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This report proposes a stepwise process covering the range of considerations to systematically consider key choices for study design and data analysis for non-interventional studies with the central objective of fostering generation of reliable and reproducible evidence. These steps include (1) formulating a well defined causal question via specification of the target trial protocol; (2) describing the emulation of each component of the target trial protocol and identifying fit-for-purpose data; (3) assessing expected precision and conducting diagnostic evaluations; (4) developing a plan for robustness assessments including deterministic sensitivity analyses, quantitative bias analyses, and net bias evaluation; and (5) inferential analyses.

COVID-19 vaccinations protect against severe illness and death, but associations with post-COVID conditions (PCC) are less clear. We aimed to evaluate the association between prior COVID-19 vaccination and new-onset PCC among individuals with SARS-CoV-2 infection across eight large healthcare systems in the United States. This retrospective matched cohort study used electronic health records (EHR) from patients with SARS-CoV-2 positive tests during March 2021-February 2022. Vaccinated and unvaccinated COVID-19 cases were matched on location, test date, severity of acute infection, age, and sex. Vaccination status was ascertained using EHR and integrated data on externally administered vaccines. Adjusted relative risks (RRs) were obtained from Poisson regression. PCC was defined as a new diagnosis in one of 13 PCC categories 30 days to 6 months following a positive SARS-CoV-2 test. The study included 161,531 vaccinated COVID-19 cases and 161,531 matched unvaccinated cases. Compared to unvaccinated cases, vaccinated cases had a similar or lower risk of all PCC categories except mental health disorders (RR: 1.06, 95% CI: 1.02–1.10). Vaccination was associated with ≥10% lower risk of sensory (RR: 0.90, 0.86–0.95), circulatory (RR: 0.88, 0.83–0.94), blood and hematologic (RR: 0.79, 0.71–0.89), skin and subcutaneous (RR: 0.69, 0.66–0.72), and non-specific COVID-19 related disorders (RR: 0.53, 0.51–0.56). In general, associations were stronger at younger ages but mostly persisted regardless of SARS-CoV-2 variant period, receipt of ≥3 vs. 1–2 vaccine doses, or time since vaccination. Pre-infection vaccination was associated with reduced risk of several PCC outcomes and hence may decrease the long-term consequences of COVID-19. The impact of COVID-19 vaccination on post-COVID conditions is not well understood. Here, the authors use electronic health record data from a network of eight integrated healthcare systems in the United States to compare rates of post-COVID conditions in those with and without vaccination.

Pneumonia is a common complication of influenza infection in elderly individuals and could therefore potentially be prevented by influenza vaccination. In studies with data from administrative sources, vaccinated elderly people had a reduced risk of admission for pneumonia compared with unvaccinated seniors; however, these findings could have been biased by underlying differences in health between the groups. Furthermore, since most individuals with pneumonia are not treated in hospital, such studies should include both outpatient and inpatient events. We therefore assessed whether influenza vaccination is associated with a reduced risk of community-acquired pneumonia in immunocompetent elderly people after controlling for health status indicators. We did a population-based, nested case-control study in immunocompetent elderly people aged 65–94 years (cases and controls) enrolled in Group Health (a health maintenance organisation) during the 2000, 2001, and 2002 preinfluenza periods and influenza seasons. Cases were individuals with an episode of outpatient or inpatient community-acquired pneumonia (validated by review of medical records or chest radiograph reports). We randomly selected two age-matched and sex-matched controls for each case. The exposure of interest was influenza vaccination. We reviewed medical records to define potential confounders, including smoking history, presence and severity of lung and heart disease, and frailty indicators. 1173 cases and 2346 controls were included in the study. After we adjusted for the presence and severity of comorbidities, as defined by chart review, influenza vaccination was not associated with a reduced risk of community-acquired pneumonia (odds ratio 0·92, 95% CI 0·77–1·10) during the influenza season. The effect of influenza vaccination on the risk of pneumonia in elderly people during influenza seasons might be less than previously estimated. Group Health Center for Health Studies internal funds and Group Health Community Foundation fellowship grant.

► We identified the underlying assumptions of the test-negative (TN) design. ► The TN design reduces bias due to misclassification of infection. ► The TN design reduces confounding by differences in health care-seeking. ► TN studies of influenza vaccine must adjust for calendar time. ► TN studies of influenza vaccine must restrict to times when influenza circulates. The test-negative design has emerged in recent years as the preferred method for estimating influenza vaccine effectiveness (VE) in observational studies. However, the methodologic basis of this design has not been formally developed. In this paper we develop the rationale and underlying assumptions of the test-negative study. Under the test-negative design for influenza VE, study subjects are all persons who seek care for an acute respiratory illness (ARI). All subjects are tested for influenza infection. Influenza VE is estimated from the ratio of the odds of vaccination among subjects testing positive for influenza to the odds of vaccination among subjects testing negative. With the assumptions that (a) the distribution of non-influenza causes of ARI does not vary by influenza vaccination status, and (b) VE does not vary by health care-seeking behavior, the VE estimate from the sample can generalized to the full source population that gave rise to the study sample. Based on our derivation of this design, we show that test-negative studies of influenza VE can produce biased VE estimates if they include persons seeking care for ARI when influenza is not circulating or do not adjust for calendar time. The test-negative design is less susceptible to bias due to misclassification of infection and to confounding by health care-seeking behavior, relative to traditional case-control or cohort studies. The cost of the test-negative design is the additional, difficult-to-test assumptions that incidence of non-influenza respiratory infections is similar between vaccinated and unvaccinated groups within any stratum of care-seeking behavior, and that influenza VE does not vary across care-seeking strata.

The Sentinel System is a major component of the United States Food and Drug Administration’s (FDA) approach to active medical product safety surveillance. While Sentinel has historically relied on large quantities of health insurance claims data, leveraging longitudinal electronic health records (EHRs) that contain more detailed clinical information, as structured and unstructured features, may address some of the current gaps in capabilities. We identify key challenges when using EHR data to investigate medical product safety in a scalable and accelerated way, outline potential solutions, and describe the Sentinel Innovation Center’s initiatives to put solutions into practice by expanding and strengthening the existing system with a query-ready, large-scale data infrastructure of linked EHR and claims data. We describe our initiatives in four strategic priority areas: (1) data infrastructure, (2) feature engineering, (3) causal inference, and (4) detection analytics, with the goal of incorporating emerging data science innovations to maximize the utility of EHR data for medical product safety surveillance.

Background: Adult Changes in Thought (ACT), a prospective cohort study, enrolls older adult members of Kaiser Permanente Washington. We describe an ambitious project to abstract medical records facilitating epidemiological investigation. Methods: Abstracted data include medications; laboratory results; women’s health; blood pressure; physical injuries; cardiovascular, neurological, psychiatric and other medical conditions. Results: Of 1419 of 5763 participants with completed abstractions, 1387 (97.7%) were deceased; 602 (42.4%) were diagnosed with Alzheimer’s Disease and Related Dementias; 985 (69.4%) had a brain autopsy. Each participant had an average of 34.3 (SD = 13.4) years of data abstracted. Over 64% had pharmacy data preceding 1977; 87.5% had laboratory data preceding 1988. Stroke, anxiety, depression and confusion during hospitalization were common among participants diagnosed with dementia. Conclusions: Medical records are transformed into data for analyses with outcomes derived from other ACT data. We provide detailed, unparalleled longitudinal clinical data to support a variety of epidemiological research on clinical-pathological correlations.

Understanding the long-term impact of the COVID-19 pandemic on health care utilization is important to health care organizations and policy makers for strategic planning, as well as to researchers when designing studies that use observational electronic health record data during the pandemic period. This study aimed to evaluate the changes in health care utilization across all care settings among a large, diverse, and insured population in the United States during the COVID-19 pandemic. We conducted a retrospective cohort study within 8 health care organizations participating in the Vaccine Safety Datalink Project using electronic health record data from members of all ages from January 1, 2017, to December 31, 2021. The visit rates per person-year were calculated monthly during the study period for 4 health care settings combined as well as by inpatient, emergency department (ED), outpatient, and telehealth settings, both among all members and members without COVID-19. Difference-in-difference analysis and interrupted time series analysis were performed to assess the changes in visit rates from the prepandemic period (January 2017 to February 2020) to the early pandemic period (April-December 2020) and the later pandemic period (July-December 2021), respectively. An exploratory analysis was also conducted to assess trends through June 2023 at one of the largest sites, Kaiser Permanente Southern California. The study included more than 11 million members from 2017 to 2021. Compared with the prepandemic period, we found reductions in visit rates during the early pandemic period for all in-person care settings. During the later pandemic period, overall use reached 8.36 visits per person-year, exceeding the prepandemic level of 7.49 visits per person-year in 2019 (adjusted percent change 5.1%, 95% CI 0.6%-9.9%); inpatient and ED visits returned to prepandemic levels among all members, although they remained low at 0.095 and 0.241 visits per person-year, indicating a 7.5% and 8% decrease compared to pre-pandemic levels among members without COVID-19, respectively. Telehealth visits, which were approximately 42% of the volume of outpatient visits during the later pandemic period, were increased by 97.5% (95% CI 86.0%-109.7%) from 0.865 visits per person-year in 2019 to 2.35 visits per person-year in the later pandemic period. The trends in Kaiser Permanente Southern California were similar to those of the entire study population. Visit rates from January 2022 to June 2023 were stable and appeared to be a continuation of the use levels observed at the end of 2021. Telehealth services became a mainstay of the health care system during the late COVID-19 pandemic period. Inpatient and ED visits returned to prepandemic levels, although they remained low among members without evidence of COVID-19. Our findings provide valuable information for strategic resource allocation for postpandemic patient care and for designing observational studies involving the pandemic period.

Evidence indicates that mRNA COVID-19 vaccination is associated with risk of myocarditis and possibly pericarditis, especially in young males. It is not clear if risk differs between mRNA-1273 versus BNT162b2. We assessed if risk differs using comprehensive health records on a diverse population. Members 18–39 years of age at eight integrated healthcare-delivery systems were monitored using data updated weekly and supplemented with medical record review of myocarditis and pericarditis cases. Incidence of myocarditis and pericarditis events that occurred among vaccine recipients 0 to 7 days after either dose 1 or 2 of a messenger RNA (mRNA) vaccine was compared with that of vaccinated concurrent comparators who, on the same calendar day, had received their most recent dose 22 to 42 days earlier. Rate ratios (RRs) were estimated by conditional Poisson regression, adjusted for age, sex, race and ethnicity, health plan, and calendar day. Head-to-head comparison directly assessed risk following mRNA-1273 versus BNT162b2 during 0–7 days post-vaccination. From December 14, 2020 – January 15, 2022 there were 41 cases after 2,891,498 doses of BNT162b2 and 38 cases after 1,803,267 doses of mRNA-1273. Cases had similar demographic and clinical characteristics. Most were hospitalized for ≤1 day; none required intensive care. During days 0–7 after dose 2 of BNT162b2, the incidence was 14.3 (CI: 6.5–34.9) times higher than the comparison interval, amounting to 22.4 excess cases per million doses; after mRNA-1273 the incidence was 18.8 (CI: 6.7–64.9) times higher than the comparison interval, amounting to 31.2 excess cases per million doses. In head-to-head comparisons 0–7 days after either dose, risk was moderately higher after mRNA-1273 than after BNT162b2 (RR: 1.61, CI 1.02–2.54). Both vaccines were associated with increased risk of myocarditis and pericarditis in 18–39-year-olds. Risk estimates were modestly higher after mRNA-1273 than after BNT162b2.

In this retrospective cohort study involving pregnant women, those who had been vaccinated against Covid-19 did not have a higher risk of clinically serious adverse events than those who were unvaccinated.

Postauthorization monitoring of vaccines in a large population may detect rare adverse events not identified in clinical trials such as Guillain-Barré syndrome (GBS), which has a background rate of 1 to 2 per 100 000 person-years. To describe cases and incidence of GBS following COVID-19 vaccination and assess the risk of GBS after vaccination for Ad.26.COV2.S (Janssen) and mRNA vaccines. This cohort study used surveillance data from the Vaccine Safety Datalink at 8 participating integrated health care systems in the United States. There were 10 158 003 participants aged at least 12 years. Data analysis was performed from November 2021 to February 2022. Ad.26.COV2.S, BNT162b2 (Pfizer-BioNTech), or mRNA-1273 (Moderna) COVID-19 vaccine, including mRNA vaccine doses 1 and 2, December 13, 2020, to November 13, 2021. GBS with symptom onset in the 1 to 84 days after vaccination, confirmed by medical record review and adjudication. Descriptive characteristics of confirmed cases, GBS incidence rates during postvaccination risk intervals after each type of vaccine compared with the background rate, rate ratios (RRs) comparing GBS incidence in the 1 to 21 vs 22 to 42 days postvaccination, and RRs directly comparing risk of GBS after Ad.26.COV2.S vs mRNA vaccination, using Poisson regression adjusted for age, sex, race and ethnicity, site, and calendar day. From December 13, 2020, through November 13, 2021, 15 120 073 doses of COVID-19 vaccines were administered to 7 894 989 individuals (mean [SE] age, 46.5 [0.02] years; 8 138 318 doses received [53.8%] by female individuals; 3 671 199 doses received [24.3%] by Hispanic or Latino individuals, 2 215 064 doses received [14.7%] by Asian individuals, 6 266 424 doses received [41.4%] by White individuals), including 483 053 Ad.26.COV2.S doses, 8 806 595 BNT162b2 doses, and 5 830 425 mRNA-1273 doses. Eleven cases of GBS after Ad.26.COV2.S were confirmed. The unadjusted incidence rate of GBS per 100 000 person-years in the 1 to 21 days after Ad.26.COV2.S was 32.4 (95% CI, 14.8-61.5), significantly higher than the background rate, and the adjusted RR in the 1 to 21 vs 22 to 42 days following Ad.26.COV2.S was 6.03 (95% CI, 0.79-147.79). Thirty-six cases of GBS after mRNA vaccines were confirmed. The unadjusted incidence rate per 100 000 person-years in the 1 to 21 days after mRNA vaccines was 1.3 (95% CI, 0.7-2.4) and the adjusted RR in the 1 to 21 vs 22 to 42 days following mRNA vaccines was 0.56 (95% CI, 0.21-1.48). In a head-to-head comparison of Ad.26.COV2.S vs mRNA vaccines, the adjusted RR was 20.56 (95% CI, 6.94-64.66). In this cohort study of COVID-19 vaccines, the incidence of GBS was elevated after receiving the Ad.26.COV2.S vaccine. Surveillance is ongoing.