Dataset Information

Parameter estimation in Cox models with missing failure indicators and the OPPERA study.

ABSTRACT: In a prospective cohort study, examining all participants for incidence of the condition of interest may be prohibitively expensive. For example, the "gold standard" for diagnosing temporomandibular disorder (TMD) is a physical examination by a trained clinician. In large studies, examining all participants in this manner is infeasible. Instead, it is common to use questionnaires to screen for incidence of TMD and perform the "gold standard" examination only on participants who screen positively. Unfortunately, some participants may leave the study before receiving the "gold standard" examination. Within the framework of survival analysis, this results in missing failure indicators. Motivated by the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study, a large cohort study of TMD, we propose a method for parameter estimation in survival models with missing failure indicators. We estimate the probability of being an incident case for those lacking a "gold standard" examination using logistic regression. These estimated probabilities are used to generate multiple imputations of case status for each missing examination that are combined with observed data in appropriate regression models. The variance introduced by the procedure is estimated using multiple imputation. The method can be used to estimate both regression coefficients in Cox proportional hazard models as well as incidence rates using Poisson regression. We simulate data with missing failure indicators and show that our method performs as well as or better than competing methods. Finally, we apply the proposed method to data from the OPPERA study.

SUBMITTER: Brownstein NC

PROVIDER: S-EPMC4715503 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Parameter estimation in Cox models with missing failure indicators and the OPPERA study.

Brownstein Naomi C NC Cai Jianwen J Slade Gary D GD Bair Eric E

Statistics in medicine 20150804 30

In a prospective cohort study, examining all participants for incidence of the condition of interest may be prohibitively expensive. For example, the "gold standard" for diagnosing temporomandibular disorder (TMD) is a physical examination by a trained clinician. In large studies, examining all participants in this manner is infeasible. Instead, it is common to use questionnaires to screen for incidence of TMD and perform the "gold standard" examination only on participants who screen positively ...[more]

PMID: 26242613

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Project description:BackgroundDynamic modelling is a core element in the systems biology approach to understanding complex biosystems. Here, we consider the problem of parameter estimation in models of biological oscillators described by deterministic nonlinear differential equations. These problems can be extremely challenging due to several common pitfalls: (i) a lack of prior knowledge about parameters (i.e. massive search spaces), (ii) convergence to local optima (due to multimodality of the cost function), (iii) overfitting (fitting the noise instead of the signal) and (iv) a lack of identifiability. As a consequence, the use of standard estimation methods (such as gradient-based local ones) will often result in wrong solutions. Overfitting can be particularly problematic, since it produces very good calibrations, giving the impression of an excellent result. However, overfitted models exhibit poor predictive power. Here, we present a novel automated approach to overcome these pitfalls. Its workflow makes use of two sequential optimisation steps incorporating three key algorithms: (1) sampling strategies to systematically tighten the parameter bounds reducing the search space, (2) efficient global optimisation to avoid convergence to local solutions, (3) an advanced regularisation technique to fight overfitting. In addition, this workflow incorporates tests for structural and practical identifiability.ResultsWe successfully evaluate this novel approach considering four difficult case studies regarding the calibration of well-known biological oscillators (Goodwin, FitzHugh-Nagumo, Repressilator and a metabolic oscillator). In contrast, we show how local gradient-based approaches, even if used in multi-start fashion, are unable to avoid the above-mentioned pitfalls.ConclusionsOur approach results in more efficient estimations (thanks to the bounding strategy) which are able to escape convergence to local optima (thanks to the global optimisation approach). Further, the use of regularisation allows us to avoid overfitting, resulting in more generalisable calibrated models (i.e. models with greater predictive power).

Dataset Information

Parameter estimation in Cox models with missing failure indicators and the OPPERA study.

Publications

Parameter estimation in Cox models with missing failure indicators and the OPPERA study.

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