Such an approximation leads to a na?ve Bayes model, which assumes independence between the markers. specificity in a separate verification set, with similar performance for early and late stage NSCLC. Conclusions/Significance This study is a significant advance in clinical proteomics in an area of high unmet clinical need. Our analysis exceeds the breadth and dynamic range of proteome interrogated of previously published clinical studies of broad serum proteome profiling platforms including mass spectrometry, antibody arrays, and autoantibody arrays. The sensitivity and specificity of our 12-biomarker panel improves upon published protein and gene expression panels. Separate verification of classifier performance provides evidence against over-fitting and is encouraging for the next development phase, independent validation. This careful study provides a solid foundation Tecadenoson to develop tests sorely needed to identify early stage lung cancer. Introduction Lung cancer is the leading cause of cancer deaths, because 84% of cases are diagnosed at an advanced stage [1]C[3]. Worldwide in 2008, 1.5 million people were diagnosed and 1.3 million died [4] C a survival rate unchanged since 1960. However, patients diagnosed at an early Tecadenoson stage and have surgery experience an 86% overall 5-year survival [2], [3]. New diagnostics are therefore needed to identify early stage lung cancer. Over the past decade the clinical utility of low-dose CT has been evaluated [5]C[8] with the hope that high-resolution imaging can help detect lung cancer earlier and improve patient outcomes, much as screening has done for breast and colorectal cancers [9]. Definitive conclusions about CT screening and lung cancer mortality await results from randomized trials in the US [8] and Europe [10]C[13]. Tecadenoson CT can detect small, early-stage lung tumors, but distinguishing rare cancers from common benign conditions is difficult and has led to unnecessary procedures, radiation exposure, anxiety, and cost [6], [14]C[16]. We (J.M.S., J.L.W., and colleagues) recently reported such conclusions for the Pittsburgh Lung Screening Study (PLuSS), the largest single-institution Rabbit Polyclonal to OR2B2 CT screening study reported to date [5]. Other types of biomarkers have also been sought [17]. Proteins are attractive because they are an immediate measure of phenotype, in contrast to DNA which provides genotype, largely a measure of disease risk [18]. Single protein biomarkers are the foundation of molecular diagnostics in the clinic today. It is widely thought that multiple biomarkers could improve the sensitivity and specificity of diagnostic tests, and that complex diseases like cancer change the concentrations of multiple proteins [19]. However, discovering multiple protein biomarkers by measuring many proteins simultaneously (proteomics) in complex samples like blood has proven difficult for reasons of coverage, precision, throughput, preanalytical variability, and cost [20]. To enable biomarker discovery, we developed a new proteomic technology that is based on a new generation of aptamer protein binding reagents and has potentially broad application [18]. The current assay measures 813 diverse human proteins in just 15 L of blood with low limits of detection (1 pM average and as low as 100 fM), 7 logs of overall dynamic range, and high reproducibility (5% median coefficient of variation) [18]. Here we present the first large scale clinical application of our proteomics technology to discover blood protein biomarkers in a large multi-center case-control study conducted in archived samples from 1,326 subjects from four independent studies of non-small cell lung cancer (NSCLC) in long-term tobacco-exposed populations. Materials and Methods Ethics Statement All samples were collected from study participants after obtaining written informed consent under clinical research protocols approved by the.