The impact of coarsening an exposure on partial identifiability in instrumental variable settings.

In instrumental variable (IV) settings, such as imperfect randomized trials and observational studies with Mendelian randomization, one may encounter a continuous exposure, the causal effect of which is not of true interest. Instead, scientific interest may lie in a coarsened version of this exposure. Although there is a lengthy literature on the impact of coarsening of an exposure with several works focusing specifically on IV settings, all methods proposed in this literature require parametric assumptions.

Bespoke instrumental variables with non-ideal reference populations.

Recently, a bespoke instrumental variable method was proposed, which, under certain assumptions, can eliminate bias due to unmeasured confounding when estimating the causal exposure effect among the exposed. This method uses data from both the study population of interest, and a reference population in which the exposure is completely absent. In this paper, we extend the bespoke instrumental variable method to allow for a non-ideal reference population that may include exposed subjects.

Propensity weighting plus adjustment in proportional hazards model is not doubly robust.

Recently, it has become common for applied works to combine commonly used survival analysis modeling methods, such as the multivariable Cox model and propensity score weighting, with the intention of forming a doubly robust estimator of an exposure effect hazard ratio that is unbiased in large samples when either the Cox model or the propensity score model is correctly specified. This combination does not, in general, produce a doubly robust estimator, even after regression standardization, when there is truly a causal effect. We demonstrate via simulation this lack of double robustness for the semiparametric Cox model, the Weibull proportional hazards model, and a simple proportional hazards flexible parametric model, with both the latter models fit via maximum likelihood.

The use, adherence, and evaluation of interactive text-messaging among women admitted to prevention of mother-to-child transmission of HIV care in Kenya (WelTel PMTCT).

Background: To improve future mobile health (mHealth) interventions in resource-limited settings, knowledge of participants' adherence to interactive interventions is needed, but previous studies are limited. We aimed to investigate how women in prevention of mother-to-child transmission of HIV (PMTCT) care in Kenya used, adhered to, and evaluated an interactive text-messaging intervention.

Methods: We conducted a cohort study nested within the WelTel PMTCT trial among 299 pregnant women living with HIV aged ≥ 18 years.

Inverse probability of treatment weighting with generalized linear outcome models for doubly robust estimation.

There are now many options for doubly robust estimation; however, there is a concerning trend in the applied literature to believe that the combination of a propensity score and an adjusted outcome model automatically results in a doubly robust estimator and/or to misuse more complex established doubly robust estimators. A simple alternative, canonical link generalized linear models (GLM) fit via inverse probability of treatment (propensity score) weighted maximum likelihood estimation followed by standardization (the -formula) for the average causal effect, is a doubly robust estimation method. Our aim is for the reader not just to be able to use this method, which we refer to as IPTW GLM, for doubly robust estimation, but to fully understand why it has the doubly robust property.

The effect of an interactive weekly text-messaging intervention on retention in prevention of mother-to-child transmission of HIV care: a randomised controlled trial (WelTel PMTCT).

Retention in prevention of mother-to-child transmission (PMTCT) care is critical to prevent vertical HIV transmission and reduce morbidity and mortality of mother-infant pairs. We investigated whether weekly, interactive text-messaging improved 18-month postpartum retention in PMTCT care. This randomised, two-armed, parallel trial was conducted at six PMTCT clinics in western Kenya.

Target parameters and bias in non-causal change-score analyses with measurement errors.

In studies where the outcome is a change-score, it is often debated whether or not the analysis should adjust for the baseline score. When the aim is to make causal inference, it has been argued that the two analyses (adjusted vs. unadjusted) target different causal parameters, which may both be relevant.

Causal inference in survival analysis under deterministic missingness of confounders in register data.

Long-term register data offer unique opportunities to explore causal effects of treatments on time-to-event outcomes, in well-characterized populations with minimum loss of follow-up. However, the structure of the data may pose methodological challenges. Motivated by the Swedish Renal Registry and estimation of survival differences for renal replacement therapies, we focus on the particular case when an important confounder is not recorded in the early period of the register, so that the entry date to the register deterministically predicts confounder missingness.

Confirmatory prediction-driven RCTs in comparative effectiveness settings for cancer treatment.

Background: Medical advances in the treatment of cancer have allowed the development of multiple approved treatments and prognostic and predictive biomarkers for many types of cancer. Identifying improved treatment strategies among approved treatment options, the study of which is termed comparative effectiveness, using predictive biomarkers is becoming more common. RCTs that incorporate predictive biomarkers into the study design, called prediction-driven RCTs, are needed to rigorously evaluate these treatment strategies.

Flexible evaluation of surrogacy in platform studies.

Trial-level surrogates are useful tools for improving the speed and cost effectiveness of trials but surrogates that have not been properly evaluated can cause misleading results. The evaluation procedure is often contextual and depends on the type of trial setting. There have been many proposed methods for trial-level surrogate evaluation, but none, to our knowledge, for the specific setting of platform studies.

Cross-direct effects in settings with two mediators.

When multiple mediators are present, there are additional effects that may be of interest beyond the well-known natural (NDE) and controlled direct effects (CDE). These effects cross the type of control on the mediators, setting one to a constant level and one to its natural level, which differs across subjects. We introduce five such estimands for the cross-CDE and -NDE when two mediators are measured.

Confidence bands in survival analysis.

Background: Providing estimates of uncertainty for statistical quantities is important for statistical inference. When the statistical quantity of interest is a survival curve, which is a function over time, the appropriate type of uncertainty estimate is a confidence band constructed to account for the correlation between points on the curve, we will call this a simultaneous confidence band. This, however, is not the type of confidence band provided in standard software, which is constructed by joining the confidence intervals at given time points.

Survival stacking with multiple data types using pseudo-observation-based-AUC loss.

There have been many strategies to adapt machine learning algorithms to account for right censored observations in survival data in order to build more accurate risk prediction models. These adaptions have included pre-processing steps such as pseudo-observation transformation of the survival outcome or inverse probability of censoring weighted (IPCW) bootstrapping of the observed binary indicator of an event prior to a time point of interest. These pre-processing steps allow existing or newly developed machine learning methods, which were not specifically developed with time-to-event data in mind, to be applied to right censored survival data for predicting the risk of experiencing an event.

The effect of weekly interactive text-messaging on early infant HIV testing in Kenya: a randomised controlled trial (WelTel PMTCT).

Mother-to-child transmission of HIV remains a significant concern in Africa despite earlier progress. Early infant diagnosis (EID) of HIV is crucial to reduce mortality among infected infants through early treatment initiation. However, a large proportion of HIV-exposed infants are still not tested in Kenya.

Direct modeling of relative and absolute risks in register data: Mortality risk in sarcoidosis.

Purpose: This paper aims to illustrate the use and interpretation of regression based on pseudo-observations for estimating risks of time-to-event outcomes in epidemiological studies.

Methods: We use pseudo-observation based regression for estimation of contrasts in the relative and absolute risks at specific times. This relaxes the proportional hazards assumption and directly estimates relative and absolute risks without the need for secondary calculations or standardization.

Distinct Metabolic Profile Associated with a Fatal Outcome in COVID-19 Patients during the Early Epidemic in Italy.

In one year of the coronavirus disease 2019 (COVID-19) pandemic, many studies have described the different metabolic changes occurring in COVID-19 patients, linking these alterations to the disease severity. However, a complete metabolic signature of the most severe cases, especially those with a fatal outcome, is still missing. Our study retrospectively analyzes the metabolome profiles of 75 COVID-19 patients with moderate and severe symptoms admitted to Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Lombardy Region, Italy) following SARS-CoV-2 infection between March and April 2020.

Prediction-driven pooled testing methods: Application to HIV treatment monitoring in Rakai, Uganda.

Chronic medical conditions often necessitate regular testing for proper treatment. Regular testing of all afflicted individuals may not be feasible due to limited resources, as is true with HIV monitoring in resource-limited settings. Pooled testing methods have been developed in order to allow regular testing for all while reducing resource burden.

Alcohol and illicit and non-medical prescription drug use before and during pregnancy in Stockholm, Sweden: A cross-sectional study.

Objectives: To provide current estimates of alcohol and drug use among pregnant women attending antenatal care lectures in preparation for childbirth in Stockholm, Sweden.

Study Design: A cross-sectional study. Data was collected anonymously among women attending lectures in preparation for childbirth.

A Deferred-Vaccination Design to Assess Durability of COVID-19 Vaccine Effect After the Placebo Group Is Vaccinated.

Multiple candidate vaccines to prevent COVID-19 have entered large-scale phase 3 placebo-controlled randomized clinical trials, and several have demonstrated substantial short-term efficacy. At some point after demonstration of substantial efficacy, placebo recipients should be offered the efficacious vaccine from their trial, which will occur before longer-term efficacy and safety are known. The absence of a placebo group could compromise assessment of longer-term vaccine effects.

Adjustment for Disease Severity in the Test-Negative Study Design.

The test-negative study design is often used to estimate vaccine effectiveness in influenza studies, but it has also been proposed in the context of other infectious diseases, such as cholera, dengue, or Ebola. It was introduced as a variation of the case-control design, in an attempt to reduce confounding bias due to health-care-seeking behavior, and has quickly gained popularity because of its logistic advantages. However, examination of the directed acyclic graphs that describe the test-negative design reveals that without strong assumptions, the estimated odds ratio derived under this sampling mechanism is not collapsible over the selection variable, such that the results obtained for the sampled individuals cannot be generalized to the whole population.

Pfs230 yields higher malaria transmission-blocking vaccine activity than Pfs25 in humans but not mice.

BACKGROUNDVaccines that block human-to-mosquito Plasmodium transmission are needed for malaria eradication, and clinical trials have targeted zygote antigen Pfs25 for decades. We reported that a Pfs25 protein-protein conjugate vaccine formulated in alum adjuvant induced serum functional activity in both US and Malian adults. However, antibody levels declined rapidly, and transmission-reducing activity required 4 vaccine doses.

On Causal Inferences for Personalized Medicine: How Hidden Causal Assumptions Led to Erroneous Causal Claims About the D-Value.

Personalized medicine asks if a new treatment will help a particular patient, rather than if it improves the average response in a population. Without a causal model to distinguish these questions, interpretational mistakes arise. These mistakes are seen in an article by Demidenko [2016] that recommends the "D-value," which is the probability that a randomly chosen person from the new-treatment group has a higher value for the outcome than a randomly chosen person from the control-treatment group.

Assessing Durability of Vaccine Effect Following Blinded Crossover in COVID-19 Vaccine Efficacy Trials.

Background: Several candidate vaccines to prevent COVID-19 disease have entered large-scale phase 3 placebo-controlled randomized clinical trials and some have demonstrated substantial short-term efficacy. Efficacious vaccines should, at some point, be offered to placebo participants, which will occur before long-term efficacy and safety are known.

Methods: Following vaccination of the placebo group, we show that placebo-controlled vaccine efficacy can be derived by assuming the benefit of vaccination over time has the same profile for the original vaccine recipients and the placebo crossovers.