Comparison of normalisation methods for surface-enhanced laser desorption and ionisation (SELDI) time-of-flight (TOF) mass spectrometry data

<p>Abstract</p> <p>Background</p> <p>Mass spectrometry for biological data analysis is an active field of research, providing an efficient way of high-throughput proteome screening. A popular variant of mass spectrometry is SELDI, which is often used to measure sample populations with the goal of developing (clinical) classifiers. Unfortunately, not only is the data resulting from such measurements quite noisy, variance between replicate measurements of the same sample can be high as well. Normalisation of spectra can greatly reduce the effect of this technical variance and further improve the quality and interpretability of the data. However, it is unclear which normalisation method yields the most informative result.</p> <p>Results</p> <p>In this paper, we describe the first systematic comparison of a wide range of normalisation methods, using two objectives that should be met by a good method. These objectives are minimisation of inter-spectra variance and maximisation of signal with respect to class separation. The former is assessed using an estimation of the coefficient of variation, the latter using the classification performance of three types of classifiers on real-world datasets representing two-class diagnostic problems. To obtain a maximally robust evaluation of a normalisation method, both objectives are evaluated over multiple datasets and multiple configurations of baseline correction and peak detection methods. Results are assessed for statistical significance and visualised to reveal the performance of each normalisation method, in particular with respect to using no normalisation. The normalisation methods described have been implemented in the freely available MASDA R-package.</p> <p>Conclusion</p> <p>In the general case, normalisation of mass spectra is beneficial to the quality of data. The majority of methods we compared performed significantly better than the case in which no normalisation was used. We have shown that normalisation methods that scale spectra by a factor based on the dispersion (e.g., standard deviation) of the data clearly outperform those where a factor based on the central location (e.g., mean) is used. Additional improvements in performance are obtained when these factors are estimated locally, using a sliding window within spectra, instead of globally, over full spectra. The underperforming category of methods using a globally estimated factor based on the central location of the data includes the method used by the majority of SELDI users.</p

On the combination of omics data for prediction of binary outcomes

Enrichment of predictive models with new biomolecular markers is an important task in high-dimensional omic applications. Increasingly, clinical studies include several sets of such omics markers available for each patient, measuring different levels of biological variation. As a result, one of the main challenges in predictive research is the integration of different sources of omic biomarkers for the prediction of health traits. We review several approaches for the combination of omic markers in the context of binary outcome prediction, all based on double cross-validation and regularized regression models. We evaluate their performance in terms of calibration and discrimination and we compare their performance with respect to single-omic source predictions. We illustrate the methods through the analysis of two real datasets. On the one hand, we consider the combination of two fractions of proteomic mass spectrometry for the calibration of a diagnostic rule for the detection of early-stage breast cancer. On the other hand, we consider transcriptomics and metabolomics as predictors of obesity using data from the Dietary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome (DILGOM) study, a population-based cohort, from Finland

Biomarker discovery and redundancy reduction towards classification using a multi-factorial MALDI-TOF MS T2DM mouse model dataset

Diabetes like many diseases and biological processes is not mono-causal. On the one hand multifactorial studies with complex experimental design are required for its comprehensive analysis. On the other hand, the data from these studies often include a substantial amount of redundancy such as proteins that are typically represented by a multitude of peptides. Coping simultaneously with both complexities (experimental and technological) makes data analysis a challenge for Bioinformatics

Genomic and oncoproteomic advances in detection and treatment of colorectal cancer

<p>Abstract</p> <p>Aims</p> <p>We will examine the latest advances in genomic and proteomic laboratory technology. Through an extensive literature review we aim to critically appraise those studies which have utilized these latest technologies and ascertain their potential to identify clinically useful biomarkers.</p> <p>Methods</p> <p>An extensive review of the literature was carried out in both online medical journals and through the Royal College of Surgeons in Ireland library.</p> <p>Results</p> <p>Laboratory technology has advanced in the fields of genomics and oncoproteomics. Gene expression profiling with DNA microarray technology has allowed us to begin genetic profiling of colorectal cancer tissue. The response to chemotherapy can differ amongst individual tumors. For the first time researchers have begun to isolate and identify the genes responsible. New laboratory techniques allow us to isolate proteins preferentially expressed in colorectal cancer tissue. This could potentially lead to identification of a clinically useful protein biomarker in colorectal cancer screening and treatment.</p> <p>Conclusion</p> <p>If a set of discriminating genes could be used for characterization and prediction of chemotherapeutic response, an individualized tailored therapeutic regime could become the standard of care for those undergoing systemic treatment for colorectal cancer. New laboratory techniques of protein identification may eventually allow identification of a clinically useful biomarker that could be used for screening and treatment. At present however, both expression of different gene signatures and isolation of various protein peaks has been limited by study size. Independent multi-centre correlation of results with larger sample sizes is needed to allow translation into clinical practice.</p

Mass spectrometry and multivariate analysis to classify cervical intraepithelial neoplasia from blood plasma: an untargeted lipidomic study

Cervical cancer is still an important issue of public health since it is the fourth most frequent type of cancer in women worldwide. Much effort has been dedicated to combating this cancer, in particular by the early detection of cervical pre-cancerous lesions. For this purpose, this paper reports the use of mass spectrometry coupled with multivariate analysis as an untargeted lipidomic approach to classifying 76 blood plasma samples into negative for intraepithelial lesion or malignancy (NILM, n = 42) and squamous intraepithelial lesion (SIL, n = 34). The crude lipid extract was directly analyzed with mass spectrometry for untargeted lipidomics, followed by multivariate analysis based on the principal component analysis (PCA) and genetic algorithm (GA) with support vector machines (SVM), linear (LDA) and quadratic (QDA) discriminant analysis. PCA-SVM models outperformed LDA and QDA results, achieving sensitivity and specificity values of 80.0% and 83.3%, respectively. Five types of lipids contributing to the distinction between NILM and SIL classes were identified, including prostaglandins, phospholipids, and sphingolipids for the former condition and Tetranor-PGFM and hydroperoxide lipid for the latter. These findings highlight the potentiality of using mass spectrometry associated with chemometrics to discriminate between healthy women and those suffering from cervical pre-cancerous lesions

Expression of the phosphorylated MEK5 protein is associated with TNM staging of colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Activation of MEK5 in many cancers is associated with carcinogenesis through aberrant cell proliferation. In this study, we determined the level of phosphorylated MEK5 (pMEK5) expression in human colorectal cancer (CRC) tissues and correlated it with clinicopathologic data.</p> <p>Methods</p> <p>pMEK5 expression was examined by immunohistochemistry in a tissue microarray (TMA) containing 335 clinicopathologic characterized CRC cases and 80 cases of nontumor colorectal tissues. pMEK5 expression of 19 cases of primary CRC lesions and paired with normal mucosa was examined by Western blotting. The relationship between pMEK5 expression in CRC and clinicopathologic parameters, and the association of pMEK5 expression with CRC survival were analyzed respectively.</p> <p>Results</p> <p>pMEK5 expression was significantly higher in CRC tissues (185 out of 335, 55.2%) than in normal tissues (6 out of 80, 7.5%; <it>P </it>< 0.001). Western blotting demonstrated that pMEK5 expression was upregulated in 12 of 19 CRC tissues (62.1%) compared to the corresponding adjacent nontumor colorectal tissues. Overexpression of pMEK5 in CRC tissues was significantly correlated to the depth of invasion (<it>P </it>= 0.001), lymph node metastasis (<it>P </it>< 0.001), distant metastasis (<it>P </it>< 0.001) and high preoperative CEA level (<it>P </it>< 0.001). Consistently, the pMEK5 level in CRC tissues was increased following stage progression of the disease (<it>P </it>< 0.001). Analysis of the survival curves showed a significantly worse 5-year disease-free (<it>P </it>= 0.002) and 5-year overall survival rate (<it>P </it>< 0.001) for patients whose tumors overexpressed pMEK5. However, in multivariate analysis, pMEK5 was not an independent prognostic factor for CRC (DFS: <it>P </it>= 0.139; OS: <it>P </it>= 0.071).</p> <p>Conclusions</p> <p>pMEK5 expression is correlated with the staging of CRC and its expression might be helpful to the TNM staging system of CRC.</p

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative

Background: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. Material and methods: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. Results: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. Conclusion: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative

Background: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. Material and methods: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. Results: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. Conclusion: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting