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    The development of composite circulating biomarker models for use in anti-cancer drug clinical development.

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    Authors
    Lancashire, Lee J
    Roberts, Darren L
    Dive, Caroline
    Renehan, Andrew G
    Affiliation
    Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester, United Kingdom.
    Issue Date
    2010-06-14
    
    Metadata
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    Abstract
    The development of informative composite circulating biomarkers predicting cancer presence or therapy response is clinically attractive but optimal approaches to modelling are as yet unclear. This study investigated multi-dimensional relationships within an example panel of serum insulin-like growth factor (IGF) peptides using logistic regression (LR), fractional polynomial (FP) regression, artificial neural networks (ANNs), and support vector machines (SVMs) to derive predictive models for colorectal cancer (CRC). Two phase 2 biomarker validation analyses were performed: controls were ambulant adults (n = 722); cases were: (i) CRC patients (n = 90) and (ii) patients with acromegaly (n = 52), the latter as "positive" discriminators. Serum IGF-I, IGF-II, IGF binding protein (IGFBP)-2, and -3 were measured. Discriminatory characteristics were compared within and between models. For the LR, FP and ANN models, and to a lesser extent SVMs, the addition of covariates at several steps improved discrimination characteristics. The optimum biomarker combination discriminating CRC versus controls was achieved using ANN models [sensitivity, 94%; specificity, 90%; accuracy, 0.975 (95% CIs: 0.948 1.000)]. ANN modelling significantly outperformed LR, FP, and SVM in terms of discrimination (P < 0.0001) and calibration. The acromegaly analysis demonstrated expected high performance characteristics in the ANN model [accuracy, 0.993 (95% CIs: 0.977, 1.000)]. Curved decision surfaces generated from the ANNs revealed the potential clinical utility. This example demonstrated improved discriminatory characteristics within the composite biomarker ANN model and a final model that outperformed the three other models. This modelling approach forms the basis to evaluate composite biomarkers as pharmacological and predictive biomarkers in future clinical trials.
    Citation
    The development of composite circulating biomarker models for use in anti-cancer drug clinical development. 2010: Int J Cancer
    Journal
    International Journal of Cancer
    URI
    http://hdl.handle.net/10541/109424
    DOI
    10.1002/ijc.25513
    PubMed ID
    20549702
    Type
    Article
    Language
    en
    ISSN
    1097-0215
    ae974a485f413a2113503eed53cd6c53
    10.1002/ijc.25513
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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