Dataset Information

Quantitative approach for cardiac risk assessment and interpretation in tuberculosis drug development.

ABSTRACT: Cardiotoxicity is among the top drug safety concerns, and is of specific interest in tuberculosis, where this is a known or potential adverse event of current and emerging treatment regimens. As there is a need for a tool, beyond the QT interval, to quantify cardiotoxicity early in drug development, an empirical decision tree based classifier was developed to predict the risk of Torsades de pointes (TdP). The cardiac risk algorithm was developed using pseudo-electrocardiogram (ECG) outputs derived from cardiac myocyte electromechanical model simulations of increasing concentrations of 96 reference compounds which represented a range of clinical TdP risk. The algorithm correctly classified 89% of reference compounds with moderate sensitivity and high specificity (71 and 96%, respectively) as well as 10 out of 12 external validation compounds and the anti-TB drugs moxifloxacin and bedaquiline. The cardiac risk algorithm is suitable to help inform early drug development decisions in TB and will evolve with the addition of emerging data.

SUBMITTER: Polak S

PROVIDER: S-EPMC5953981 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Quantitative approach for cardiac risk assessment and interpretation in tuberculosis drug development.

Polak Sebastian S Romero Klaus K Berg Alexander A Patel Nikunjkumar N Jamei Masoud M Hermann David D Hanna Debra D

Journal of pharmacokinetics and pharmacodynamics 20180308 3

Cardiotoxicity is among the top drug safety concerns, and is of specific interest in tuberculosis, where this is a known or potential adverse event of current and emerging treatment regimens. As there is a need for a tool, beyond the QT interval, to quantify cardiotoxicity early in drug development, an empirical decision tree based classifier was developed to predict the risk of Torsades de pointes (TdP). The cardiac risk algorithm was developed using pseudo-electrocardiogram (ECG) outputs deriv ...[more]

PMID: 29520534

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Project description:The assimilation of population models into ecological risk assessment (ERA) has been hindered by their range of complexity, uncertainty, resource investment, and data availability. Likewise, ensuring that the models address risk assessment objectives has been challenging. Recent research efforts have begun to tackle these challenges by creating an integrated modeling framework and decision guide to aid the development of population models with respect to ERA objectives and data availability. In the framework, the trade-offs associated with the generality, realism, and precision of an assessment are used to guide the development of a population model commensurate with the protection goal. The decision guide provides risk assessors with a stepwise process to assist them in developing a conceptual model that is appropriate for the assessment objective and available data. We have merged the decision guide and modeling framework into a comprehensive approach, Population modeling Guidance, Use, Interpretation, and Development for Ecological risk assessment (Pop-GUIDE), for the development of population models for ERA that is applicable across regulatory statutes and assessment objectives. In Phase 1 of Pop-GUIDE, assessors are guided through the trade-offs of ERA generality, realism, and precision, which are translated into model objectives. In Phase 2, available data are assimilated and characterized as general, realistic, and/or precise. Phase 3 provides a series of dichotomous questions to guide development of a conceptual model that matches the complexity and uncertainty appropriate for the assessment that is in concordance with the available data. This phase guides model developers and users to ensure consistency and transparency of the modeling process. We introduce Pop-GUIDE as the most comprehensive guidance for population model development provided to date and demonstrate its use through case studies using fish as an example taxon and the US Federal Insecticide Fungicide and Rodenticide Act and Endangered Species Act as example regulatory statutes. Integr Environ Assess Manag 2021;17:767-784. © 2020 SETAC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Project description:BackgroundWhile there is a prevailing perception that coronary artery disease (CAD) is a "man's disease," little is known about the factors which influence cardiac risk assessment and whether it varies by gender.Objectives1) Qualitatively capture the complexity of cardiac risk assessment from a patient-centered perspective. 2) Explore how risk assessment may vary by gender. 3) Quantitatively validate qualitative findings among a new sample.DesignThis study was conducted in two parts: (1) semi-structured in-depth interviews were audio-recorded, transcribed verbatim, and analyzed using modified grounded theory; (2) emergent themes were surveyed in a separate sample to validate findings quantitatively. Differences were estimated using 2-tailed t-tests and kappa.ParticipantsParticipants who were referred for their first elective coronary angiogram for suspected CAD with at least 1 prior abnormal test were recruited from a tertiary care hospital.Main measuresPatient-centered themes were derived from part one. In part two, patients estimated the probability that their symptoms were heart-related at multiple time points.ResultsPart 1 included 14 men and 17 women (mean age=63.3±11.8 years). Part 2 included 237 patients, of which 109 (46%) were women (mean age=66.0±11.3 years). Part 1 revealed that patients' risk assessment evolves in three distinct phases, which were captured using an Ishikawa framework entitled "Patient Risk Interpretation of Symptoms Model" (PRISM). Part 2 validated PRISM findings; while patients were more likely to attribute their symptoms to CAD over time (phase 1 vs. 3: 21% vs. 73%, p<0.001), women were marginally less likely than men to perceive symptoms as heart-related by phase 3 (67% women vs. 78% men, p=0.054).ConclusionsPatient assessment of CAD risk evolves, and women are more likely to underestimate their risk than men. PRISM may be used as a clinical aid to optimize patient-centered care. Future studies should validate PRISM in different clinical settings.

Dataset Information

Quantitative approach for cardiac risk assessment and interpretation in tuberculosis drug development.

Publications

Quantitative approach for cardiac risk assessment and interpretation in tuberculosis drug development.

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