Artificial neural network to predict the effect of obesity on the risk of tuberculosis infection

Background: Body weight has been implicated as a risk factor for latent tuberculosis infection (LTBI) and the active disease.Design and Methods: This study aimed to develop artificial neural network (ANN) models for predicting LTBI from body weight and other host-related disease risk factors. We used datasets from participants of the US-National Health and Nutrition Examination Survey (NHANES; 2012; n=5,156; 514 with LTBI and 4,642 controls) to develop three ANNs employing body mass index (BMI, Network I), BMI and HbA1C (as a proxy for diabetes; Network II) and BMI, HbA1C and education (as a proxy for socioeconomic status; Network III). The models were trained on n=1018 age- and sex-matched subjects equally distributed between the control and LTBI groups. The endpoint was the prediction of LTBI.Results: When data was adjusted for age, sex, diabetes and level of education, odds ratio (OR) and 95% confidence intervals (CI) for risk of LTBI with increased BMI was 0.85 (95%CI: 0.77 – 0.96, p=0.01). The three ANNs had a predictive accuracy varied from 75 to 80% with sensitivities ranged from 85% to 94% and specificities of approximately 70%. Areas under the receiver operating characteristic curve (AUC) were between 0.82 and 0.87. Optimal ANN performance was noted using BMI as a risk indicator.Conclusion: Body weight can be employed in developing artificial intelligence-based tool to predict LTBI. This can be useful in precise decision making in clinical and public health practices aiming to curb the burden of tuberculosis, e.g., in the management and monitoring of the tuberculosis prevention programs and to evaluate the impact of healthy weight on tuberculosis risk and burden

Quantitative bias analysis for external control arms using real-world data in clinical trials: a primer for clinical researchers

Development of medicines in rare oncologic patient populations are growing, but well-powered randomized controlled trials are typically extremely challenging or unethical to conduct in such settings. External control arms using real-world data are increasingly used to supplement clinical trial evidence where no or little control arm data exists. The construction of an external control arm should always aim to match the population, treatment settings and outcome measurements of the corresponding treatment arm. Yet, external real-world data is typically fraught with limitations including missing data, measurement error and the potential for unmeasured confounding given a nonrandomized comparison. Quantitative bias analysis (QBA) comprises a collection of approaches for modelling the magnitude of systematic errors in data which cannot be addressed with conventional statistical adjustment. Their applications can range from simple deterministic equations to complex hierarchical models. QBA applied to external control arm represent an opportunity for evaluating the validity of the corresponding comparative efficacy estimates. We provide a brief overview of available QBA approaches and explore their application in practice. Using a motivating example of a comparison between pralsetinib single-arm trial data versus pembrolizumab alone or combined with chemotherapy real-world data for RET fusion-positive advanced non-small cell lung cancer (aNSCLC) patients (1–2% among all NSCLC), we illustrate how QBA can be applied to external control arms. We illustrate how QBA is used to ascertain robustness of results despite a large proportion of missing data on baseline ECOG performance status and suspicion of unknown confounding. The robustness of findings is illustrated by showing that no meaningful change to the comparative effect was observed across several ‘tipping-point’ scenario analyses, and by showing that suspicion of unknown confounding was ruled out by use of E-values. Full R code is also provided