title: The impact of companion diagnostic device measurement performance on clinical validation of personalized medicine.
abstract: A key component of personalized medicine is companion diagnostics that measure biomarkers, for example, protein expression, gene amplification or specific mutations. Most of the recent attention concerning molecular cancer diagnostics has been focused on the biomarkers of response to therapy, such as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in metastatic colorectal cancer, epidermal growth factor receptor mutations in metastatic malignant melanoma. The presence or absence of these markers is directly linked to the response rates of particular targeted therapies with small-molecule kinase inhibitors or antibodies. Therefore, testing for these markers has become a critical step in the target therapy of the aforementioned tumors. The core capability of personalized medicine is the companion diagnostic devices' (CDx) ability to accurately and precisely stratify patients by their likelihood of benefit (or harm) from a particular therapy. There is no reference in the literature discussing the impact of device's measurement performance, for example, analytical accuracy and precision on treatment effects, variances, and sample sizes of clinical trial for the personalized medicine. In this paper, using both analytical and estimation method, we assessed the impact of CDx measurement performance as a function of positive and negative predictive values and imprecision (standard deviation) on treatment effects, variances of clinical outcome, and sample sizes for the clinical trials.
authors.affiliation: Division of Biostatistics, Office of Surveillance and Biometrics, Center for Devices and Radiological Health, USA Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, U.S.A.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Li
authors.affiliation: Division of Biostatistics, Office of Surveillance and Biometrics, Center for Devices and Radiological Health, USA Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, U.S.A.
authors.forename: Tinghui
authors.initials: T
authors.lastname: Yu
authors.affiliation: Division Of Molecular Genetics And Pathology Office Of In Vitro Diagnostics And Radiological Health Center for Devices and Radiological Health, USA Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, U.S.A.
authors.forename: Yun-Fu
authors.initials: YF
authors.lastname: Hu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics; D053327:Apolipoprotein E4 / Q000032:analysis / Q000235:genetics; D002986:Clinical Trials as Topic / Q000379:methods* / Q000706:statistics & numerical data; D042241:Early Diagnosis; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D016013:Likelihood Functions; D008967:Molecular Biology / Q000379:methods* / Q000706:statistics & numerical data; D017063:Outcome Assessment, Health Care / Q000379:methods* / Q000706:statistics & numerical data; D057285:Precision Medicine / Q000379:methods* / Q000706:statistics & numerical data; D015203:Reproducibility of Results; D012307:Risk Factors; D055502:Secondary Prevention
chemical_list: D053327:Apolipoprotein E4; D005819:Genetic Markers
keywords: analytical accuracy; biomarker; clinical validation trial; companion diagnostic device; imprecision; positive and negative percentage agreements; positive and negative predictive values