Early Initiation of Biologics and Disease Outcomes in Adults and Children With Inflammatory Bowel Diseases: Results From the Epidemiology Group of the Nationwide Israeli Inflammatory Bowel Disease Research Nucleus Cohort.

BACKGROUND & AIMS: In this nationwide study, we explored whether early initiation of biologics is associated with improved outcomes in children and adults with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: All patients diagnosed with CD or UC in Israel (2005-2020) were included in the Epidemiology Group of the Israeli Inflammatory Bowel Disease Research Nucleus cohort, encompassing 98% of the population. We compared disease duration at biologics initiation (ie, 0-3 months, >3-12 months, >1-2 years, and >2-3 years) using the cloning, censoring, and weighting by inverse probabilities method to emulate a target trial, adjusting for time-varying confounders and selection bias. RESULTS: Of the 34,375 included patients (of whom 5240 [15%] were children), 7452 of 19,264 (39%) with CD and 2235 of 15,111 (15%) with UC received biologics. In CD, by 10 years postdiagnosis, the probability of CD-related surgery decreased gradually but modestly with earlier initiation of biologics; a significant difference was noted between >2-3 years (31%) and 0-3 months (18%; P = .02; number needed to treat, 7.7), whereas there was no difference between the 0-3-month and >3-12-month periods. The 10-year probability of steroid dependency for the 0-3-month period (19%) differed both from the >2-3-year (31%; P < .001) and 1-2-year periods (37%; P < .001). In UC, no significant differences in colectomy or steroid dependency rates were observed between the treatment initiation periods. Similar trends were noted in the pediatric population. CONCLUSIONS: Very early initiation of biologics was not associated with some outcomes except for a modest risk reduction of surgery and steroid dependency for CD, which requires confirmation in future studies. In UC, early introduction of biologics was not associated with reduced risk of colectomy or steroid dependency.

Distinguishing Immunologic and Behavioral Effects of Vaccination.

The interpretation of vaccine efficacy estimands is subtle, even in randomized trials designed to quantify the immunologic effects of vaccination. In this article, we introduce terminology to distinguish between different vaccine efficacy estimands and clarify their interpretations. This allows us to explicitly consider the immunologic and behavioral effects of vaccination, and establish that policy-relevant estimands can differ substantially from those commonly reported in vaccine trials. We further show that a conventional vaccine trial allows the identification and estimation of different vaccine estimands under plausible conditions if one additional post-treatment variable is measured. Specifically, we utilize a "belief variable" that indicates the treatment an individual believed they had received. The belief variable is similar to "blinding assessment" variables that are occasionally collected in placebo-controlled trials in other fields. We illustrate the relations between the different estimands, and their practical relevance, in numerical examples based on an influenza vaccine trial.

Characterizing CRP dynamics during acute infections.

PURPOSE: C-reactive protein (CRP) is a common proxy of inflammation, but accurate characterizations of its dynamics during acute infections are scant. The goal of this study was to examine C-reactive protein (CRP) trajectories in hospitalized patients with viral infections, confirmed bacteremia (stratified by Gram-negative or Gram-positive bacteria), and non-bacteremic infections/inflammations, considering antibiotic treatment. METHODS: Electronic medical records from Tel Aviv Sourasky Medical Center (July 2007-May 2023) were analyzed. Patients with blood cultures or positive viral tests were included. CRP levels were modeled using generalized additive mixed-effects models (GAMMs) and observed up to 150 h after initial infection diagnosis. Patients with initial CRP levels > 31.9 were excluded, to remove individuals already in a highly active inflammatory process. The shapes of the CRP curves were characterized and peak CRP as well as area under the CRP curve were the primary variables of interest. RESULTS: Viral infections had the lowest and flattest CRP curves. Non-bacteremic infections showed intermediate levels, while bacteremia (especially Gram-negative under antibiotic treatment) had the highest CRP peaks. For instance, peak CRP ranged from 15.4 mg/L in viral infections without antibiotics to 140.9 mg/L in Gram-negative bacteremia with antibiotics. CONCLUSIONS: CRP trajectories significantly differ based on infection type and antibiotic treatment. Frequent CRP measurement could be a valuable diagnostic and risk stratification tool in hospitalized patients.

Causal inference for semi-competing risks data.

The causal effects of Apolipoprotein E $\epsilon4$ allele (APOE) on late-onset Alzheimer's disease (AD) and death are complicated to define because AD may occur under one intervention but not under the other, and because AD occurrence may affect age of death. In this article, this dual outcome scenario is studied using the semi-competing risks framework for time-to-event data. Two event times are of interest: a nonterminal event time (age at AD diagnosis), and a terminal event time (age at death). AD diagnosis time is observed only if it precedes death, which may occur before or after AD. We propose new estimands for capturing the causal effect of APOE on AD and death. Our proposal is based on a stratification of the population with respect to the order of the two events. We present a novel assumption utilizing the time-to-event nature of the data, which is more flexible than the often-invoked monotonicity assumption. We derive results on partial identifiability, suggest a sensitivity analysis approach, and give conditions under which full identification is possible. Finally, we present and implement nonparametric and semiparametric estimation methods under right-censored semi-competing risks data for studying the complex effect of APOE on AD and death.

A sensitivity analysis approach for the causal hazard ratio in randomized and observational studies.

The hazard ratio (HR) is often reported as the main causal effect when studying survival data. Despite its popularity, the HR suffers from an unclear causal interpretation. As already pointed out in the literature, there is a built-in selection bias in the HR, because similarly to the truncation by death problem, the HR conditions on post-treatment survival. A recently proposed alternative, inspired by the Survivor Average Causal Effect, is the causal HR, defined as the ratio between hazards across treatment groups among the study participants that would have survived regardless of their treatment assignment. We discuss the challenge in identifying the causal HR and present a sensitivity analysis identification approach in randomized controlled trials utilizing a working frailty model. We further extend our framework to adjust for potential confounders using inverse probability of treatment weighting. We present a Cox-based and a flexible non-parametric kernel-based estimation under right censoring. We study the finite-sample properties of the proposed estimation methods through simulations. We illustrate the utility of our framework using two real-data examples.

Prenatal and postnatal exposure to NO2 and rapid infant weight gain - A population-based cohort study.

BACKGROUND: Childhood overweight and obesity is a global public health problem. Rapid infant weight gain is predictive of childhood overweight. Studies found that exposure to ambient air pollution is associated with childhood overweight, and have linked prenatal exposure to air pollution with rapid infant weight gain. OBJECTIVES: To examine the association between prenatal and postnatal ambient NO2 exposure, a traffic-related marker, with rapid weight gain in infants. METHODS: We carried out a population-based historical cohort study using data from the Israeli national network of maternal and child health clinics. The study included 474,136 infants born at term with birthweight ≥2500 g in 2011-2019 in central Israel. Weekly averages of NO2 concentration throughout pregnancy (prenatal) and the first 4 weeks of life (postnatal) were assessed using an optimized dispersion model and were linked to geocoded home addresses. We modelled weight gain velocity throughout infancy using the SuperImposition by Translation and Rotation (SITAR) method, a mixed-effects nonlinear model specialized for modelling growth curves, and defined rapid weight gain as the highest velocity tertile. Distributed-lag models were used to assess critical periods of risk and to measure relative risks for rapid weight gain. Adjustments were made for socioeconomic status, population group, subdistrict, month and year of birth, and the alternate exposure period - prenatal or postnatal. RESULTS: The cumulative adjusted relative risk for rapid weight gain of NO2 exposure was 1.02 (95% confidence intereval [CI] 1.00, 1.04) for exposure throughout pregnancy and 1.02 (95% CI 1.01, 1.04) for exposure during the first four postnatal weeks per NO2 interquartile range increase (7.3 ppb). An examination of weekly associations revealed that the critical period of risk for the prenatal exposure was from mid-pregnancy to birth. CONCLUSIONS: Prenatal and postnatal exposures to higher concentrations of traffic-related air pollution are each independently associated with rapid infant weight gain, a risk factor for childhood overweight and obesity.

Ambient temperature and preeclampsia: A historical cohort study.

Previous studies found inconsistent associations between ambient temperature during pregnancy and the risk of preeclampsia. If such associations are causal, they may impact the future burden of preeclampsia in the context of climate change. We used a historical cohort of 129,009 pregnancies (5074 preeclampsia cases) from southern Israel that was merged with temperature assessments from a hybrid satellite-based exposure model. Distributed-lag and cause-specific hazard models were employed to study time to all preeclampsia cases, followed by stratification according to early (≤34 weeks) and late (>34 weeks) onset disease and identify critical exposure periods. We found a positive association between temperature and preeclampsia during gestation, which was stronger in the 3rd trimester. For example, during week 33, compared to the reference temperature of 22.4 °C, the cause-specific hazard ratio (HRCS) of preeclampsia was 1.01 (95% confidence interval (CI): 1.01-1.02) when exposed to 30 °C, 1.05 (95%CI: 1.03-1.08) at 35 °C, and 1.07 (95%CI: 1.04-1.10) at 37 °C. The associations existed with both early- and late-onset preeclampsia; however, the associations with the early-onset disease were somewhat stronger, limited to the first weeks of pregnancy and the third trimester, and with larger confidence intervals. The HRCS for early preeclampsia onset, when exposed to 37 °C compared to 22.4 °C during week 33, was 1.12 (95%CI: 0.96-1.30), and for late-onset preeclampsia, the HRCS was 1.09 (95%CI: 1.05-1.13). To conclude, exposure to high temperatures at the beginning and, particularly, the end of gestation is associated with an increased risk of preeclampsia in southern Israel.

COVID-19 Vaccine Is Effective in Inflammatory Bowel Disease Patients and Is Not Associated With Disease Exacerbation.

BACKGROUND & AIMS: Studies have shown decreased response to coronavirus disease 2019 (COVID-19) vaccinations in some populations. In addition, it is possible that vaccine-triggered immune activation could trigger immune dysregulation and thus exacerbate inflammatory bowel diseases (IBD). In this population-based study we used the epi-Israeli IBD Research Nucleus validated cohort to explore the effectiveness of COVID-19 vaccination in IBD and to assess its effect on disease outcomes. METHODS: We included all IBD patients insured in 2 of the 4 Israeli health maintenance organizations, covering 35% of the population. Patients receiving 2 Pfizer-BioNTech BNT162b2 vaccine doses between December 2020 and June 2021 were individually matched to non-IBD controls. To assess IBD outcomes, we matched vaccinated to unvaccinated IBD patients, and response was analyzed per medical treatment. RESULTS: In total, 12,109 IBD patients received 2 vaccine doses, of whom 4946 were matched to non-IBD controls (mean age, 51 ± 16 years; median follow-up, 22 weeks; interquartile range, 4-24). Fifteen patients in each group (0.3%) developed COVID-19 after vaccination (odds ratio, 1; 95% confidence interval, 0.49-2.05; P = 1.0). Patients on tumor necrosis factor (TNF) inhibitors and/or corticosteroids did not have a higher incidence of infection. To explore IBD outcomes, 707 vaccinated IBD patients were compared with unvaccinated IBD patients by stringent matching (median follow-up, 14 weeks; interquartile range, 2.3-20.4). The risk of exacerbation was 29% in the vaccinated patients compared with 26% in unvaccinated patients (P = .3). CONCLUSIONS: COVID-19 vaccine effectiveness in IBD patients is comparable with that in non-IBD controls and is not influenced by treatment with TNF inhibitors or corticosteroids. The IBD exacerbation rate did not differ between vaccinated and unvaccinated patients.

Perianal Crohn's Disease Is Associated With Poor Disease Outcome: A Nationwide Study From the epiIIRN Cohort.

BACKGROUND & AIMS: Limited population-based data have explored perianal involvement in Crohn's disease (CD) and compared the disease course between severe and non-severe perianal CD (PCD). We aimed to explore the disease course of these phenotypes in a population-based study of CD. METHODS: Cases were identified from the epi-IIRN cohort and included 2 Israeli health maintenance organizations covering 78% of the population. We validated specific algorithms to identify fistulizing PCD and to differentiate severe from non-severe disease by medication utilization, International Classification of Disease, 9th Revision codes, and perianal procedures. RESULTS: A total of 12,904 CD patients were included in an inception cohort from 2005 (2186 pediatric-onset, 17%) providing 86,119 person-years of follow-up. Fistulizing PCD was diagnosed in 1530 patients (12%) (574 with severe PCD, 4%). The prevalence of PCD was 7.9%, 9.4%, 10.3%, and 11.6% at 1, 3, 5, and 10 years from CD diagnosis, respectively. At 5 years, PCD patients were more likely to be hospitalized (36% in non-PCD vs 64% in PCD; P < .001), undergo inflammatory bowel disease-related surgeries (9% vs 38%, respectively; P < .001), and develop anorectal cancer (1.2/10,000 person-years for non-PCD vs 4.2/10,000 for PCD; P = .01). Severe PCD was associated with poorer outcomes compared with non-severe PCD, as shown for hospitalizations (61% in non-severe PCD vs 73% in severe; P = .004) and surgeries (35% vs 43%; P = .001). CONCLUSIONS: Despite higher utilization of immunomodulators and biologics, PCD is associated with poor disease outcomes, especially in severe PCD.

Estimating the impact of cefuroxime versus cefazolin and amoxicillin/clavulanate use on future collateral resistance: a retrospective comparison.

BACKGROUND: Quantitative estimates of collateral resistance induced by antibiotic use are scarce. OBJECTIVES: To estimate the effects of treatment with amoxicillin/clavulanate or cefazolin, compared with cefuroxime, on future resistance to ceftazidime among hospitalized patients. METHODS: A retrospective analysis of patients with positive bacterial cultures hospitalized in an Israeli hospital during 2016-19 was conducted. Patients were restricted to those treated with amoxicillin/clavulanate, cefazolin or cefuroxime and re-hospitalized with a positive bacterial culture during the following year. Matching was performed using exact, Mahalanobis and propensity score matching. Each patient in the amoxicillin/clavulanate and cefazolin groups was matched to a single patient from the cefuroxime group, yielding 185:185 and 298:298 matched patients. Logistic regression and the g-formula (standardization) were used to estimate the OR, risk difference (RD) and number needed to harm (NNH). RESULTS: Cefuroxime induced significantly higher resistance to ceftazidime than amoxicillin/clavulanate or cefazolin; the marginal OR was 1.76 (95% CI = 1.16-2.83) compared with amoxicillin/clavulanate and 1.98 (95% CI = 1.41-2.8) compared with cefazolin and the RD was 0.118 (95% CI = 0.031-0.215) compared with amoxicillin/clavulanate and 0.131 (95% CI = 0.058-0.197) compared with cefazolin. We also estimated the NNH; replacing amoxicillin/clavulanate or cefazolin with cefuroxime would yield ceftazidime resistance in 1 more patient for every 8.5 (95% CI = 4.66-32.14) or 7.6 (95% CI = 5.1-17.3) patients re-hospitalized in the following year, respectively. CONCLUSIONS: Our results indicate that treatment with amoxicillin/clavulanate or cefazolin is preferable to cefuroxime, in terms of future collateral resistance. The results presented here are a first step towards quantitative estimations of the ecological damage caused by different antibiotics.

Modeling semi-competing risks data as a longitudinal bivariate process.

As individuals age, death is a competing risk for Alzheimer's disease (AD) but the reverse is not the case. As such, studies of AD can be placed within the semi-competing risks framework. Central to semi-competing risks, and in contrast to standard competing risks , is that one can learn about the dependence structure between the two events. To-date, however, most methods for semi-competing risks treat dependence as a nuisance and not a potential source of new clinical knowledge. We propose a novel regression-based framework that views the two time-to-event outcomes through the lens of a longitudinal bivariate process on a partition of the time scales of the two events. A key innovation of the framework is that dependence is represented in two distinct forms, local and global dependence, both of which have intuitive clinical interpretations. Estimation and inference are performed via penalized maximum likelihood, and can accommodate right censoring, left truncation, and time-varying covariates. An important consequence of the partitioning of the time scale is that an ambiguity regarding the specific form of the likelihood contribution may arise; a strategy for sensitivity analyses regarding this issue is described. The framework is then used to investigate the role of gender and having ≥1 apolipoprotein E (APOE) ε4 allele on the joint risk of AD and death using data from the Adult Changes in Thought study.

Perianal Crohn Disease Is More Common in Children and Is Associated With Complicated Disease Course Despite Higher Utilization of Biologics: A Population-based Study From The epidemiology group of the Israeli IBD Research Nucleus (epiIIRN).

BACKGROUND AND OBJECTIVES: Both perianal and pediatric-onset Crohn disease (CD) disease are associated with complicated disease course and higher drug utilization. we aimed to explore the differences between pediatric and adult-onset perianal CD and their disease course. METHODS: We included all patients with newly diagnosed CD from 2005 to 2019 at two Israeli Health Maintenance Organizations, covering 78% of the population. A combination of ICD-9 codes, radiology and procedures was used to define fistulizing perianal CD (PCD) and its severity according to the association with simple and complex perianal disease. RESULTS: A total of 12,905 patients were included (2186 [17%] pediatric-onset, 10,719 [83%] adults), with a median follow-up of 7.8 years. PCD was diagnosed in 1530 (12%) patients, with higher incidence in children (308 [14%] children vs 1222 adults [11%]; P  < 0.001). Children had higher incidence of severe PCD (141/308 [47%] vs 433/1222 [35%]; P < 0.001). At 5 years, children with PCD were more likely than adults to be treated with biologics (212 [69%] vs 515 [42%]; odds ratio [OR] 2.6 [95% confidence interval (CI) 1.6-4.0]; P < 0.001) and immunomodulators (238 [74%] vs 643 [53%]; OR 2.8 [95% CI 2.1-3.6]; P < 0.001). PCD in children was still associated with poorer disease outcomes as shown for surgeries (36 [12%] vs 93 [8%]; P = 0.02) and steroid-dependency (52 [17%] vs 156 [13%]; P < 0.001). Multivariable modeling indicated that the severity of PCD is a stronger predictor of disease course than age. CONCLUSION: PCD is more common in pediatric-onset CD and is associated with higher drug utilization and worse disease outcomes, in large due to higher rate of severe PCD in children.

Associations Between Prenatal Exposure to Air Pollution and Congenital Hypothyroidism.

Adequate thyroid hormone availability is required for normal brain development. Studies have found associations between prenatal exposure to air pollutants and thyroid hormones in pregnant women and newborns. We aimed to examine associations of trimester-specific residential exposure to common air pollutants with congenital hypothyroidism (CHT). All term infants born in Israel during 2009-2015 were eligible for inclusion. We used data on CHT from the national neonatal screening lab of Israel, and exposure data from spatiotemporal air pollution models. We used multivariable logistic regression models to estimate associations of exposures with CHT, adjusting for ethnicity, socioeconomic status, geographical area, conception season, conception year, gestational age, birth weight, and child sex. To assess residual confounding, we used postnatal exposures to the same pollutants as negative controls. The study population included 696,461 neonates. We found a positive association between third-trimester nitrogen oxide exposure and CHT (per interquartile-range change, odds ratio = 1.23, 95% confidence interval: 1.08, 1.41) and a similar association for nitrogen dioxide. There was no evidence of residual confounding or bias by correlation among exposure periods for these associations.

A novel calibration framework for survival analysis when a binary covariate is measured at sparse time points.

The goals in clinical and cohort studies often include evaluation of the association of a time-dependent binary treatment or exposure with a survival outcome. Recently, several impactful studies targeted the association between initiation of aspirin and survival following colorectal cancer (CRC) diagnosis. The value of this exposure is zero at baseline and may change its value to one at some time point. Estimating this association is complicated by having only intermittent measurements on aspirin-taking. Commonly used methods can lead to substantial bias. We present a class of calibration models for the distribution of the time of status change of the binary covariate. Estimates obtained from these models are then incorporated into the proportional hazard partial likelihood in a natural way. We develop non-parametric, semiparametric, and parametric calibration models, and derive asymptotic theory for the methods that we implement in the aspirin and CRC study. We further develop a risk-set calibration approach that is more useful in settings in which the association between the binary covariate and survival is strong.

Revealing antibiotic cross-resistance patterns in hospitalized patients through Bayesian network modelling.

OBJECTIVES: Microbial resistance exhibits dependency patterns between different antibiotics, termed cross-resistance and collateral sensitivity. These patterns differ between experimental and clinical settings. It is unclear whether the differences result from biological reasons or from confounding, biasing results found in clinical settings. We set out to elucidate the underlying dependency patterns between resistance to different antibiotics from clinical data, while accounting for patient characteristics and previous antibiotic usage. METHODS: Additive Bayesian network modelling was employed to simultaneously estimate relationships between variables in a dataset of bacterial cultures derived from hospitalized patients and tested for resistance to multiple antibiotics. Data contained resistance results, patient demographics and previous antibiotic usage, for five bacterial species: Escherichia coli (n = 1054), Klebsiella pneumoniae (n = 664), Pseudomonas aeruginosa (n = 571), CoNS (n = 495) and Proteus mirabilis (n = 415). RESULTS: All links between resistance to the various antibiotics were positive. Multiple direct links between resistance of antibiotics from different classes were observed across bacterial species. For example, resistance to gentamicin in E. coli was directly linked with resistance to ciprofloxacin (OR = 8.39, 95% credible interval 5.58-13.30) and sulfamethoxazole/trimethoprim (OR = 2.95, 95% credible interval 1.97-4.51). In addition, resistance to various antibiotics was directly linked with previous antibiotic usage. CONCLUSIONS: Robust relationships among resistance to antibiotics belonging to different classes, as well as resistance being linked to having taken antibiotics of a different class, exist even when taking into account multiple covariate dependencies. These relationships could help inform choices of antibiotic treatment in clinical settings.

Air Pollution and Autism Spectrum Disorder in Israel: A Negative Control Analysis.

BACKGROUND: Residual confounding is a major concern for causal inference in observational studies on air pollution-autism spectrum disorder (ASD) associations. This study is aimed at assessing confounding in these associations using negative control exposures. METHODS: This nested case-control study included all children diagnosed with ASD (detected through 31 December 2016) born during 2007-2012 in Israel and residing in the study area (N = 3,843), and matched controls of the same age (N = 38,430). We assigned individual house-level exposure estimates for each child. We estimated associations using logistic regression models, mutually adjusted for all relevant exposure periods (prepregnancy, pregnancy, and postnatal). We assessed residual confounding using postoutcome negative control exposure at age 28-36 months. RESULTS: In mutually adjusted models, we observed positive associations with ASD for postnatal exposures to NOx (odds ratio per interquartile range, 95% confidence interval: 1.19, 1.02-1.38) and NO2 (1.20, 1.00-1.43), and gestational exposure to PM2.5-10 (1.08, 1.01-1.15). The result for the negative control period was 1.04, 0.99-1.10 for PM2.5, suggesting some residual confounding, but no associations for PM2.5-10 (0.98, 0.81-1.18), NOx (1.02, 0.84-1.25), or NO2 (0.98, 0.81-1.18), suggesting no residual confounding. CONCLUSIONS: Our results further support a hypothesized causal link with ASD that is specific to postnatal exposures to traffic-related pollution.

ANALYSIS OF "LEARN-AS-YOU-GO" (LAGO) STUDIES.

In Learn-As-you-GO (LAGO) adaptive studies, the intervention is a complex multicomponent package, and is adapted in stages during the study based on past outcome data. This design formalizes standard practice in public health intervention studies. An effective intervention package is sought, while minimizing intervention package cost. In LAGO study data, the interventions in later stages depend upon the outcomes in the previous stages, violating standard statistical theory. We develop an estimator for the intervention effects, and prove consistency and asymptotic normality using a novel coupling argument, ensuring the validity of the test for the hypothesis of no overall intervention effect. We develop a confidence set for the optimal intervention package and confidence bands for the success probabilities under alternative package compositions. We illustrate our methods in the BetterBirth Study, which aimed to improve maternal and neonatal outcomes among 157,689 births in Uttar Pradesh, India through a multicomponent intervention package.

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.

Invited Commentary: Opportunities That Come With Studying the Co-Occurrence of Multiple Outcomes.

In almost all clinical settings, patients are at risk for multiple potential events and, in consultation with health-care providers, must weigh the potential benefits and harms across these events when making decisions. As researchers seek to build an evidence base to inform these decisions, they must contend with a choice as to how they will handle the different events. One approach, arguably the standard approach in the literature, is to consider the events individually by conducting analyses and publishing results for each one at a time. Doing so, however, fails to acknowledge or exploit the inherent multivariate nature of the data, represents a lost opportunity, and results in an evidence base that is not aligned with how clinical decision-making is actually performed. The article by Prentice et al. (Am J Epidemiol. 2020;189(9):972-981) in this issue of the Journal moves beyond this standard by illustrating recently developed methods that directly take advantage of information on the co-occurrence of multiple events. Moreover, their article highlights the role of modern methods in deriving additional information and insight from studies of multiple clinical outcomes by making full use of multivariate data, with the goal being to complement, not replace, existing methods.

Calcium intake and colon cancer risk subtypes by tumor molecular characteristics.

BACKGROUND: A preventive potential of high calcium intake against colorectal cancer has been indicated for distal colon cancer, which is inversely associated with high-level CpG island methylator phenotype (CIMP), high-level microsatellite instability (MSI), and BRAF and PIK3CA mutations. In addition, BRAF mutation is strongly inversely correlated with KRAS mutation. We hypothesized that the association between calcium intake and colon cancer risk might vary by these molecular features. METHODS: We prospectively followed 88,506 women from the Nurses' Health Study and 47,733 men from the Health Professionals Follow-up Study for up to 30 years. Duplication-method Cox proportional cause-specific hazards regression was used to estimate multivariable hazard ratios (HRs), and 95% confidence intervals (95% CIs) for the associations between calcium intake and the risk of colon cancer subtypes. By Bonferroni correction, the α-level was adjusted to 0.01. RESULTS: Based on 853 colon cancer cases, the inverse association between dietary calcium intake and colon cancer risk differed by CIMP status (pheterogeneity = 0.01). Per each 300 mg/day increase in intake, multivariable HRs were 0.84 (95% CI 0.76-0.94) for CIMP-negative/low and 1.12 (95% CI 0.93-1.34) for CIMP-high. Similar differential associations were suggested for MSI subtypes (pheterogeneity = 0.02), with the corresponding HR being 0.86 (95% CI 0.77-0.95) for non-MSI-high and 1.10 (95% CI 0.92-1.32) for MSI-high. No differential associations were observed by BRAF, KRAS, or PIK3CA mutations. CONCLUSION: The inverse association between dietary calcium intake and colon cancer risk may be specific to CIMP-negative/low and possibly non-MSI-high subtypes.