title: The development of composite circulating biomarker models for use in anticancer drug clinical development.
abstract: The development of informative composite circulating biomarkers predicting cancer presence or therapy response is clinically attractive but optimal approaches to modeling are as yet unclear. This study investigated multidimensional 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 = 100) 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 vs. controls was achieved using ANN models [sensitivity, 94%; specificity, 90%; accuracy, 0.975 (95% CIs: 0.948 1.000)]. ANN modeling 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 modeling approach forms the basis to evaluate composite biomarkers as pharmacological and predictive biomarkers in future clinical trials.
authors.affiliation: Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester, UK.
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Lancashire
authors.forename: Darren L
authors.initials: DL
authors.lastname: Roberts
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Renehan
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000097:blood / Q000175:diagnosis*; D005260:Female; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008297:Male; D015233:Models, Statistical; D011863:Radioimmunoassay; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II