Bayesian safety surveillance with adaptive bias correction.

Postmarket safety surveillance is an integral part of mass vaccination programs. Typically relying on sequential analysis of real-world health data as they accrue, safety surveillance is challenged by sequential multiple testing and by biases induced by residual confounding in observational data. The current standard approach based on the maximized sequential probability ratio test (MaxSPRT) fails to satisfactorily address these practical challenges and it remains a rigid framework that requires prespecification of the surveillance schedule. We develop an alternative Bayesian surveillance procedure that addresses both aforementioned challenges using a more flexible framework. To mitigate bias, we jointly analyze a large set of negative control outcomes that are adverse events with no known association with the vaccines in order to inform an empirical bias distribution, which we then incorporate into estimating the effect of vaccine exposure on the adverse event of interest through a Bayesian hierarchical model. To address multiple testing and improve on flexibility, at each analysis timepoint, we update a posterior probability in favor of the alternative hypothesis that vaccination induces higher risks of adverse events, and then use it for sequential detection of safety signals. Through an empirical evaluation using six US observational healthcare databases covering more than 360 million patients, we benchmark the proposed procedure against MaxSPRT on testing errors and estimation accuracy, under two epidemiological designs, the historical comparator and the self-controlled case series. We demonstrate that our procedure substantially reduces Type 1 error rates, maintains high statistical power and fast signal detection, and provides considerably more accurate estimation than MaxSPRT. Given the extensiveness of the empirical study which yields more than 7 million sets of results, we present all results in a public R ShinyApp. As an effort to promote open science, we provide full implementation of our method in the open-source R package EvidenceSynthesis.

Composite Measures of Brain Activation Predict Individual Differences in Behavioral Stroop Interference.

The goal of the current study was to interrogate aspects of the cascade-of-control model [Banich, M. T. Executive function: The search for an integrated account. Current Directions in Psychological Science, 18, 89-94, 2009; Banich, M. T. The Stroop effect occurs at multiple points along a cascade of control: Evidence from cognitive neuroscience approaches. Frontiers in Psychology, 10, 2164, 2019], a neurocognitive model that posits how portions of pFC interact in a cascade-like manner to overcome interference from task-irrelevant information, and to test whether it could be used to predict individual differences in cognitive control outside the scanner. Participants (n = 62) completed two fMRI Word-Picture Stroop tasks, one containing emotional stimuli and one containing non-emotional stimuli, as well as a behavioral out-of-scanner Color-Word Stroop task at each of two time points. In a departure from the traditional approach of using a single task contrast to index neural activation across all ROIs, the current study utilized specific ROI by contrast pairings selected based on the specific level of control hypothesized by the cascade-of-control model to occur within that region. In addition, data across both tasks and both time points were combined to create composite measures of neural activation and of behavior. Consistent with the cascade-of-control model, individual differences in brain activation for specific contrasts within each of the three ROIs were associated with behavioral interference on the standard Color-Word Stroop task. Testing of alternative models revealed that these brain-behavior relationships were specific to the theoretically driven ROI by contrast pairings. Furthermore, such relationships were not observed across single-task and single-time point measures, but instead emerged from the composite measures. These findings provide evidence that brain activation observed across multiple regions of frontal cortex, each of which likely exerts cognitive control in a differential manner, is capable of predicting individual differences in behavioral performance.

Comparative Effectiveness and Safety of Seizure Prophylaxis Among Adults After Acute Ischemic Stroke.

BACKGROUND: Older adults occasionally receive seizure prophylaxis in an acute ischemic stroke (AIS) setting, despite safety concerns. There are no trial data available about the net impact of early seizure prophylaxis on post-AIS survival. METHODS: Using a stroke registry (American Heart Association's Get With The Guidelines) individually linked to electronic health records, we examined the effect of initiating seizure prophylaxis (ie, epilepsy-specific antiseizure drugs) within 7 days of an AIS admission versus not initiating in patients ≥65 years admitted for a new, nonsevere AIS (National Institutes of Health Stroke Severity score ≤20) between 2014 and 2021 with no recorded use of epilepsy-specific antiseizure drugs in the previous 3 months. We addressed confounding by using inverse-probability weights. We performed standardization accounting for pertinent clinical and health care factors (eg, National Institutes of Health Stroke Severity scale, prescription counts, seizure-like events). RESULTS: The study sample included 151 patients who received antiseizure drugs and 3020 who did not. The crude 30-day mortality risks were 219 deaths per 1000 patients among epilepsy-specific antiseizure drugs initiators and 120 deaths per 1000 among noninitiators. After standardization, the estimated mortality was 251 (95% CI, 190-307) deaths per 1000 among initiators and 120 (95% CI, 86-144) deaths per 1000 among noninitiators, corresponding to a risk difference of 131 (95% CI, 65-200) excess deaths per 1000 patients. In the prespecified subgroup analyses, the risk difference was 52 (95% CI, 11-72) among patients with minor AIS and 138 (95% CI, 52-222) among moderate-to-severe AIS patients. Similarly, the risk differences were 86 (95% CI, 18-118) and 157 (95% CI, 57-219) among patients aged 65 to 74 years and ≥75 years, respectively. CONCLUSIONS: There was a higher risk of 30-day mortality associated with initiating versus not initiating seizure prophylaxis within 7 days post-AIS. This study does not support the role of seizure prophylaxis in reducing 30-day poststroke mortality.

Identification of Vaccine Effects When Exposure Status Is Unknown.

Results from randomized controlled trials (RCTs) help determine vaccination strategies and related public health policies. However, defining and identifying estimands that can guide policies in infectious disease settings is difficult, even in an RCT. The effects of vaccination critically depend on characteristics of the population of interest, such as the prevalence of infection, the number of vaccinated, and social behaviors. To mitigate the dependence on such characteristics, estimands, and study designs, that require conditioning or intervening on exposure to the infectious agent have been advocated. But a fundamental problem for both RCTs and observational studies is that exposure status is often unavailable or difficult to measure, which has made it impossible to apply existing methodology to study vaccine effects that account for exposure status. In this study, we present new results on this type of vaccine effects. Under plausible conditions, we show that point identification of certain relative effects is possible even when the exposure status is unknown. Furthermore, we derive sharp bounds on the corresponding absolute effects. We apply these results to estimate the effects of the ChAdOx1 nCoV-19 vaccine on SARS-CoV-2 disease (COVID-19) conditional on postvaccine exposure to the virus, using data from a large RCT.

Bias analyses to investigate the impact of differential participation: Application to a birth defects case-control study.

BACKGROUND: Certain associations observed in the National Birth Defects Prevention Study (NBDPS) contrasted with other research or were from areas with mixed findings, including no decrease in odds of spina bifida with periconceptional folic acid supplementation, moderately increased cleft palate odds with ondansetron use and reduced hypospadias odds with maternal smoking. OBJECTIVES: To investigate the plausibility and extent of differential participation to produce effect estimates observed in NBDPS. METHODS: We searched the literature for factors related to these exposures and participation and conducted deterministic quantitative bias analyses. We estimated case-control participation and expected exposure prevalence based on internal and external reports, respectively. For the folic acid-spina bifida and ondansetron-cleft palate analyses, we hypothesized the true odds ratio (OR) based on prior studies and quantified the degree of exposure over- (or under-) representation to produce the crude OR (cOR) in NBDPS. For the smoking-hypospadias analysis, we estimated the extent of selection bias needed to nullify the association as well as the maximum potential harmful OR. RESULTS: Under our assumptions (participation, exposure prevalence, true OR), there was overrepresentation of folic acid use and underrepresentation of ondansetron use and smoking among participants. Folic acid-exposed spina bifida cases would need to have been ≥1.2× more likely to participate than exposed controls to yield the observed null cOR. Ondansetron-exposed cleft palate cases would need to have been 1.6× more likely to participate than exposed controls if the true OR is null. Smoking-exposed hypospadias cases would need to have been ≥1.2 times less likely to participate than exposed controls for the association to falsely appear protective (upper bound of selection bias adjusted smoking-hypospadias OR = 2.02). CONCLUSIONS: Differential participation could partly explain certain associations observed in NBDPS, but questions remain about why. Potential impacts of other systematic errors (e.g. exposure misclassification) could be informed by additional research.

International Registry of Coronavirus Exposure in Pregnancy (IRCEP): Cohort Description and Methodological Considerations.

Limited data are available about the potential health effects of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on pregnant women and their developing offspring. We established the International Registry of Coronavirus Exposure in Pregnancy (IRCEP) to provide data on the risk of major adverse obstetric and neonatal outcomes among women with varying degrees of severity and timing of coronavirus disease 2019 (COVID-19) during pregnancy. We describe here the cohort and share the lessons learned. The IRCEP enrolls women tested for SARS-CoV-2 or with a clinical diagnosis of COVID-19 during pregnancy and obtains information using an online data collection system. By March 2021, 17,532 participants from 77 countries had enrolled; 54% enrolled during pregnancy and 46% afterward. Among women with symptomatic COVID-19 with a positive SARS-CoV-2 test (n = 4,934), symptoms were mild in 41%, moderate in 52%, and severe in 7%; 7.7% were hospitalized for COVID-19 and 1.7% were admitted to an intensive care unit. The biggest challenges were retention of participants enrolled during pregnancy and the potential bias introduced when participants enroll after pregnancy outcomes are known. Multiple biases need to be considered and addressed when estimating and interpreting the effects of COVID-19 in pregnancy in these types of cohorts.

Multifoetal gestations mediate the effect of in vitro fertilisation (IVF) on ischaemic placental disease in autologous oocyte IVF more than donor oocyte IVF.

BACKGROUND: Ischaemic placental disease (IPD) affects 16%-23% of pregnancies in the United States. In vitro fertilisation (IVF) is a risk factor for IPD, and the magnitude of increase in risk differs for individuals using donor oocytes (donor IVF) versus their own oocytes (autologous IVF). In addition, multifoetal gestations, which are more common in IVF than non-IVF pregnancies, also are a risk factor for IPD. OBJECTIVE: To quantify the contribution of multifoetal gestations to the association between IVF and IPD. METHODS: We conducted a retrospective cohort study at a tertiary hospital from 1 January, 2000 to 1 August 2018 using electronic medical records and state vital statistics data. IPD was defined as preeclampsia, placental abruption, small for gestational age (SGA) birth or an intrauterine foetal demise due to placental insufficiency. We used mediation analysis to decompose the total effect of IVF on IPD into a natural direct effect and an indirect effect through multifoetal gestations. We repeated the analyses separately for donor and autologous IVF. All models were adjusted for maternal age, race, parity, insurance, year of delivery and account for multiple pregnancies per person. RESULTS: We identified 86,514 deliveries, of which 281 resulted from donor IVF and 4173 resulted from autologous IVF. IVF pregnancies had 1.99 (95% CI 1.88, 2.10) times the risk of IPD compared to non-IVF pregnancies, and 75.5% of this increased risk was mediated by multifoetal gestations. Autologous IVF pregnancies had 1.95 (95% CI 1.84, 2.07) times the risk of IPD compared to non-IVF pregnancies, and the per cent mediated was 78.8%. Donor IVF pregnancies had 2.50 (95% CI 2.09, 2.92) times the risk of IPD, but the per cent mediated was 37.5%. CONCLUSION: The majority of the association between autologous IVF and IPD was mediated through multifoetal gestations; however, this was not the case for donor IVF pregnancies.

Emulation of a target trial with sustained treatment strategies: an application to prostate cancer using both inverse probability weighting and the g-formula.

As with many chronic illnesses, recurrent prostate cancer generally requires sustained treatment to prolong survival. However, initiating treatment immediately after recurrence may negatively impact quality of life without any survival gains. Therefore, we consider sustained strategies for initiating treatment based on specific characteristics of prostate-specific antigen (PSA), which can indicate disease progression. We define the protocol for a target trial comparing treatment strategies based on PSA doubling time, in which androgen deprivation therapy is initiated only after doubling time decreases below a certain threshold. Such a treatment strategy means the timing of treatment initiation (if ever) is not known at baseline, and the target trial protocol must explicitly specify the frequency of PSA monitoring until the threshold is met, as well as the duration of treatment. We describe these and other components of a target trial that need to be specified in order for such a trial to be emulated in observational data. We then use the parametric g-formula and inverse-probability weighted dynamic marginal structural models to emulate our target trial in a cohort of prostate cancer patients from clinics across the United States.

COVID-19 pharmacotherapy utilization patterns during pregnancy: International Registry of Coronavirus Exposure in Pregnancy.

PURPOSE: Women infected with SARS-CoV-2 during pregnancy are at increased risk of developing severe illness and experience a higher rate of preterm births than pregnant women who are not infected. The use of innovative or repurposed therapies to treat COVID-19 patients is widespread; however, there are very limited data regarding the patterns of use and safety profile of most of these therapeutics in pregnant women. We assessed the patterns of use of COVID-19 therapeutics during pregnancy using data from the International Registry of Coronavirus in Pregnancy (IRCEP). METHODS: The IRCEP is an international observational cohort study intended to assess the risk of major obstetric and neonatal outcomes among pregnant women with COVID-19. Women enrolled while pregnant or within 6 months after end of pregnancy. Follow-up for women enrolled while pregnant includes monthly online questionnaires throughout the pregnancy and, for live births, through the infant's first 90 days of life. Participants provide information on demographic characteristics, health history, COVID-19 tests and symptoms, medications, and obstetric and neonatal outcomes. RESULTS: A total of 5780 women with COVID-19 during pregnancy were identified from the IRCEP. Severity of COVID-19 was classified in 372 of them as severe, 3053 moderate, and 2355 mild. The most frequently reported COVID-19 therapies, other than analgesics, included azithromycin (12.8%), steroids (3.5%), interferon (2.4%), oseltamivir (2.1%), chloroquine/hydroxychloroquine (1.7%), anticoagulants (2.0%), antibodies (0.9%), and remdesivir (0.3%). Most drugs were preferentially used for severe cases. Patterns of use varied by country. CONCLUSIONS: IRCEP participants reported use of therapeutics for COVID-19 during pregnancy for which there is little safety information. Findings on COVID-19 pharmacotherapy utilization patterns can guide future studies examining the safety of COVID-19 therapies during pregnancy.

Timing and severity of COVID-19 during pregnancy and risk of preterm birth in the International Registry of Coronavirus Exposure in Pregnancy.

BACKGROUND: Studies of preterm delivery after COVID-19 are often subject to selection bias and do not distinguish between early vs. late infection in pregnancy, nor between spontaneous vs. medically indicated preterm delivery. This study aimed to estimate the risk of preterm birth (overall, spontaneous, and indicated) after COVID-19 during pregnancy, while considering different levels of disease severity and timing. METHODS: Pregnant and recently pregnant people who were tested for or clinically diagnosed with COVID-19 during pregnancy enrolled in an international internet-based cohort study between June 2020 and July 2021. We used several analytic approaches to minimize confounding and immortal time bias, including multivariable regression, time-to-delivery models, and a case-time-control design. RESULTS: Among 14,264 eligible participants from 70 countries who did not report a pregnancy loss before 20 gestational weeks, 5893 had completed their pregnancies and reported delivery information; others were censored at time of their last follow-up. Participants with symptomatic COVID-19 before 20 weeks' gestation had no increased risk of preterm delivery compared to those testing negative, with adjusted risks of 10.0% (95% CI 7.8, 12.0) vs. 9.8% (9.1, 10.5). Mild COVID-19 later in pregnancy was not clearly associated with preterm delivery. In contrast, severe COVID-19 after 20 weeks' gestation led to an increase in preterm delivery compared to milder disease. For example, the risk ratio for preterm delivery comparing severe to mild/moderate COVID-19 at 35 weeks was 2.8 (2.0, 4.0); corresponding risk ratios for indicated and spontaneous preterm delivery were 3.7 (2.0, 7.0) and 2.3 (1.2, 3.9), respectively. CONCLUSIONS: Severe COVID-19 late in pregnancy sharply increased the risk of preterm delivery compared to no COVID-19. This elevated risk was primarily due to an increase in medically indicated preterm deliveries, included preterm cesarean sections, although an increase in spontaneous preterm delivery was also observed. In contrast, mild or moderate COVID-19 conferred minimal risk, as did severe disease early in pregnancy.

Supporting the involvement of older adults with complex needs in evaluation of outcomes in long-term care at home programmes.

BACKGROUND: It is important to involve older people in evaluating public programmes that affect their lives. This includes those with physical and cognitive impairments (such as dementia) who may need support to live at home. Many countries have implemented new approaches to support older people to live well at home for longer. However, it can be challenging to involve disabled people in service evaluation, so we are unclear whether services are meeting their needs. AIM: This study explored how a cascading methodology, offering different supports enabled the involvement of home care users with cognitive and physical impairments in the assessment of their care-related quality of life. METHOD: We used multiple tools from the Adult Social Care Outcomes Toolkit (ASCOT) with n = 63 older adults who were recipients of home care in the Illawarra. We also offered different physical and cognitive supports as needed. RESULTS: We started with the standard ASCOT questionnaire to assess the care-related quality of life, but then offered alternative formats (including Easy Read) and supports (including physical and cognitive assistance) if the older person needed them to participate. This allowed us to involve a greater diversity of older people in the evaluation, and changed what we found out about whether their care needs were being met. CONCLUSION: There is a need to implement more flexible and inclusive methods to increase the involvement of vulnerable users of long-term care in the assessment of service outcomes. This is important to ensure that the perspectives of all service users inform the delivery of person-centred care. It is also critical to understand the extent to which programmes are meeting the needs of vulnerable service users. PATIENT OR PUBLIC CONTRIBUTION: Service users with dementia were involved in the design of the 'Easy Read' questionnaire used in the study.

Multiple-bias Sensitivity Analysis Using Bounds.

Confounding, selection bias, and measurement error are well-known sources of bias in epidemiologic research. Methods for assessing these biases have their own limitations. Many quantitative sensitivity analysis approaches consider each type of bias individually, although more complex approaches are harder to implement or require numerous assumptions. By failing to consider multiple biases at once, researchers can underestimate-or overestimate-their joint impact. We show that it is possible to bound the total composite bias owing to these three sources and to use that bound to assess the sensitivity of a risk ratio to any combination of these biases. We derive bounds for the total composite bias under a variety of scenarios, providing researchers with tools to assess their total potential impact. We apply this technique to a study where unmeasured confounding and selection bias are both concerns and to another study in which possible differential exposure misclassification and confounding are concerns. The approach we describe, though conservative, is easier to implement and makes simpler assumptions than quantitative bias analysis. We provide R functions to aid implementation.

Movement Imitation via an Abstract Trajectory Representation in Dorsal Premotor Cortex.

Humans are particularly good at copying novel and meaningless gestures. The mechanistic and anatomical basis for this specialized imitation ability remains largely unknown. One idea is that imitation occurs by matching body configurations. Here we propose an alternative route to imitation that depends on a body-independent representation of the trajectory path of the end-effector. We studied a group of patients with strokes in the left frontoparietal cortices. We found that they were equally impaired at imitating movement trajectories using the ipsilesional limb (i.e., the nonparetic side) that were cued either by an actor using their whole arm or just by a cursor, suggesting that body configuration information is not always critical for imitation and that a representation of abstract trajectory shape may suffice. In addition, imitation ability was uncorrelated to the ability to identify the trajectory shape, suggesting that imitation deficits were unlikely to arise from perceptual impairments. Finally, a lesion-symptom mapping analysis found that imitation deficits were associated with lesions in left dorsal premotor but not parietal cortex. Together, these findings suggest a novel body-independent route to imitation that relies on the ability to plan abstract movement trajectories within dorsal premotor cortex.SIGNIFICANCE STATEMENT The ability to imitate is critical for rapidly learning to produce new gestures and actions, but how the brain translates observed movements into motor commands is poorly understood. Examining the ability of patients with strokes affecting the left hemisphere revealed that meaningless gestures can be imitated by succinctly representing only the motion of the hand in space, rather than the posture of the entire arm. Moreover, performance deficits correlated with lesions in dorsal premotor cortex, an area not previously associated with impaired imitation of arm postures. These findings thus describe a novel route to imitation that may also be impaired in some patients with apraxia.

The importance of mediation in reproductive health studies.

A mediator is a factor that occurs after the exposure of interest, precedes the outcome of interest (i.e. between the exposure and the outcome) and is associated with both the exposure and the outcome of interest (i.e. is on the pathway between exposure and outcome). Mediation analyses can be valuable in many reproductive health contexts, as mediation analysis can help researchers to better identify, quantify and understand the underlying pathways of the association they are studying. The purpose of this commentary is to introduce the concept of mediation and provide examples that solidify understanding of mediation for valid discovery and interpretation in the field of reproductive medicine.

Boy Interrupted - Biographical disruption during the transition to adulthood.

Most studies on the gendered aspects of biographical disruption are predicated on adult experiences of chronic illness, often based on heterogeneous samples. This paper goes beyond typologies by analysing the life-history case study of 'Sam', a 23-year-old Australian man raised in a refugee family, who developed a disabling chronic health condition at 15 years of age. The analysis illustrates how critical contextual factors like life-phase, combine with powerful social structures like ethnicity and gender to shape Sam's experiences of, and responses to, biographical disruption. Even before the onset of any symptoms, Sam was railing against the marginal position he occupied in the Australian gender order as a young Asian man. With little guidance on how to adapt his biography to integrate his new differently functioning body, Sam's transition to adulthood stalls, and he becomes in effect, a boy interrupted.

Mediational E-values: Approximate Sensitivity Analysis for Unmeasured Mediator-Outcome Confounding.

BACKGROUND: Mediation analysis is a powerful tool for understanding mechanisms, but conclusions about direct and indirect effects will be invalid if there is unmeasured confounding of the mediator-outcome relationship. Sensitivity analysis methods allow researchers to assess the extent of this bias but are not always used. One particularly straightforward technique that requires minimal assumptions is nonetheless difficult to interpret, and so would benefit from a more intuitive parameterization. METHODS: We conducted an exhaustive numerical search over simulated mediation effects, calculating the proportion of scenarios in which a bound for unmeasured mediator-outcome confounding held under an alternative parameterization. RESULTS: In over 99% of cases, the bound for the bias held when we described the strength of confounding directly via the confounder-mediator relationship instead of via the conditional exposure-confounder relationship. CONCLUSIONS: Researchers can conduct sensitivity analysis using a method that describes the strength of the confounder-outcome relationship and the approximate strength of the confounder-mediator relationship that, together, would be required to explain away a direct or indirect effect.

Bounding Bias Due to Selection.

When epidemiologic studies are conducted in a subset of the population, selection bias can threaten the validity of causal inference. This bias can occur whether or not that selected population is the target population and can occur even in the absence of exposure-outcome confounding. However, it is often difficult to quantify the extent of selection bias, and sensitivity analysis can be challenging to undertake and to understand. In this article, we demonstrate that the magnitude of the bias due to selection can be bounded by simple expressions defined by parameters characterizing the relationships between unmeasured factor(s) responsible for the bias and the measured variables. No functional form assumptions are necessary about those unmeasured factors. Using knowledge about the selection mechanism, researchers can account for the possible extent of selection bias by specifying the size of the parameters in the bounds. We also show that the bounds, which differ depending on the target population, result in summary measures that can be used to calculate the minimum magnitude of the parameters required to shift a risk ratio to the null. The summary measure can be used to determine the overall strength of selection that would be necessary to explain away a result. We then show that the bounds and summary measures can be simplified in certain contexts or with certain assumptions. Using examples with varying selection mechanisms, we also demonstrate how researchers can implement these simple sensitivity analyses. See video abstract at, http://links.lww.com/EDE/B535.

'I don't feel like I'm in this on my own': Peer support for mothers of children with intellectual disability and challenging behaviour.

This article reports on the peer support experiences of mothers with a son or daughter with intellectual disability and challenging behaviour. Engagement in parent peer support programs can improve family quality of life and may have multifaceted benefits at the interpersonal, intra-individual self-change and sociopolitical levels. Thirteen mothers were interviewed about their experiences of participating in a parent peer support program. Thematic analysis focused on the process elements of the program that contributed to its effectiveness in providing support to parents. There were three process-related themes: the role of a paid coordinator, diversity of engagement strategies and matching of peer support partners. Mothers appreciated the opportunities provided to engage in a range of strategies tailored to individual preferences, time and capacity constraints, supported by the paid coordinator. One-to-one peer support proved difficult to sustain given the challenges mothers faced in their day-to-day lives.