The development of composite circulating biomarker models for use in anti-cancer drug clinical development.
AffiliationClinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester, United Kingdom.
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AbstractThe 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.
CitationThe development of composite circulating biomarker models for use in anti-cancer drug clinical development. 2010: Int J Cancer
JournalInternational Journal of Cancer
- Paradoxical elevations in serum IGF-II and IGF binding protein-2 in acromegaly: insights into the regulation of these peptides.
- Authors: Renehan AG, Toogood AA, Ryder WD, Jones J, Potten CS, O'Dwyer ST, Shalet SM
- Issue date: 2001 Oct
- Alterations in serum levels of insulin-like growth factors and insulin-like growth-factor-binding proteins in patients with colorectal cancer.
- Authors: el Atiq F, Garrouste F, Remacle-Bonnet M, Sastre B, Pommier G
- Issue date: 1994 May 15
- Serum insulin-like growth factor (IGF)-I and IGF-binding proteins in lung cancer patients.
- Authors: Lee DY, Kim SJ, Lee YC
- Issue date: 1999 Aug
- Do insulin-like growth factor associated proteins qualify as a tumor marker? Results of a prospective study in 163 cancer patients.
- Authors: Matuschek C, Rudoy M, Peiper M, Gerber PA, Hoff NP, Buhren BA, Flehmig B, Budach W, Knoefel WT, Bojar H, Prisack HB, Steinbach G, Shukla V, Schwarz A, Kammers K, Erhardt A, Scherer A, Bölke E, Schauer M
- Issue date: 2011 Oct 10
- Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women.
- Authors: Kaaks R, Toniolo P, Akhmedkhanov A, Lukanova A, Biessy C, Dechaud H, Rinaldi S, Zeleniuch-Jacquotte A, Shore RE, Riboli E
- Issue date: 2000 Oct 4