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Vital Sign alterations within 24 hours prior to death in children with retinopathy-positive Cerebral Malaria at Queen Elizabeth Central Hospital Malawi
Malaria is a significant obstacle to child health and survival. Plasmodium falciparum infections, especially in children under five, lead to high morbidity and mortality. Cerebral malaria (CM) is a life-threatening complication characterized by coma, and its diagnosis can be improved by observing malarial retinopathy in children. Monitoring vital signs is essential for managing patients with CM. To determine if changes in vital signs predict death in children with retinopathy positive cerebral malaria (RPCM). This was a retrospective case-control study using data collected from children admitted to the Paediatric Research Ward at Queen Elizabeth Central Hospital in Blantyre between 1997 and 2020. Patients who died 24 hours or more after admission were matched with control patients who survived. Linear regression analyses were used to assess the differential time trends of each vital sign in the survivor group and death group. Classification models were used to quantify various vital signs’ predictive power of death. Among the population that died, the estimated change in average respiratory rate per hour approaching death was 0.02 breaths per minute compared to -0.25 breaths per minute among those who survive (p < 0.001), and the estimated change in average BCS per hour approaching death was -0.01 compared to 0.06 among the survivors (p < 0.001). Changes in temperature and heart rate were not associated with clinical deterioration. Three models were developed, and the best receiver operating characteristic curve was 100% sensitive, the corresponding false positive rate was 75%. Changes in respiratory rate and BCS have prognostic significance in the final 24 hours before death in children with cerebral malaria. Extra attention should be paid to these two vital signs as they may help to identify children who are at increased risk of deteriorating.
Generalizing the intention-to-treat effect of an active control from historical placebo-controlled trials: A case study of the efficacy of daily oral TDF/FTC in the HPTN 084 study
In many clinical settings, an active-controlled trial design (e.g., a non-inferiority or superiority design) is often used to compare an experimental medicine to an active control (e.g., an FDA-approved, standard therapy). One prominent example is a recent phase 3 efficacy trial, HIV Prevention Trials Network Study 084 (HPTN 084), comparing long-acting cabotegravir, a new HIV pre-exposure prophylaxis (PrEP) agent, to the FDA-approved daily oral tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) in a population of heterosexual women in 7 African countries. One key complication of interpreting study results in an active-controlled trial like HPTN 084 is that the placebo arm is not present and the efficacy of the active control (and hence the experimental drug) compared to the placebo can only be inferred by leveraging other data sources. In this article, we study statistical inference for the intention-to-treat (ITT) effect of the active control using relevant historical placebo-controlled trials data under the potential outcomes (PO) framework. We highlight the role of adherence and unmeasured confounding, discuss in detail identification assumptions and two modes of inference (point vs. partial identification), propose estimators under identification assumptions permitting point identification, and lay out sensitivity analyses needed to relax identification assumptions. We applied our framework to estimating the intention-to-treat effect of daily oral TDF/FTC versus placebo in HPTN 084 using data from an earlier Phase 3, placebo-controlled trial of daily oral TDF/FTC (Partners PrEP). Supplementary materials for this article are available online, including a standardized description of the materials available for reproducing the work.
Testing clinical selection criteria for intraoperative transoesophageal echocardiography in isolated coronary artery bypass graft surgery
There is a lack of evidence associating intraoperative transoesophageal echocardiography (TOE) use with improved outcomes among coronary artery bypass graft (CABG) surgery subpopulations.This matched retrospective cohort study used a US private claims dataset to compare outcomes among different CABG surgery patient populations with vs without TOE. Statistical analyses involved exact matching on pre-selected subgroups (congestive heart failure, single vessel, and multivessel CABG) and used fine and propensity-score balanced techniques to conduct multiple matched comparisons and sensitivity analyses.Of 42 249 patients undergoing isolated CABG surgery, 24 919 (59.0%) received and 17 330 (41.0%) did not receive TOE. After matching, intraoperative TOE was significantly associated with a lower, 30-day mortality: 2.63% vs 3.20% (odds ratio [OR]: 0.81; 95% confidence interval [CI]: 0.71–0.92; P=0.002). In the subgroup matched comparisons, intraoperative TOE was significantly associated with a lower, 30-daymortality rate among those with congestive heart failure: 4.20% vs 5.26% (OR: 0.78; 95% CI: 0.66–0.94; P=0.007) and among those undergoing multivessel CABG with congestive heart failure: 4.23% vs 5.24% (OR: 0.80; 95% CI: 0.65–0.97; P=0.025), but not among those undergoing multivessel CABG without congestive heart failure: 1.83% vs 2.15% (OR: 0.85; 95% CI: 0.70–1.02; P=0.089, nor any of the remaining three subgroups. Among US adults undergoing isolated CABG surgery, intraoperative TOE was associated with improved outcomes in patients with congestive heart failure (vs without) and among patients undergoing multivessel (vs single vessel) CABG. These findings support prioritised TOE allocation to these patient populations at centres with limited TOE capabilities.
Efficient Algorithms for Building Representative Matched Pairs with Enhanced Generalizability
Many recent efforts center on assessing the ability of real-world evidence (RWE) generated from non-randomized, observational data to produce results compatible with those from randomized controlled trials (RCTs). One noticeable endeavor is the RCT DUPLICATE initiative. To better reconcile findings from an observational study and an RCT, or two observational studies based on different databases, it is desirable to eliminate differences between study populations. We outline an efficient, network-flow-based statistical matching algorithm that designs well-matched pairs from observational data that resemble the covariate distributions of a target population, for instance, the target-RCT-eligible population in the RCT DUPLICATE initiative studies or a generic population of scientific interest. We demonstrate the usefulness of the method by revisiting the inconsistency regarding a cardioprotective effect of the hormone replacement therapy (HRT) in the Women’s Health Initiative (WHI) clinical trial and corresponding observational study. We found that the discrepancy between the trial and observational study persisted in a design that adjusted for the difference in study populations' cardiovascular risk profile, but seemed to disappear in a study design that further adjusted for the difference in HRT initiation age and previous estrogen-plus-progestin use. The proposed method is integrated into the R package match2C.
Instrumental variables: To strengthen or not to strengthen?
Instrumental variables (IVs) are extensively used to estimate treatment effects when the treatment and outcome are confounded by unmeasured confounders; however, weak IVs are often encountered in empirical studies and may cause problems. Many studies have considered building a stronger IV from the original, possibly weak, IV in the design stage of a matched study at the cost of not using some of the samples in the analysis. It is widely accepted that strengthening an IV tends to render nonparametric tests more powerful and will increase the power of sensitivity analyses in large samples. In this article, we re-evaluate this conventional wisdom to bring new insights into this topic. We consider matched observational studies from three perspectives. First, we evaluate the trade-off between IV strength and sample size on nonparametric tests assuming the IV is valid and exhibit conditions under which strengthening an IV increases power and conversely conditions under which it decreases power. Second, we derive a necessary condition for a valid sensitivity analysis model with continuous doses. We show that the Γ sensitivity analysis model, which has been previously used to come to the conclusion that strengthening an IV increases the power of sensitivity analyses in large samples, does not apply to the continuous IV setting and thus this previously reached conclusion may be invalid. Third, we quantify the bias of the Wald estimator with a possibly invalid IV under an oracle and leverage it to develop a valid sensitivity analysis framework; under this framework, we show that strengthening an IV may amplify or mitigate the bias of the estimator, and may or may not increase the power of sensitivity analyses. We also discuss how to better adjust for the observed covariates when building an IV in matched studies.
Matching One Sample According to Two Criteria in Observational Studies
Multivariate matching has two goals: (i) to construct treated and control groups that have similar distributions of observed covariates, and (ii) to produce matched pairs or sets that are homogeneous in a few key covariates. When there are only a few binary covariates, both goals may be achieved by matching exactly for these few covariates. Commonly, however, there are many covariates, so goals (i) and (ii) come apart, and must be achieved by different means. As is also true in a randomized experiment, similar distributions can be achieved for a high-dimensional covariate, but close pairs can be achieved for only a few covariates. We introduce a new polynomial-time method for achieving both goals that substantially generalizes several existing methods; in particular, it can minimize the earthmover distance between two marginal distributions. The method involves minimum cost flow optimization in a network built around a tripartite graph, unlike the usual network built around a bipartite graph. In the tripartite graph, treated subjects appear twice, on the far left and the far right, with controls sandwiched between them, and efforts to balance covariates are represented on the right, while efforts to find close individual pairs are represented on the left. In this way, the two efforts may be pursued simultaneously without conflict. The method is applied to our on-going study in the Medicare population of the relationship between superior nursing and sepsis mortality. The match2C package in R implements the method.
Differential Effects of Antimalarial Drugs on Parasite Clearance Rates Are Reflected by Plasmodium falciparum Ring Ratio
The location of Plasmodium falciparum within the body is determined by the life cycle of the parasite; young rings are in the peripheral blood, whereas mature parasites are sequestered in deep tissues. We can calculate a “ring ratio,” the proportion of parasites in the periphery to the total number of parasites in the body. Artesunate acts on all parasite life stages, whereas quinine is effective only on sequestered parasites. Children with cerebral malaria (CM) treated with artesunate clear parasites faster than those treated with quinine. In this study, we established the relationship between ring ratio and parasite clearance rate and used the ring ratio to determine if the benefit derived from artesunate treatment could be attributed to its broader effect on life cycle stages. Ring ratios were calculated for 400 hospitalized children with CM in Blantyre, Malawi between 2010 and 2019 (quinine: 2010–2013, artesunate: 2014–2019). In both treatment groups, parasite clearance rates were positively associated with the ring ratios, with a stronger association in the artesunate era than the quinine era. In the quinine era, an increase of 1-unit log10 difference between parasitemia and plasma P falciparum histidine-rich protein 2 (a proxy for ring ratio) resulted in a 0.27-unit increase in the parasite clearance rate, whereas in the artesunate era an equal increase resulted in a 0.41-unit increase (P = .04 for the difference).This analysis provides in vivo evidence supporting the hypothesis that more rapid parasite clearance rates in artesunate recipients are due to its superiority over quinine in killing ring-stage parasites.