact of clinical factors, treatment modalities and RAS/BRAF status on the outcomes of CRC patients with BM.PatientsWe retrospectively analysed CRC patients who developed BM in our centre between January 1997 and June 2017. Clinical factors, treatment modalities, RAS/BRAF status and survival were evaluated.ResultsTwenty-eight patients were recorded; 82% had left-sided (LS) CRC and 71% had lung metastases. Median time to BM diagnosis was 36months (m) and 93% of patients received local treatment of BM (43% whole brain radiotherapy, 50% surgery). Right-sided (RS) CRC showed shorter time to BM, not previously described (9.3 vs 46.6m for RS and LS CRC, respectively; HR=4.7, p=0.006). Median overall survival (mOS) from BM treatment was 9.5m, better in patients who underwent surgery than those treated with radiotherapy alone (12.1 vs 4.6m, respectively; HR=0.3, p=0.019) and in those without progressive metastatic extracranial disease (7.2 vs 20.9m, for progressive and non-progressive, respectively; HR=0.3, p=0.056). Patients with two or more metastatic extracranial locations showed worse prognosis (5.9 vs 16.3m, for >2 vs 0-1, respectively; HR=3.7, p=0.015). RAS/BRAF status did not showed prognostic value.ConclusionsTime to BM diagnosis is shorter in RS CRC. The presence of two or more metastatic extracranial locations and progressive metastatic extracranial disease at the time of BM diagnosis could be bad prognosis factors for CRC BM patients.

For longitudinal studies with multivariate observations, we propose statistical methods to identify clusters of archetypal subjects by using techniques from functional data analysis and to relate longitudinal patterns to outcomes. We demonstrate how this approach can be applied to examine associations between multiple time-varying exposures and subsequent health outcomes, where the former are recorded sparsely and irregularly in time, with emphasis on the utility of multiple longitudinal observations in the framework of dimension reduction techniques. In applications to children's growth data, we investigate archetypes of infant growth patterns and identify subgroups that are related to cognitive development in childhood. Specifically, "Stunting" and "Faltering" time-dynamic patterns of head circumference, body length and weight in the first 12 months are associated with lower levels of long-term cognitive development in comparison to "Generally Large" and "Catch-up" growth. Our findings provide evidence for the statistical association between multivariate growth patterns in infancy and long-term cognitive development.

International audience; QMCPACK is an open source quantum Monte Carlo package for ab-initio electronic structure calculations. It supports calculations of metallic and insulating solids, molecules, atoms, and some model Hamiltonians. Implemented real space quantum Monte Carlo algorithms include variational, diffusion, and reptation Monte Carlo. QMCPACK uses Slater-Jastrow type trial wave functions in conjunction with a sophisticated optimizer capable of optimizing tens of thousands of parameters. The orbital space auxiliary field quantum Monte Carlo method is also implemented, enabling cross validation between different highly accurate methods. The code is specifically optimized for calculations with large numbers of electrons on the latest high performance computing architectures, including multicore central processing unit (CPU) and graphical processing unit (GPU) systems. We detail the program's capabilities, outline its structure, and give examples of its use in current research calculations. The package is available at http://www.qmcpack.org .

Background The therapeutic management of people with metastatic colorectal cancer (CRC) who did not respond to first-line treatment represents a formidable challenge. Objectives To determine the efficacy and toxicity of second-line systemic therapy in people with metastatic CRC. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 4), Ovid MEDLINE (1950 to May 2016), Ovid MEDLINE In-process & Other Non-Indexed Citations (1946 to May 2016) and Ovid Embase (1974 to May 2016). There were no language or date of publication restrictions. Selection criteria Randomized controlled trials (RCTs) assessing the efficacy (survival, tumour response) and toxicity (incidence of severe adverse effects (SAEs)) of second-line systemic therapy (single or combined treatment with any anticancer drug, at any dose and number of cycles) in people with metastatic CRC that progressed, recurred or did not respond to first-line systemic therapy. Data collection and analysis Authors performed a descriptive analysis of each included RCT in terms of primary (survival) and secondary (tumour response, toxicity) endpoints. In the light of the variety of drug regimens tested in the included trials, we could carry out meta-analysis considering classes of (rather than single) anticancer regimens; to this aim, we applied the random-effects model to pool the data. We used hazard ratios (HRs) and risk ratios (RRs) to describe the strength of the association for survival (overall (OS) and progression-free survival (PFS)) and dichotomous (overall response rate (ORR) and SAE rate) data, respectively, with 95% confidence intervals (CI). Main results Thirty-four RCTs (enrolling 13,787 participants) fulfilled the eligibility criteria. Available evidence enabled us to address multiple clinical issues regarding the survival effects of second-line systemic therapy of people with metastatic CRC. 1. Chemotherapy (irinotecan) was more effective than best supportive care (HR for OS: 0.58, 95% CI 0.43 to 0.80; 1 RCT; moderate-quality evidence); 2. modern chemotherapy (FOLFOX (5-fluorouracil plus leucovorin plus oxaliplatin), irinotecan) is more effective than outdated chemotherapy (5-fluorouracil) (HR for PFS: 0.59, 95% CI 0.49 to 0.73; 2 RCTs; high-quality evidence) (HR for OS: 0.69, 95% CI 0.51 to 0.94; 1 RCT; moderate-quality evidence); 3. irinotecan-based combinations were more effective than irinotecan alone (HR for PFS: 0.68, 95% CI 0.60 to 0.76; 6 RCTs; moderate-quality evidence); 4. targeted agents improved the efficacy of conventional chemotherapy both when considered together (HR for OS: 0.84, 95% CI 0.77 to 0.91; 6 RCTs; high-quality evidence) and when bevacizumab was used alone (HR for PFS: 0.67, 95% CI 0.60 to 0.75; 4 RCTs; high-quality evidence). With regard to secondary endpoints, tumour response rates generally paralleled the survival results; moreover, higher anticancer efficacy was generally associated with worse treatment-related toxicity, with the important exception of bevacizumab-containing regimens, where the addition of the targeted agent to chemotherapy did not result in a significant increase in the rate of SAE. Finally, we found that oral (instead of intravenous) fluoropyrimidines significantly reduced the incidence of adverse effects (without compromising efficacy) in people treated with oxaliplatin-based regimens. We could not draw any conclusions on other debated aspects in this field of oncology, such as ranking of treatments (not all possible comparisons have been tested and many comparisons were based on single trials enrolling a small number of participants) and quality of life (virtually no data available). Authors' conclusions Systemic therapy offers a survival benefit to people with metastatic CRC who did not respond to first-line treatment, especially when targeted agents are combined with conventional chemotherapeutic drugs. Further research is needed to define the optimal regimen and to identify people who most benefit from each treatment.

Coffee consumption has been shown in some studies to be associated with lower risk of prostate cancer. However, it is unclear if this association is causal or due to confounding or reverse causality. We conducted a Mendelian randomisation analysis to investigate the causal effects of coffee consumption on prostate cancer risk and progression. We used two genetic variants robustly associated with caffeine intake (rs4410790 and rs2472297) as proxies for coffee consumption in a sample of 46,687 men of European ancestry from 25 studies in the PRACTICAL consortium. Associations between genetic variants and prostate cancer case status, stage and grade were assessed by logistic regression and with all‐cause and prostate cancer‐specific mortality using Cox proportional hazards regression. There was no clear evidence that a genetic risk score combining rs4410790 and rs2472297 was associated with prostate cancer risk (OR per additional coffee increasing allele: 1.01, 95% CI: 0.98,1.03) or having high‐grade compared to low‐grade disease (OR: 1.01, 95% CI: 0.97,1.04). There was some evidence that the genetic risk score was associated with higher odds of having nonlocalised compared to localised stage disease (OR: 1.03, 95% CI: 1.01, 1.06). Amongst men with prostate cancer, there was no clear association between the genetic risk score and all‐cause mortality (HR: 1.00, 95% CI: 0.97,1.04) or prostate cancer‐specific mortality (HR: 1.03, 95% CI: 0.98,1.08). These results, which should have less bias from confounding than observational estimates, are not consistent with a substantial effect of coffee consumption on reducing prostate cancer incidence or progression., What's new? Does coffee consumption reduce prostate cancer risk? It's biologically plausible that it could, but studies showing a link have relied on observational evidence, which could be affected by confounding factors. These authors set out to isolate coffee's contribution. They focused on two genetic variants that correspond with caffeine intake, and used them as proxies for coffee drinking. Alleles are not affected by behavior or demographic factors, nor can behavior changes after diagnosis change whether a person carries an allele. The authors found no correlation between either of the alleles and prostate cancer risk, suggesting drinking coffee may not protect against prostate cancer.

Background: Autologous tumour lysate dendritic cell vaccine (ADC) has T-cell stimulatory capacity and, therefore, potential antitumour activity. We designed a phase II randomised trial of ADC + best supportive care (BSC) (experimental arm [EA]) compared with BSC (control arm [CA]), in pre-treated metastatic colorectal cancer (mCRC) patients. Patients and methods: Patients with progressive mCRC, at least to two chemotherapy regimens and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, were randomised to EA versus CA. Stratification criteria: ECOG PS (0-1 versus 2) and lactate dehydrogenase (ULN). EA was administered subcutaneously till progressive disease. Primary end-point was progression-free survival (PFS) at 4 months. Results: Fifty-two patients were included (28 EA/24 CA). An interim analysis recommended early termination for futility. No objective radiological response was observed in EA. Median PFS in EA was 2.7 months (95% confidence interval [CI], 2.3-3.2 months) versus 2.3 months (95% CI, 2.1-2.5 months) in CA (p = 0.628). Median overall survival (OS) was 6.2 months (95% CI, 4.4-7.9 months) in EA versus 4.7 months (95% CI, 2.3-7 months) in CA (p = 0.41). No ADC-related adverse events were reported. Immunization induces tumour-specific T-cell response in 21 of 25 (84%) patients. Responder patients have an OS of 7.3 months (95% CI, 5.2-9.4 months) versus 3.8 months (95% CI, 0.6-6.9 months) in non-responders; p = 0.026). Conclusion: Our randomised clinical trial comparing ADC + BSC versus BSC in mCRC demonstrates that ADC generates a tumour-specific immune response but not benefit on PFS and OS. Our results do not support the use of ADC alone, in a phase III trial. (C) 2016 Elsevier Ltd. All rights reserved.

BackgroundIndividual studies have suggested that circulating carotenoids, retinol, or tocopherols may be associated with prostate cancer risk, but the studies have not been large enough to provide precise estimates of associations, particularly by stage and grade of disease.ObjectiveThe objective of this study was to conduct a pooled analysis of the associations of the concentrations of 7 carotenoids, retinol, α-tocopherol, and γ-tocopherol with risk of prostate cancer and to describe whether any associations differ by stage or grade of the disease or other factors.DesignPrincipal investigators of prospective studies provided individual participant data for prostate cancer cases and controls. Risk by study-specific fifths of each biomarker was estimated by using multivariable-adjusted conditional logistic regression in matched case-control sets.ResultsData were available for up to 11,239 cases (including 1654 advanced stage and 1741 aggressive) and 18,541 controls from 15 studies. Lycopene was not associated with overall risk of prostate cancer, but there was statistically significant heterogeneity by stage of disease, and the OR for aggressive disease for the highest compared with the lowest fifth of lycopene was 0.65 (95% CI: 0.46, 0.91; P-trend = 0.032). No other carotenoid was significantly associated with overall risk of prostate cancer or with risk of advanced-stage or aggressive disease. For retinol, the OR for the highest compared with the lowest fifth was 1.13 (95% CI: 1.04, 1.22; P-trend = 0.015). For α-tocopherol, the OR for the highest compared with the lowest fifth was 0.86 (95% CI: 0.78, 0.94; P-trend < 0.001), with significant heterogeneity by stage of disease; the OR for aggressive prostate cancer was 0.74 (95% CI: 0.59, 0.92; P-trend = 0.001). γ-Tocopherol was not associated with risk.ConclusionsOverall prostate cancer risk was positively associated with retinol and inversely associated with α-tocopherol, and risk of aggressive prostate cancer was inversely associated with lycopene and α-tocopherol. Whether these associations reflect causal relations is unclear.

Gastric cancer is the fourth cause of death by cancer in Spain and a significant medical problem. Molecular biology results evidence that gastroesophageal junction tumors and gastric cancer should be considered as two independent entities with a different prognosis and treatment approach. Endoscopic resection in very early tumors is feasible. Neoadjuvant and adjuvant therapy in locally advanced resectable tumor increase overall survival and should be considered standard treatments. In stage IV tumors, platinum-fluoropyrimidine-based schedule, with trastuzumab in HER2-overexpressed tumors, is the first-line treatment. Different therapies in second line have demonstrated in randomized studies their clear benefit in survival improvement.

Objective Although KRAS mutation status has been identified as a strong predictor of response to anti-epidermal growth factor receptor (EGFR) therapies, not all wild-type patients respond. The lethal-7 (let-7) family of microRNAs regulates KRAS activity. A functional polymorphism (rs61764370) has been described in the let-7 complementary site (LCS6). We hypothesized a possible association between this KRAS let-7 LCS6 polymorphism and the response to anti-EGFR treatments in KRAS and BRAF wild-type metastatic colorectal cancer patients (mCRC). Materials and methods We studied the association of the KRAS let-7 LCS6 polymorphism with the response in 100 refractory mCRC patients treated with anti-EGFR antibodies. To assess the real effect of this polymorphism in relation to the treatment administered, we also studied this association in an independent cohort of patients treated exclusively with chemotherapy. The KRAS let-7 LCS6 polymorphism was genotyped using the BioMark system in blood and tumor DNA samples. The BRAF V600E mutation was analyzed in tumor samples. Results The KRAS let-7 LCS6 G-allele showed a statistically significant association with nonresponse to anti-EGFR-based treatment: 31.9% of patients with the P T/T genotype presented a complete or a partial response versus no patients with T/G or G/G genotypes (P = 0.004). No statistically significant differences were observed in the patients who received chemotherapy only. Conclusion These data support the pharmacogenetic role of the KRAS let-7 LCS6 polymorphism in predicting the efficacy of anti-EGFR-based therapy in mCRC patients with the KRAS and the BRAF wild-type genotype. Pharmacogenetics and Genomics 23:142-147 (c) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Transport measurements of the two-dimensional electron gas at the LaAlO3-SrTiO3 interface have found a density of carriers much lower than expected from the polar catastrophe arguments. From a detail density-functional study, we suggest how this discrepancy may be reconciled. We find that electrons occupy multiple subbands at the interface leading to a rich array of transport properties. Some electrons are confined to a single interfacial layer and susceptible to localization, while others with small masses and extended over several layers are expected to contribute to transport.

We present an approach to calculate total energies of nanoclusters based on first principles estimates. For very large clusters the total energy can be separated into surface, edge and corner energies, in addition to bulk contributions. Using this separation and estimating these with direct, first principles calculations, together with the relevant chemical potentials, we have calculated the total energies of Cu and CdSe tetrahedrons containing a large number of atoms. In our work we consider polyhedral clusters so that in addition our work provides direct information on relaxation. For Cu the effects are very small and the clusters vary uniformly from very small to very large sizes. For CdSe there are important variations in surface and edge structures for specific sizes; nevertheless, the approach can be used to extrapolate to large non-stoichiometric clusters with polar surfaces., Comment: 5 pages, 3 figures and 2 tables

Using first-principles total-energy methods, we investigate Jahn-Teller distortions in III-V dilute magnetic semiconductors, GaAs:Mn and GaN:Mn in the cubic zinc blende structure. The results for an isolated Mn impurity on a Ga site show that there is no appreciable effect in GaAs, whereas, in GaN there is a Jahn-Teller effect in which the symmetry around the impurity changes from T$_{d}$ to D$_{2d}$ or to C$_{2v}$. The large effect in GaN occurs because of the localized d$^4$ character, which is further enhanced by the distortion. The lower symmetry should be detectable experimentally in cubic GaN with low Mn concentration, and should be affected by charge compensation (reductions of holes and conversion of Mn ions to d$^5$ with no Jahn-Teller effect). Jahn-Teller effect is greatly reduced because the symmetry at each Mn site is lowered due to the Mn-Mn interaction. The tendency toward ferromagnetism is found to be stronger in GaN:Mn than in GaAs:Mn and to be only slightly reduced by charge compensation., Comment: 6 pages, 3 figures

We present a theoretical study of diluted magnetic semiconductors that treats the local sp-d exchange interaction J between the itinerant carriers and the Mn d electrons within a realistic band structure and goes beyond previous mean-field approaches. In case of (Ga,Mn)As, we find that strong exchange potentials tightly bind carriers near impurity sites. Spin-orbit coupling is found to have a more pronounced effect on spin polarization at weak coupling and this feature can be exploited for magnetotransport. For low doping regime, we predict that spin-orbit coupling splits impurity bands and can induce a novel insulating phase., Comment: 4 pages, 5 figures

The ``14-1-11'' phase compounds based on magnetic Mn ions and typified by Ca14MnBi11 and Ba14MnBi11 show unusual magnetic behavior, but the large number (104) of atoms in the primitive cell has precluded any previous full electronic structure study. Using an efficient, local orbital based method within the local spin density approximation to study the electronic structure, we find a gap between a bonding valence band complex and an antibonding conduction band continuum. The bonding bands lack one electron per formula unit of being filled, making them low carrier density p-type metals. The hole resides in the MnBi4 tetrahedral unit and partially compensates the high spin d^5 Mn moment, leaving a net spin near 4 \mu_B that is consistent with experiment. These manganites are composed of two disjoint but interpenetrating `jungle gym' networks of spin 4/2 MnBi4^{9-} units with ferromagnetic interactions within the same network, and weaker couplings between the networks whose sign and magnitude is sensitive to materials parameters. Ca14MnBi11 is calculated to be ferromagnetic as observed, while for Ba14MnBi11 (which is antiferromagnetic) the ferro- and antiferromagnetic states are calculated to be essentially degenerate. The band structure of the ferromagnetic states is very close to half metallic., Comment: 17 pages, containing 10 postscript figures and 5 tables. Two additional figures (Fig.8 and 11 of the paper) are provided in JPG format in separate files. Submitted to Phys. Rev. B on September 20th 2001

We study metallization of molecular hydrogen under pressure using exact exchange (EXX) Kohn-Sham density-functional theory in order to avoid well-known underestimates of band gaps associated with standard local-density or generalized-gradient approximations. Compared with the standard methods, the EXX approach leads to considerably (1 - 2 eV) higher gaps and significant changes in the relative energies of different structures. Metallization is predicted to occur at a density of >= 0.6 mol/cm^3 (corresponding to a pressure of >= 400 GPa), consistent with all previous measurements., 11 pages, 4 postscript figures

Fullerides are crystals made from C60 molecules. When doped with alkali metals the valence electrons of the alkali atoms are transfered to the C60 molecules. We show how to set up a model Hamiltonian to describe the correlated hopping of these electrons between C60 molecules. Then we discuss Monte Carlo methods for such lattice Hamiltonians, putting special emphasis on the optimization of Gutzwiller wavefunctions both in variational and fixed-node diffusion Monte Carlo. As application of these methods we analyze the metal-insulator transition in the integer-doped Fullerides., Comment: 16 pages, 10 eps figures included; Proceedings of the NATO ASI Quantum Monte Carlo Methods in Physics and Chemistry, Cornell University, July, 12-25, 1998; additional information is available at http://www.mpi-stuttgart.mpg.de/docs/ANDERSEN/fullerene/

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+ve) 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.

Results from genome-wide association studies (GWAS) can be used to infer causal relationships between phenotypes, using a strategy known as 2-sample Mendelian randomization (2SMR) and bypassing the need for individual-level data. However, 2SMR methods are evolving rapidly and GWAS results are often insufficiently curated, undermining efficient implementation of the approach. We therefore developed MR-Base (http://www.mrbase.org): a platform that integrates a curated database of complete GWAS results (no restrictions according to statistical significance) with an application programming interface, web app and R packages that automate 2SMR. The software includes several sensitivity analyses for assessing the impact of horizontal pleiotropy and other violations of assumptions. The database currently comprises 11 billion single nucleotide polymorphism-trait associations from 1673 GWAS and is updated on a regular basis. Integrating data with software ensures more rigorous application of hypothesis-driven analyses and allows millions of potential causal relationships to be efficiently evaluated in phenome-wide association studies., Supported by Cancer Research UK grant C18281/A19169 (the Integrative Cancer Epidemiology Programme) and the Roy Castle Lung Cancer Foundation (2013/18/Relton). The Medical Research Council Integrative Epidemiology Unit is supported by grants MC_UU_12013/1, MC_UU_12013/2 and MC_UU_12013/8. PCH is supported by a Cancer Research UK Population Research Postdoctoral Fellowship (C52724/A20138). Jack Bowden is supported by a MRC Methodology Research Fellowship (grant MR/N501906/1). DME supported by the NHMRC APP1125200, APP1137714. GH is supported by Wellcome (208806/Z/17/Z).

BACKGROUND: Several 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 FINDINGS: Genetic 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. CONCLUSIONS: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10-180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.

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+ve) 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.

Additional file 2: Supplementary Figure 1a: Kaplan-Meier survival curves based on demographic and clinical covariates. Comorbidity categories were defined according to the severity or organ decompensation: none (coded 0), mild (coded 1), moderate (coded 2), or severe (coded 3). See text for more details. Supplementary Figure 1b: Kaplan-Meier survival curves based on our phenotypes of interest. Supplementary Figure 2: The association between variance explained by DNAm score and hazard ratio for 4-year mortality (Model 3). Hazard ratios are plotted as absolute log-transformed values for comparability. Supplementary Figure 3: ROC curves detailing the predictive accuracy of DNAm risk scores, self-reported phenotype and a combination of the two, against ~4-year mortality (median 3.9 years) in HN5000. ROC curves are provided for smoking, alcohol consumption, BMI and educational attainment. DNAm AUCs reflect use of the DNAm scores for these phenotypes which explained the greatest phenotypic variance: smoking = Trejo Bayesian model, alcohol consumption = Liu et al. model 4, BMI = Trejo Bayesian model, educational attainment = McCartney LASSO model. Abbreviations: AUC, area under curve; DNAm, DNA methylation; ROC, receiver-operator curve