Genome-wide analysis to assess if heavy alcohol consumption modifies the association between SNPs and pancreatic cancer risk.

BACKGROUND: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk. METHODS: We conducted a genome-wide interaction analysis of single nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than 3 drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies (GWAS). Our analysis included 3,707 cases and 4,167 controls from case-control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed effect meta-analyses were conducted. RESULTS: A potential novel region of association on 10p11.22, lead SNP rs7898449 (Pinteraction = 5.1 x 10-8 in the meta-analysis, Pinteraction = 2.1x10-9 in the case-control studies, Pinteraction = 0.91 cohort studies) was identified. A SNP correlated with this lead SNP is an eQTL for the NRP1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004). CONCLUSIONS: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an eQTL for the NRP1, a protein that plays an important role in the development and progression of pancreatic cancer Impact: This work can provide insight into the etiology of pancreatic cancer particularly in heavy drinkers.

Impact of phase lag on synchronization in frustrated Kuramoto model with higher-order interactions.

The study of first order transition (explosive synchronization) in an ensemble (network) of coupled oscillators has been the topic of paramount interest among the researchers for more than one decade. Several frameworks have been proposed to induce explosive synchronization in a network and it has been reported that phase frustration in a network usually suppresses first order transition in the presence of pairwise interactions among the oscillators. However, on the contrary, by considering networks of phase frustrated coupled oscillators in the presence of higher-order interactions (up to 2-simplexes) we show here, under certain conditions, phase frustration can promote explosive synchronization in a network. A low-dimensional model of the network in the thermodynamic limit is derived using the Ott-Antonsen ansatz to explain this surprising result. Analytical treatment of the low-dimensional model, including bifurcation analysis, explains the apparent counter intuitive result quite clearly.

Perfect synchronization in complex networks with higher-order interactions.

Achieving perfect synchronization in a complex network, specially in the presence of higher-order interactions (HOIs) at a targeted point in the parameter space, is an interesting, yet challenging task. Here we present a theoretical framework to achieve the same under the paradigm of the Sakaguchi-Kuramoto (SK) model. We analytically derive a frequency set to achieve perfect synchrony at some desired point in a complex network of SK oscillators with higher-order interactions. Considering the SK model with HOIs on top of the scale-free, random, and small world networks, we perform extensive numerical simulations to verify the proposed theory. Numerical simulations show that the analytically derived frequency set not only provides stable perfect synchronization in the network at a desired point but also proves to be very effective in achieving a high level of synchronization around it compared to the other choices of frequency sets. The stability and the robustness of the perfect synchronization state of the system are determined using the low-dimensional reduction of the network and by introducing a Gaussian noise around the derived frequency set, respectively.

Dimension reduction in higher-order contagious phenomena.

We investigate epidemic spreading in a deterministic susceptible-infected-susceptible model on uncorrelated heterogeneous networks with higher-order interactions. We provide a recipe for the construction of one-dimensional reduced model (resilience function) of the N-dimensional susceptible-infected-susceptible dynamics in the presence of higher-order interactions. Utilizing this reduction process, we are able to capture the microscopic and macroscopic behavior of infectious networks. We find that the microscopic state of nodes (fraction of stable healthy individual of each node) inversely scales with their degree, and it becomes diminished due to the presence of higher-order interactions. In this case, we analytically obtain that the macroscopic state of the system (fraction of infectious or healthy population) undergoes abrupt transition. Additionally, we quantify the network's resilience, i.e., how the topological changes affect the stable infected population. Finally, we provide an alternative framework of dimension reduction based on the spectral analysis of the network, which can identify the critical onset of the disease in the presence or absence of higher-order interactions. Both reduction methods can be extended for a large class of dynamical models.

Estimating Burden of Mortality due to Excess Body Mass Index in the US Adult Population by Combining Evidence from a Mendelian Randomization Study and National Health Surveys.

Importance: Assessment of the burden of mortality due to excess body weight in a population and its subgroups is important for designing health policies for interventions. Mendelian randomization (MR) studies can provide an opportunity to correct for unmeasured confounding bias present in observational studies, but such evidence has not been used to assess population burden of mortality due to excess BMI. Objective: Combine results from a recent Mendelian randomization (MR) study and data from the National Health Surveys to estimate preventable fraction (PF) of 10-year all-cause and cause-specific mortality by different degrees of BMI reduction in the US adult population and underlying risk strata. Designs: We use cross-sectional data on the distribution of BMI and other risk factors of mortality from the National Health and Nutritional Examination Surveys (NHANES) across two-time spans (1999-2006 and 2017-2018). We use linked data from National Death Index to characterize the observed risk of 10-year mortality associated with BMI and other risk factors based on the NHANES 1999-2006 cohort. We further import results from an external MR study on linear and non-linear effects of BMI and use novel methods to estimate preventable fraction (PF) for deaths under different counterfactual scenarios of BMI reduction in the NHANES population. Settings: Primary analysis is restricted to the NHANES non-Hispanic white population (age range 40-69 years) due to the unavailability of MR studies in other groups, but projections are provided for the African American population under the assumption of homogeneity of causal effects. Outcome: Preventable fraction for 10-year all-cause mortality and cause-specific mortality due to 50% and 100% reduction of excess BMI (BMI>25.6 kg/m2) for the US adult population in the age range of 40-69 years. Results: Nearly 33% and 43% of the NHANES 2017-2018 target population are overweight (25.6 kg/m2≤BMI<30.7 kg/m2) and obese (BMI>30.7 kg/m2), respectively, according to WHO definitions. Estimates of relative risks for different BMI categories (relative to normal BMI) from the external MR study range from 1.05 (25.6 kg/m2 ≤ BMI < 27.8 kg/m2) to 5.95 (BMI> 42.4 kg/m2). We estimate PF for 10-year all-cause mortality due to 50% and 100% reduction of excess BMI for the population to be 24% (95% CI: 14 - 34) and 35% (95% CI: 22-48), respectively. The estimate of PF of death due to heart disease and cancer for this population reaches up to 48% (95% CI: 25-71) and 18% (95% CI: -2-38), respectively. Partitioning of PF shows that 60% of all BMI-attributable deaths arise from only 12% of the population who are at the highest risk due to obesity and a combination of other risk factors. Conclusions: Nearly one in three deaths in a contemporary US adult population can be attributed to overweight and obesity. A substantial fraction of these deaths are likely to be preventable through pragmatic and targeted BMI interventions.

Early warnings for multi-stage transitions in dynamics on networks.

Successfully anticipating sudden major changes in complex systems is a practical concern. Such complex systems often form a heterogeneous network, which may show multi-stage transitions in which some nodes experience a regime shift earlier than others as an environment gradually changes. Here we investigate early warning signals for networked systems undergoing a multi-stage transition. We found that knowledge of both the ongoing multi-stage transition and network structure enables us to calculate effective early warning signals for multi-stage transitions. Furthermore, we found that small subsets of nodes could anticipate transitions as well as or even better than using all the nodes. Even if we fix the network and dynamical system, no single best subset of nodes provides good early warning signals, and a good choice of sentinel nodes depends on the tipping direction and the current stage of the dynamics within a multi-stage transition, which we systematically characterize.

Pathogen exposure misclassification can bias association signals in GWAS of infectious diseases when using population-based common control subjects.

Genome-wide association studies (GWASs) have been performed to identify host genetic factors for a range of phenotypes, including for infectious diseases. The use of population-based common control subjects from biobanks and extensive consortia is a valuable resource to increase sample sizes in the identification of associated loci with minimal additional expense. Non-differential misclassification of the outcome has been reported when the control subjects are not well characterized, which often attenuates the true effect size. However, for infectious diseases the comparison of affected subjects to population-based common control subjects regardless of pathogen exposure can also result in selection bias. Through simulated comparisons of pathogen-exposed cases and population-based common control subjects, we demonstrate that not accounting for pathogen exposure can result in biased effect estimates and spurious genome-wide significant signals. Further, the observed association can be distorted depending upon strength of the association between a locus and pathogen exposure and the prevalence of pathogen exposure. We also used a real data example from the hepatitis C virus (HCV) genetic consortium comparing HCV spontaneous clearance to persistent infection with both well-characterized control subjects and population-based common control subjects from the UK Biobank. We find biased effect estimates for known HCV clearance-associated loci and potentially spurious HCV clearance associations. These findings suggest that the choice of control subjects is especially important for infectious diseases or outcomes that are conditional upon environmental exposures.

Logistic regression analysis of two-phase studies using generalized method of moments.

Two-phase designs can reduce the cost of epidemiological studies by limiting the ascertainment of expensive covariates or/and exposures to an efficiently selected subset (phase-II) of a larger (phase-I) study. Efficient analysis of the resulting data set combining disparate information from phase-I and phase-II, however, can be complex. Most of the existing methods, including semiparametric maximum-likelihood estimator, require the information in phase-I to be summarized into a fixed number of strata. In this paper, we describe a novel method for the analysis of two-phase studies where information from phase-I is summarized by parameters associated with a reduced logistic regression model of the disease outcome on available covariates. We then setup estimating equations for parameters associated with the desired extended logistic regression model, based on information on the reduced model parameters from phase-I and complete data available at phase-II after accounting for nonrandom sampling design. We use generalized method of moments to solve overly identified estimating equations and develop the resulting asymptotic theory for the proposed estimator. Simulation studies show that the use of reduced parametric models, as opposed to summarizing data into strata, can lead to more efficient utilization of phase-I data. An application of the proposed method is illustrated using the data from the U.S. National Wilms Tumor Study.

Accuracy of a one-dimensional reduction of dynamical systems on networks.

Resilience is an ability of a system with which the system can adjust its activity to maintain its functionality when it is perturbed. To study resilience of dynamics on networks, Gao et al. [Nature (London) 530, 307 (2016)0028-083610.1038/nature16948] proposed a theoretical framework to reduce dynamical systems on networks, which are high dimensional in general, to one-dimensional dynamical systems. The accuracy of this one-dimensional reduction relies on three approximations in addition to the assumption that the network has a negligible degree correlation. In the present study, we analyze the accuracy of the one-dimensional reduction assuming networks without degree correlation. We do so mainly through examining the validity of the individual assumptions underlying the method. Across five dynamical system models, we find that the accuracy of the one-dimensional reduction hinges on the spread of the equilibrium value of the state variable across the nodes in most cases. Specifically, the one-dimensional reduction tends to be accurate when the dispersion of the node's state is small. We also find that the correlation between the node's state and the node's degree, which is common for various dynamical systems on networks, is unrelated to the accuracy of the one-dimensional reduction.

Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3.

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10-8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, P interaction = 3.08 × 10-9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r 2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.

Individual and community-level risk for COVID-19 mortality in the United States.

Reducing COVID-19 burden for populations will require equitable and effective risk-based allocations of scarce preventive resources, including vaccinations1. To aid in this effort, we developed a general population risk calculator for COVID-19 mortality based on various sociodemographic factors and pre-existing conditions for the US population, combining information from the UK-based OpenSAFELY study with mortality rates by age and ethnicity across US states. We tailored the tool to produce absolute risk estimates in future time frames by incorporating information on pandemic dynamics at the community level. We applied the model to data on risk factor distribution from a variety of sources to project risk for the general adult population across 477 US cities and for the Medicare population aged 65 years and older across 3,113 US counties, respectively. Validation analyses using 54,444 deaths from 7 June to 1 October 2020 show that the model is well calibrated for the US population. Projections show that the model can identify relatively small fractions of the population (for example 4.3%) that might experience a disproportionately large number of deaths (for example 48.7%), but there is wide variation in risk across communities. We provide a web-based risk calculator and interactive maps for viewing community-level risks.

Quantifying the Predictive Performance of Objectively Measured Physical Activity on Mortality in the UK Biobank.

BACKGROUND: Objective measures of physical activity (PA) derived from wrist-worn accelerometers are compared with traditional risk factors in terms of mortality prediction performance in the UK Biobank. METHOD: A subset of participants in the UK Biobank study wore a tri-axial wrist-worn accelerometer in a free-living environment for up to 7 days. A total of 82 304 individuals over the age of 50 (439 707 person-years of follow-up, 1959 deaths) had both accelerometry data that met specified quality criteria and complete data on a set of traditional mortality risk factors. Predictive performance was assessed using cross-validated Concordance (C) for Cox regression models. Forward selection was used to obtain a set of best predictors of mortality. RESULTS: In univariate Cox regression, age was the best predictor of all-cause mortality (C = 0.681) followed by 12 PA predictors, led by minutes of moderate-to-vigorous PA (C = 0.661) and total acceleration (C = 0.661). Overall, 16 of the top 20 predictors were objective PA measures (C = 0.578-0.661). Using a threshold of 0.001 improvement in Concordance, the Concordance for the best model that did not include PA measures was 0.735 (9 covariates) compared with 0.748 (12 covariates) for the best model with PA variables (p-value < .001). CONCLUSIONS: Objective measures of PA derived from accelerometry outperform traditional predictors of all-cause mortality in the UK Biobank except age and substantially improve the prediction performance of mortality models based on traditional risk factors. Results confirm and complement previous findings in the National Health and Nutrition Examination Survey (NHANES).

Combined Utility of 25 Disease and Risk Factor Polygenic Risk Scores for Stratifying Risk of All-Cause Mortality.

While genome-wide association studies have identified susceptibility variants for numerous traits, their combined utility for predicting broad measures of health, such as mortality, remains poorly understood. We used data from the UK Biobank to combine polygenic risk scores (PRS) for 13 diseases and 12 mortality risk factors into sex-specific composite PRS (cPRS). These cPRS were moderately associated with all-cause mortality in independent data within the UK Biobank: the estimated hazard ratios per standard deviation were 1.10 (95% confidence interval: 1.05, 1.16) and 1.15 (1.10, 1.19) for women and men, respectively. Differences in life expectancy between the top and bottom 5% of the cPRS were estimated to be 4.79 (1.76, 7.81) years and 6.75 (4.16, 9.35) years for women and men, respectively. These associations were substantially attenuated after adjusting for non-genetic mortality risk factors measured at study entry (i.e., middle age for most participants). The cPRS may be useful in counseling younger individuals at higher genetic risk of mortality on modification of non-genetic factors.

Isolated Diastolic Hypertension in the UK Biobank: Comparison of ACC/AHA and ESC/NICE Guideline Definitions.

The 2017 American College of Cardiology/American Heart Association guideline defines hypertension as a blood pressure ≥130/80 mm Hg, whereas the 2018 European Society of Cardiology (ESC) and 2019 National Institute for Health and Care Excellence (NICE) guidelines use a ≥140/90 mm Hg threshold. Our objective was to study the associations between isolated diastolic hypertension (IDH), diagnosed using these 2 blood pressure thresholds, and cardiovascular disease (CVD) in a large cohort of UK adults. We analyzed data from UK Biobank, which enrolled participants between 2006 and 2010 with follow-up through March 2019. We excluded persons with systolic hypertension or baseline CVD. We defined incident CVD as a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. We used Cox regression to quantify associations between IDH and CVD, as well as the individual outcomes included in the composite outcome. We studied 151 831 participants with normal systolic blood pressure (mean age 54 years, 40% male). Overall, 24.5% had IDH by the American College of Cardiology/American Heart Association definition compared with 6% by the ESC/NICE definition. Compared with normal diastolic blood pressure, IDH by the American College of Cardiology/American Heart Association definition was not significantly associated with CVD risk (hazard ratio, 1.08 [95% CI, 0.98-1.18]) whereas IDH by the ESC/NICE definition was significantly associated with a modest increase in CVD (hazard ratio, 1.15 [95% CI, 1.04-1.29]). Similar results were found by sex and among participants not taking baseline antihypertensives. Furthermore, neither IDH definition was associated with the individual outcomes of nonfatal myocardial infarction or stroke. In conclusion, the proportion of UK Biobank participants with IDH was significantly higher by the American College of Cardiology/American Heart Association definition compared with the ESC/NICE definitions; however, only the ESC/NICE definition was statistically associated with increased CVD risk.

Amplification of explosive width in complex networks.

We present an adaptive coupling strategy to induce hysteresis/explosive synchronization in complex networks of phase oscillators (Sakaguchi-Kuramoto model). The coupling strategy ensures explosive synchronization with significant explosive width enhancement. Results show the robustness of the strategy, and the strategy can diminish (by inducing enhanced hysteresis loop) the contrarian impact of phase frustration in the network, irrespective of the network structure or frequency distributions. Additionally, we design a set of frequency for the oscillators, which eventually ensure complete in-phase synchronization behavior among these oscillators (with enhanced explosive width) in the case of adaptive-coupling scheme. Based on a mean-field analysis, we develop a semi-analytical formalism, which can accurately predict the backward transition of the synchronization order parameter.

Case-Only Analysis of Gene-Environment Interactions Using Polygenic Risk Scores.

Investigations of gene (G)-environment (E) interactions have led to limited findings to date, possibly due to weak effects of individual genetic variants. Polygenic risk scores (PRS), which capture the genetic susceptibility associated with a set of variants, can be a powerful tool for detecting global patterns of interaction. Motivated by the case-only method for evaluating interactions with a single variant, we propose a case-only method for the analysis of interactions with a PRS in case-control studies. Assuming the PRS and E are independent, we show how a linear regression of the PRS on E in a sample of cases can be used to efficiently estimate the interaction parameter. Furthermore, if an estimate of the mean of the PRS in the underlying population is available, the proposed method can estimate the PRS main effect. Extensions allow for PRS-E dependence due to associations between variants in the PRS and E. Simulation studies indicate the proposed method offers appreciable gains in efficiency over logistic regression and can recover much of the efficiency of a cohort study. We applied the proposed method to investigate interactions between a PRS and epidemiologic factors on breast cancer risk in the UK Biobank (United Kingdom, recruited 2006-2010).

Generalized meta-analysis for multiple regression models across studies with disparate covariate information.

Meta-analysis is widely popular for synthesizing information on common parameters of interest across multiple studies because of its logistical convenience and statistical efficiency. We develop a generalized meta-analysis approach to combining information on multivariate regression parameters across multiple studies that have varying levels of covariate information. Using algebraic relationships among regression parameters in different dimensions, we specify a set of moment equations for estimating parameters of a maximal model through information available from sets of parameter estimates for a series of reduced models from the different studies. The specification of the equations requires a reference dataset for estimating the joint distribution of the covariates. We propose to solve these equations using the generalized method of moments approach, with the optimal weighting of the equations taking into account uncertainty associated with estimates of the parameters of the reduced models. We describe extensions of the iterated reweighted least-squares algorithm for fitting generalized linear regression models using the proposed framework. Based on the same moment equations, we also develop a diagnostic test for detecting violations of underlying model assumptions, such as those arising from heterogeneity in the underlying study populations. The proposed methods are illustrated with extensive simulation studies and a real-data example involving the development of a breast cancer risk prediction model using disparate risk factor information from multiple studies.

Diffusion dynamics of a conductance-based neuronal population.

We study the spatiotemporal dynamics of a conductance-based neuronal cable. The processes of one-dimensional (1D) and 2D diffusion are considered for a single variable, which is the membrane voltage. A 2D Morris-Lecar (ML) model is introduced to investigate the nonlinear responses of an excitable conductance-based neuronal cable. We explore the parameter space of the uncoupled ML model and, based on the bifurcation diagram (as a function of stimulus current), we analyze the 1D diffusion dynamics in three regimes: phasic spiking, coexistence states (tonic spiking and phasic spiking exist together), and a quiescent state. We show (depending on parameters) that the diffusive system may generate regular and irregular bursting or spiking behavior. Further, we explore a 2D diffusion acting on the membrane voltage, where striped and hexagonlike patterns can be observed. To validate our numerical results and check the stability of the existing patterns generated by 2D diffusion, we use amplitude equations based on multiple-scale analysis. We incorporate 1D diffusion in an extended 3D version of the ML model, in which irregular bursting emerges for a certain diffusion strength. The generated patterns may have potential applications in nonlinear neuronal responses and signal transmission.

Synchronization transition in Sakaguchi-Kuramoto model on complex networks with partial degree-frequency correlation.

We investigate transition to synchronization in the Sakaguchi-Kuramoto (SK) model on complex networks analytically as well as numerically. Natural frequencies of a percentage (f) of higher degree nodes of the network are assumed to be correlated with their degrees and that of the remaining nodes are drawn from some standard distribution, namely, Lorentz distribution. The effects of variation of f and phase frustration parameter α on transition to synchronization are investigated in detail. Self-consistent equations involving critical coupling strength (λc) and group angular velocity (Ωc) at the onset of synchronization have been derived analytically in the thermodynamic limit. For the detailed investigation, we considered the SK model on scale-free (SF) as well as Erdos-Rényi (ER) networks. Interestingly, explosive synchronization (ES) has been observed in both networks for different ranges of values of α and f. For SF networks, as the value of f is set within 10%≤f≤70%, the range of the values of α for existence of the ES is greatly enhanced compared to the fully degree-frequency correlated case when scaling exponent γ<3. ES is also observed in SF networks with γ>3, which is never observed in fully degree-frequency correlated environment. On the other hand, for random networks, ES observed is in a narrow window of α when the value of f is taken within 30%≤f≤50%. In all the cases, critical coupling strengths for transition to synchronization computed from the analytically derived self-consistent equations show a very good agreement with the numerical results. Finally, we observe ES in the metabolic network of the roundworm Caenorhabditis elegans in partially degree-frequency correlated environment.