Cancer Incidence and Survival Among Patients Following an Acute Coronary Syndrome.

To examine the role of acute coronary syndrome (ACS) in subsequent cancer incidence and survival, 2 cohorts of patients hospitalized with ACS were matched 1:1 by gender and age (±3 years) to cardiovascular disease (CVD)-free patients from 2 cycles of the Israeli National Health and Nutrition Surveys. Data on all-cause mortality were retrieved from national registries. Cancer incidence with death treated as a competing event, overall survival, and mortality risk associated with incident cancer as a time-dependent variable were compared between the groups. Our cohort included 2,040 cancer-free matched pairs (mean age of 60±14 years, 42.5% women). Despite higher rates of smokers and patients with hypertension and diabetes mellitus, 10-year cumulative cancer incidence was significantly lower in the ACS group compared with CVD-free group (8.0% vs 11.4%, p = 0.02). This decreased risk was more pronounced in women than men (pinteraction = 0.05). Although being free of CVD meant a significant (p <0.001) survival advantage in the general cohort, this advantage faded once a cancer diagnosis was made (p = 0.80). After adjustment for sociodemographic and clinical covariates, the hazard ratios for mortality associated with a cancer diagnosis were 2.96 (95% confidence interval: 2.36 to 3.71) in the ACS group versus 6.41 (95% confidence interval: 4.96 to 8.28) in the CVD-free group (Pinteraction<0.001). In conclusion, in this matched cohort, ACS was associated with a lower risk of cancer and mitigated the excess risk of mortality associated with cancer incidence.

The role of models in the covid-19 pandemic.

Mathematical and statistical models have played an important role in the analysis of data from COVID-19. They are important for tracking the progress of the pandemic, for understanding its spread in the population, and perhaps most significantly for forecasting the future course of the pandemic and evaluating potential policy options. This article describes the types of models that were used by research teams in Israel, presents their assumptions and basic elements, and illustrates how they were used, and how they influenced decisions. The article grew out of a "modelists' dialog" organized by the Israel National Institute for Health Policy Research with participation from some of the leaders in the local modeling effort.

Association between objective measures and parent-reported measures of child tobacco smoke exposure: A secondary data analysis of four trials.

INTRODUCTION: Tobacco smoke exposure (TSE) harms children and adults. Studies of childhood TSE exposure often relies on parental reports, but may benefit from objective measures. The objective of our study was to study the relationship between reported and objective measures of TSE. METHODS: We analyzed data from four intervention trials, conducted in clinical or community settings, to identify objective measures most closely associated with parent-reported measures and the optimal set of parent-reported measures for predicting objective measures. We also assessed whether there was a learning curve in reported exposure over time, and the importance of replicate biomarker measures. RESULTS: Correlations between objective and parent-reported measures of child TSE were modest at best, ranging from zero to 0.41. Serum cotinine and urinary cotinine were most strongly associated with parental reports. Parental questions most closely related to biomarkers were number of cigarettes and home smoking rules; together these formed the best set of predictive questions. No trial included all objective measures and all questions, precluding definitive statements about relative advantages. Within-subject repeatability of biomarker measures varied across studies, suggesting that direct pilot data are needed to assess the benefit of replicate measurements. CONCLUSIONS: Improvements in objective and parent-reported child exposure measurements are needed to accurately monitor child TSE, evaluate efforts to reduce such exposure, and better protect child health.

The role of statisticians in the response to COVID-19 in Israel: a holistic point of view.

The COVID-19 pandemic cast a dramatic spotlight on the use of data as a fundamental component of good decision-making. Evaluating and comparing alternative policies required information on concurrent infection rates and insightful analysis to project them into the future. Statisticians in Israel were involved in these processes early in the pandemic in some silos as an ad-hoc unorganized effort. Informal discussions within the statistical community culminated in a roundtable, organized by three past presidents of the Israel Statistical Association, and hosted by the Samuel Neaman Institute in April 2021. The meeting was designed to provide a forum for exchange of views on the profession's role during the COVID-19 pandemic, and more generally, on its influence in promoting evidence-based public policy. This paper builds on the insights and discussions that emerged during the roundtable meeting and presents a general framework, with recommendations, for involving statisticians and statistics in decision-making.

Statistical Emulation of Neural Simulators: Application to Neocortical L2/3 Large Basket Cells.

Many scientific systems are studied using computer codes that simulate the phenomena of interest. Computer simulation enables scientists to study a broad range of possible conditions, generating large quantities of data at a faster rate than the laboratory. Computer models are widespread in neuroscience, where they are used to mimic brain function at different levels. These models offer a variety of new possibilities for the neuroscientist, but also numerous challenges, such as: where to sample the input space for the simulator, how to make sense of the data that is generated, and how to estimate unknown parameters in the model. Statistical emulation can be a valuable complement to simulator-based research. Emulators are able to mimic the simulator, often with a much smaller computational burden and they are especially valuable for parameter estimation, which may require many simulator evaluations. This work compares different statistical models that address these challenges, and applies them to simulations of neocortical L2/3 large basket cells, created and run with the NEURON simulator in the context of the European Human Brain Project. The novelty of our approach is the use of fast empirical emulators, which have the ability to accelerate the optimization process for the simulator and to identify which inputs (in this case, different membrane ion channels) are most influential in affecting simulated features. These contributions are complementary, as knowledge of the important features can further improve the optimization process. Subsequent research, conducted after the process is completed, will gain efficiency by focusing on these inputs.

Excess mortality in Israel associated with COVID-19 in 2020-2021 by age group and with estimates based on daily mortality patterns in 2000-2019.

BACKGROUND: We aimed to build a basic daily mortality curve in Israel based on 20-year data accounting for long-term and annual trends, influenza-like illness (ILI) and climate factors among others, and to use the basic curve to estimate excess mortality during 65 weeks of the COVID-19 pandemic in 2020-2021 stratified by age groups. METHODS: Using daily mortality counts for the period 1 January 2000 to 31 December 2019, weekly ILI counts, daily climate and yearly population sizes, we fitted a quasi-Poisson model that included other temporal covariates (a smooth yearly trend, season, day of week) to define a basic mortality curve. Excess mortality was calculated as the difference between the observed and expected deaths on a weekly and periodic level. Analyses were stratified by age group. RESULTS: Between 23 March 2020 and 28 March 2021, a total of 51 361 deaths were reported in Israel, which was 12% higher than the expected number for the same period (expected 45 756 deaths; 95% prediction interval, 45 325-46 188; excess deaths, 5605). In the same period, the number of COVID-19 deaths was 6135 (12% of all observed deaths), 9.5% larger than the estimated excess mortality. Stratification by age group yielded a heterogeneous age-dependent pattern. Whereas in ages 90+ years (11% excess), 100% of excess mortality was attributed to COVID-19, in ages 70-79 years there was a greater excess (21%) with only 82% attributed to COVID-19. In ages 60-69 and 20-59 years, excess mortality was 14% and 10%, respectively, and the number of COVID-19 deaths was higher than the excess mortality. In ages 0-19 years, we found 19% fewer deaths than expected. CONCLUSION: The findings of an age-dependent pattern of excess mortality may be related to indirect pathways in mortality risk, specifically in ages <80 years, and to the implementation of the lockdown policies, specifically in ages 0-19 years with lower deaths than expected.

JAK2V617F Is a Risk Factor for TIA/Stroke in Young Patients.

The objective of this study was to assess the risk of arterial thrombosis in patients who harbor the JAK2V617F allele burden ≥1% detected during workup for myeloproliferative neoplasms (MPNs). We conducted a large cross-sectional analysis consisted of 5,220 patients who were tested for JAK2V617F and 1,047,258 people matched in age from health care insurance provider, taking into account age, sex, hypertension, diabetes, atrial fibrillation. Compared with noncarriers, mutation carriers were older, less likely to be current or past smokers and had lower body mass index. There was no significant difference between the groups regarding myocardial infarction and peripheral vascular disease. However, JAK2V617F ≥1% at age 34 to 54 years was associated with eightfold more likely to have transient ischemic attack (TIA)/stroke history unrelated to hypertension, diabetes, or atrial fibrillation. Association of JAK2V617F with TIA/stroke was also observed in the older age group, albeit a weaker association and not statistically significant. Prevalence of TIA/stroke was higher in patients with JAK2V617F negative, with odds ratio of 3.93 when compared with the general population after confounder adjustments. Further research is warranted to verify the relation between allele burden of JAK2V617F mutation and TIA/stroke and the role of JAK2V617F per se as a risk factor for arterial thrombosis in the absence of overt MPN. Also, consideration should be paid to the screened group with JAK2V617F negative due to the high incidence of TIA/stroke among them in comparison to the general population.

Effective bubble-based testing for SARS-CoV-2 using swab-pooling.

OBJECTIVES: Despite the success in developing COVID-19 vaccines, containment of the disease is obstructed worldwide by vaccine production bottlenecks, logistics hurdles, vaccine refusal, transmission through unvaccinated children, and the appearance of new viral variants. This underscores the need for effective strategies for identifying carriers/patients, which was the main aim of this study. METHODS: We present a bubble-based PCR testing approach using swab-pooling into lysis buffer. A bubble is a cluster of people who can be periodically tested for SARS-CoV-2 by swab-pooling. A positive test of a pool mandates quarantining each of its members, who are then individually tested while in isolation to identify the carrier(s) for further epidemiological contact tracing. RESULTS: We tested an overall sample of 25 831 individuals, divided into 1273 bubbles, with an average size of 20.3 ± 7.7 swabs/test tube, obtaining for all pools (≤37 swabs/pool) a specificity of 97.5% (lower bound 96.6%) and a sensitivity of 86.3% (lower bound 78.2%) and a post hoc analyzed sensitivity of 94.6% (lower bound 86.7%) and a specificity of 97.2% (lower bound 96.2%) in pools with ≤25 swabs, relative to individual testing. DISCUSSION: This approach offers a significant scale-up in sampling and testing throughput and savings in testing cost, without reducing sensitivity or affecting the standard PCR testing laboratory routine. It can be used in school classes, airplanes, hospitals, military units, and workplaces, and may be applicable to future pandemics.

Association of BNT162b2 COVID-19 Vaccination During Pregnancy With Neonatal and Early Infant Outcomes.

Importance: Pregnant women were excluded from the BNT162b2 messenger RNA (mRNA) COVID-19 vaccine (Pfizer-BioNTech) preauthorization trial. Therefore, observational data on vaccine safety for prenatally exposed newborns are critical to inform recommendations on maternal immunization. Objective: To examine whether BNT162b2 mRNA vaccination during pregnancy is associated with adverse neonatal and early infant outcomes among the newborns. Design, Setting, and Participants: Population-based cohort study comprising all singleton live births in March through September 2021, within a large state-mandated health care organization in Israel, followed up until October 31, 2021. Exposure: Maternal BNT162b2 mRNA vaccination during pregnancy. Main Outcomes and Measures: Risk ratios (RR) of preterm birth, small birth weight for gestational age (SGA), congenital malformations, all-cause hospitalizations, and infant death. Stabilized inverse probability weighting was used to adjust for maternal age, timing of conception, parity, socioeconomic status, population subgroup, and maternal influenza immunization status. Results: The cohort included 24 288 eligible newborns (49% female, 96% born at ≥37 weeks' gestation), of whom 16 697 were exposed (n = 2134 and n = 9364 in the first and second trimesters, respectively) to maternal vaccination in utero. Median (IQR) follow-up after birth was 126 days (76-179) among exposed and 152 days (88-209) among unexposed newborns. No substantial differences were observed in preterm birth rates between exposed and unexposed newborns (RR = 0.95; 95% CI, 0.83-1.10) or SGA (RR = 0.97; 95% CI, 0.87-1.08). No significant differences were observed in the incidence of all-cause neonatal hospitalizations (RR = 0.99; 95% CI, 0.88-1.12), postneonatal hospitalizations after birth (RR = 0.95; 95% CI, 0.84-1.07), congenital anomalies (RR = 0.69; 95% CI, 0.44-1.04), or infant mortality over the study period (RR = 0.84; 95% CI, 0.43-1.72). Conclusions and Relevance: This large population-based study found no evident differences between newborns of women who received BNT162b2 mRNA vaccination during pregnancy, vs those of women who were not vaccinated, and contributes to current evidence in establishing the safety of prenatal vaccine exposure to the newborns. Interpretation of study findings is limited by the observational design.

An impact of lipid profile and lipid lowering drugs on ≥70 year olds of an upper socioeconomic class: a retrospective cohort study.

BACKGROUND: Life expectancy has greatly increased, generating an improvement in screening programs for disease prevention, lifesaving drugs and medical devices. The impact of lowering low-density lipoprotein cholesterol (LDL-C) in the very elderly is not well-established. Our aim was to explore the association of LDL-C, high density lipoprotein cholesterol (HDL-C) and lipid lowering drugs (LLDs) on cognitive decline, malignancies and overall survival. METHODS: This was a retrospective cohort study. Our study comprised 1498 (72.7%) males and 561 (27.3%) females, aged ≥70 who had attended the Institute for Medical Screening (IMS), Sheba Medical Center, Israel at least twice during 2013-2019. Data were obtained from the computerized database of the IMS. A manual quality control to identify potential discrepancies was performed. RESULTS: Overall, 6.3% of the subjects treated with LLDs (95/1421) versus 4.2% not treated (28/638), cognitively declined during the study years. No statistically significant effects of LDL-C, HDL-C and LLDs on cognitive decline were observed after correcting for age, prior stroke and other vascular risk factors. With regard to cancer, after adjusting for confounders and multiple inferences, no definite relationships were found. CONCLUSIONS: This analysis of an elderly, high socioeconomic status cohort suggests several relationships between the use of LLDs and health outcomes, some beneficial, especially, with regard to certain types of cancer, but with a higher risk of cognitive decline. Further studies are warranted to clarify the health effects of these medications in the elderly.

Pre-diagnosis thyroid hormone dysfunction is associated with cancer mortality.

Research on the association between thyroid hormone levels and cancer mortality remains limited and inconclusive. We determined the relation of thyroid stimulating hormone (TSH), free T4 (FT4), and free T3 (FT3) levels with mortality in overall cancer and specific tumor types. Thyroid hormone levels 1-5 years prior to cancer diagnosis, as well as multiple clinical and demographic parameters, were retrospectively collected for 10,325 Israeli cancer patients, diagnosed between 2000 and 2016. Patients treated with thyroid altering medications were excluded. Cancer diagnosis was determined via the Israel National Cancer Registry. Multivariate-adjusted Cox proportional hazards model was used to assess the hazard ratios (HRs) based on thyroid hormone function for cancer mortality. A total of 5265 patients died during the follow-up period (median of 4.4 years). TSH, FT4, and FT3 levels in the hypothyroid range were associated with increase in overall mortality (adjusted HR 1.20, 1.74, 1.87, respectively). We further analyzed the association between TSH and mortality in 14 cancer subgroups. Specifically, TSH in both the hyperthyroid and hypothyroid range was associated with melanoma mortality (adjusted HR 2.20, 4.47, respectively). In conclusion, pre-diagnosis of thyroid dysfunction is associated with increased cancer mortality, a relation likely driven by specific cancer types. These findings suggest that thyroid hormones may potentially serve as prognostic markers in cancer.

Association Between BNT162b2 Vaccination and Incidence of SARS-CoV-2 Infection in Pregnant Women.

Importance: Data on BNT162b2 messenger RNA (mRNA) vaccine (Pfizer-BioNTech) effectiveness and safety in pregnancy are currently lacking because pregnant women were excluded from the phase 3 trial. Objective: To assess the association between receipt of BNT162b2 mRNA vaccine and risk of SARS-CoV-2 infection among pregnant women. Design, Setting, and Participants: This was a retrospective cohort study within the pregnancy registry of a large state-mandated health care organization in Israel. Pregnant women vaccinated with a first dose from December 19, 2020, through February 28, 2021, were 1:1 matched to unvaccinated women by age, gestational age, residential area, population subgroup, parity, and influenza immunization status. Follow-up ended on April 11, 2021. Exposures: Exposure was defined by receipt of the BNT162b2 mRNA vaccine. To maintain comparability, nonexposed women who were subsequently vaccinated were censored 10 days after their exposure, along with their matched pair. Main Outcomes and Measures: The primary outcome was polymerase chain reaction-validated SARS-CoV-2 infection at 28 days or more after the first vaccine dose. Results: The cohort included 7530 vaccinated and 7530 matched unvaccinated women, 46% and 33% in the second and third trimester, respectively, with a mean age of 31.1 years (SD, 4.9 years). The median follow-up for the primary outcome was 37 days (interquartile range, 21-54 days; range, 0-70). There were 118 SARS-CoV-2 infections in the vaccinated group and 202 in the unvaccinated group. Among infected women, 88 of 105 (83.8%) were symptomatic in the vaccinated group vs 149 of 179 (83.2%) in the unvaccinated group (P ≥ .99). During 28 to 70 days of follow-up, there were 10 infections in the vaccinated group and 46 in the unvaccinated group. The hazards of infection were 0.33% vs 1.64% in the vaccinated and unvaccinated groups, respectively, representing an absolute difference of 1.31% (95% CI, 0.89%-1.74%), with an adjusted hazard ratio of 0.22 (95% CI, 0.11-0.43). Vaccine-related adverse events were reported by 68 patients; none was severe. The most commonly reported symptoms were headache (n = 10, 0.1%), general weakness (n = 8, 0.1%), nonspecified pain (n = 6, <0.1%), and stomachache (n = 5, <0.1%). Conclusions and Relevance: In this retrospective cohort study of pregnant women, BNT162b2 mRNA vaccination compared with no vaccination was associated with a significantly lower risk of SARS-CoV-2 infection. Interpretation of study findings is limited by the observational design.

Efficient study design to estimate population means with multiple measurement instruments.

Outcomes from studies assessing exposure often use multiple measurements. In previous work, using a model first proposed by Buonoccorsi (1991), we showed that combining direct (eg, biomarkers) and indirect (eg, self-report) measurements provides a more accurate picture of true exposure than estimates obtained when using a single type of measurement. In this article, we propose a tool for efficient design of studies that include both direct and indirect measurements of a relevant outcome. Based on data from a pilot or preliminary study, the tool, which is available online as a shiny app at https://michalbitan.shinyapps.io/shinyApp/, can be used to compute: (1) the sample size required for a statistical power analysis, while optimizing the percent of participants who should provide direct measures of exposure (biomarkers) in addition to the indirect (self-report) measures provided by all participants; (2) the ideal number of replicates; and (3) the allocation of resources to intervention and control arms. In addition we show how to examine the sensitivity of results to underlying assumptions. We illustrate our analysis using studies of tobacco smoke exposure and nutrition. In these examples, a near-optimal allocation of the resources can be found even if the assumptions are not precise.

Opposing effects of thyroid hormones on cancer risk: a population-based study.

OBJECTIVE: The association between dysregulated thyroid hormone function and cancer risk is inconclusive, especially among different age groups and uncommon malignancies. We sought to determine the relation of TSH and free T4 levels with overall cancer risk as well as risk of specific cancer types. DESIGN AND METHODS: Data on thyroid hormone profile was collected from 375 635 Israeli patients with no prior history of cancer. Cancer cases were identified via the Israel National Cancer Registry. Cox proportional hazards model was used to assess hazard ratios for overall cancer as well as 20 cancer subgroups. RESULTS: In this study, 23 808 cases of cancer were detected over median follow up of 10.9 years. Among patients younger than 50 at inclusion, TSH in the hyperthyroid range, elevated free T4 and subclinical hyperthyroidism were associated with increased cancer risk (HR: 1.3, 1.28 and 1.31, respectively). In contrast, patients 50 or older with clinical hyperthyroidism were at lower cancer risk (HR: 0.64). Elevated TSH was associated with decreased risk of prostate cancer (HR: 0.67). Log-TSH elevation was associated with decreased risk of thyroid cancer (HR: 0.82) and increased risk of melanoma (HR: 1.11) and uterine cancer (HR: 1.27). Elevated free T4 was associated with increased lung cancer risk (HR: 1.54), while free T4 levels above the normal range and clinical hyperthyroidism were related to lower colorectal cancer risk (HR: 0.59 and 0.08, respectively). CONCLUSIONS: Thyroid hormones display opposing effects on cancer risk, based on patient age and cancer type.

The effect of civil and military flights on coagulation, fibrinolysis and blood flow: insight from a rat model.

BACKGROUND: Air travel thrombosis continues to be a controversial topic. Exposure to hypoxia and hypobaric conditions during air travel is assumed a risk factor. The aim of this study is to explore changes in parameters of coagulation, fibrinolysis and blood flow in a rat model of exposure to hypobaric conditions that imitate commercial and combat flights. METHODS: Sixty Sprague-Dawley male rats, aged 10 weeks, were divided into 5 groups according to the type and duration of exposure to hypobaric conditions. The exposure conditions were 609 m and 7620 m for 2 and 12 h duration. Blood count, thrombin- antithrombin complex, D-dimer, interleukin-1 and interleukin-6 were analyzed. All rats went through flight angiography MRI at day 13-post exposure. RESULTS: No effect of the various exposure conditions was observed on coagulation, fibrinolytic system, IL-1 or IL-6. MRI angiography showed blood flow reduction in lower limb to less than 30% in 50% of the rats. The reduction in blood flow was more pronounced in the left vessel than in the right vessel (p = 0.006, Wilcoxon signed rank test). The extent of occlusion differed across exposure groups in the right, but not the left vessel (p = 0.002, p = 0.150, respectively, Kruskal-Wallis test). However, these differences did not correlate with the exposure conditions. CONCLUSION: In the present rat model, no clear correlation between various hypobaric conditions and activation of coagulation was observed. The reduction in blood flow in the lower limb also occurred in the control group and was not related to the type of exposure.

Preexisting coronary heart disease and susceptibility to long-term effects of traffic-related air pollution: A matched cohort analysis.

BACKGROUND: Individuals with coronary heart disease are considered susceptible to traffic-related air pollution exposure. Yet, cohort-based evidence on whether preexisting coronary heart disease modifies the association of traffic-related air pollution with health outcomes is lacking. AIM: Using data of four Israeli cohorts, we compared associations of traffic-related air pollution with mortality and cancer between coronary heart disease patients and matched controls from the general population. METHODS: Subjects hospitalized with acute coronary syndrome from two patient cohorts (inception years: 1992-1993 and 2006-2014) were age- and sex-matched to coronary heart disease-free participants of two cycles of the Israeli National Health and Nutrition Surveys (inception years: 1999-2001 and 2005-2006). Ambient concentrations of nitrogen oxides at the residential place served as a proxy for traffic-related air pollution exposure across all cohorts, based on a high-resolution national land use regression model (50 m). Data on all-cause mortality (last update: 2018) and cancer incidence (last update: 2016) were retrieved from national registries. Cox-derived stratum-specific hazard ratios with 95% confidence intervals were calculated, adjusted for harmonized covariates across cohorts, including age, sex, ethnicity, neighborhood socioeconomic status, smoking, diabetes, hypertension, prior stroke and prior malignancy (the latter only in the mortality analysis). Effect-modification was examined by testing nitrogen oxides-by-coronary heart disease interaction term in the entire matched cohort. RESULTS: The cohort (mean (standard deviation) age 61.5 (14) years; 44% women) included 2393 matched pairs, among them 2040 were cancer-free at baseline. During a median (25th-75th percentiles) follow-up of 13 (10-19) and 11 (7-17) years, 1458 deaths and 536 new cancer cases were identified, respectively. In multivariable-adjusted models, a 10-parts per billion nitrogen oxides increment was positively associated with all-cause mortality among coronary heart disease patients (hazard ratio = 1.13, 95% confidence interval 1.05-1.22), but not among controls (hazard ratio = 1.00, 0.93-1.08) (pinteraction = 0.003). A similar pattern was seen for all-cancer incidence (hazard ratioCHD = 1.19 (1.03-1.37), hazard ratioCHD-Free = 0.93 (0.84-1.04) (pinteraction = 0.01)). Associations were robust to multiple sensitivity analyses. CONCLUSIONS: Coronary heart disease patients might be at increased risk for traffic-related air pollution-associated mortality and cancer, irrespective of their age and sex. Patients and clinicians should be more aware of the adverse health effects on coronary heart disease patients of chronic exposure to vehicle emissions.

Leisure-Time Physical Activity and Cancer Risk Among Older Adults: A Cohort Study.

OBJECTIVE: To examine the association between leisure-time physical activity (LTPA) and long-term cancer risk in a nationwide cohort of older adults. PARTICIPANTS AND METHODS: The cohort comprised participants of a national survey conducted between July 2005 and December 2006, constituting a random sample of Israeli community-dwelling adults aged 65 years or older. Based on self-reported LTPA habits, participants were classified as sufficiently active, insufficiently active, or inactive according to published guidelines. Cancer diagnosis was assessed via the Israeli National Cancer Registry through September 2015. Inverse probability weighted hazard ratios for incident cancer, based on propensity score, were estimated for LTPA categories. RESULTS: Analysis included 1542 participants with no history of cancer at baseline (median [25th-75th percentile] age, 73 years [69-78 years]; 826 [53.6%] women). Inactive participants (n=641 [41.6%]) were more likely to be female, of lower socioeconomic status, and with higher body mass index and poorer perceived health compared with their insufficiently active (n=443 [28.7%]) and sufficiently active (n=458 [29.7%]) counterparts. In the propensity score-weighted synthetic sample, the distribution of measured baseline covariates was similar across LTPA categories. Over a median follow-up of 9 years, 254 new cancer cases (16.5%) were diagnosed. Leisure-time physical activity was inversely associated with incident cancer, with adjusted hazard ratios (95% CIs) of 0.66 (0.46-0.93) in insufficiently active and 0.59 (0.42-0.82) in sufficiently active participants compared with inactive individuals (P value for trend = .002). CONCLUSION: Among older adults, engaging in LTPA, even at lower levels than officially recommended, may have a beneficial effect on primary prevention of cancer.

An ancestral variant causing type I xanthinuria in Turkmen and Arab families is predicted to prevail in the Afro-Asian stone-forming belt.

Classical xanthinuria is a rare autosomal recessive metabolic disorder characterized by lack of xanthine dehydrogenase activity that often manifests as xanthine urolithiasis and risk of drug toxicity. Variants in the XDH or HMCS gene underlie classical xanthinuria type I and type II, respectively. Here we present two Israeli Arab families affected by type I xanthinuria in whom a c.2164A>T (Lys722Ter) variant in the XDH gene, previously reported in a Turkish family of Turkmen origin, was identified. Analysis of polymorphic markers surrounding the variant site revealed common haplotypes spanning 0.6 Mbp shared by all three, and 1.7 Mbp shared by two of the studied families. By applying Bayesian methods to a simple model of crossover events through generations in the chromosomes carrying the variant, the most recent common ancestor of these families was found to be 179 (95% credible limit 70) generations old. The estimated antiquity of the variant, the historical genealogy of the affected families and the history and present day dispersion of their people strongly suggest prevalence of this variant in the Afro-Asian stone-forming belt. As far as we are aware, this is a first report of an ancient variant causing xanthinuria with potential wide geographical dispersion.

Estimating the intervention effect in calibration substudies.

Exposure assessment is often subject to measurement errors. We consider here the analysis of studies aimed at reducing exposure to potential health hazards, in which exposure is the outcome variable. In these studies, the intervention effect may be estimated using either biomarkers or self-report data, but it is not common to combine these measures of exposure. Bias in the self-reported measures of exposure is a well-known fact; however, only few studies attempt to correct it. Recently, Keogh et al addressed this problem, presenting a model for measurement error in this setting and investigating how self-report and biomarker data can be combined. Keogh et al find the maximum likelihood estimate for the intervention effect in their model via direct numerical maximization of the likelihood. Here, we exploit an alternative presentation of the model that leads us to a closed formula for the MLE and also for its variance, when the number of biomarker replicates is the same for all subjects in the substudy. The variance formula enables efficient design of such intervention studies. When the number of biomarker replicates is not constant, our approach can be used along with the EM-algorithm to quickly compute the MLE. We compare the MLE to Buonaccorsi's method (Buonaccorsi, 1996) and find that they have similar efficiency when most subjects have biomarker data, but that the MLE has clear advantages when only a small fraction of subjects has biomarker data. This conclusion extends the findings of Keogh et al (2016) and has practical importance for efficiently designing studies.