Toward Integration of Pharmacogenomic Tests into Daily Clinical Practice: A General Survey for Polish Healthcare Workers.

BACKGROUND Pharmacogenomics (PGx) has a direct influence on personalized drug therapy for various types of disorders and has been proven to have an important role in the future of medicine. The present study evaluated the awareness of PGx testing of clinicians and healthcare workers in the Republic of Poland. To the best of our knowledge, this is the first direct assessment of Polish healthcare professionals' attitudes toward introducing PGx tests into daily clinical practice. MATERIAL AND METHODS We used a comprehensive anonymous questionnaire with queries on level of education, background knowledge of PGx tests, advantages and barriers for implementation of such tests, and clinicians' desire to order the test that was distributed online to doctors, healthcare workers, related students/Ph.D. students, and administrative staff managing healthcare units. RESULTS We gathered 315 responses. According to the answers, two-thirds of participants had heard about PGx before (64.4%). An overwhelming majority of respondents appreciated the benefits of PGx (93.3%). Indeed, prior knowledge and level of education showed significant associations with positive attitudes toward PGx clinical testing (P≤0.05). However, all participants agreed there are major challenges for including such tests as part of routine clinical practice. CONCLUSIONS While the awareness and interest in PGx clinical testing in Polish healthcare providers are rising, some main barriers for implementation of these tests still need to be addressed in Poland.

Robust Data Integration Method for Classification of Biomedical Data.

We present a protocol for integrating two types of biological data - clinical and molecular - for more effective classification of patients with cancer. The proposed approach is a hybrid between early and late data integration strategy. In this hybrid protocol, the set of informative clinical features is extended by the classification results based on molecular data sets. The results are then treated as new synthetic variables. The hybrid protocol was applied to METABRIC breast cancer samples and TCGA urothelial bladder carcinoma samples. Various data types were used for clinical endpoint prediction: clinical data, gene expression, somatic copy number aberrations, RNA-Seq, methylation, and reverse phase protein array. The performance of the hybrid data integration was evaluated with a repeated cross validation procedure and compared with other methods of data integration: early integration and late integration via super learning. The hybrid method gave similar results to those obtained by the best of the tested variants of super learning. What is more, the hybrid method allowed for further sensitivity analysis and recursive feature elimination, which led to compact predictive models for cancer clinical endpoints. For breast cancer, the final model consists of eight clinical variables and two synthetic features obtained from molecular data. For urothelial bladder carcinoma, only two clinical features and one synthetic variable were necessary to build the best predictive model. We have shown that the inclusion of the synthetic variables based on the RNA expression levels and copy number alterations can lead to improved quality of prognostic tests. Thus, it should be considered for inclusion in wider medical practice.

Prediction of Alternative Drug-Induced Liver Injury Classifications Using Molecular Descriptors, Gene Expression Perturbation, and Toxicology Reports.

Motivation: Drug-induced liver injury (DILI) is one of the primary problems in drug development. Early prediction of DILI, based on the chemical properties of substances and experiments performed on cell lines, would bring a significant reduction in the cost of clinical trials and faster development of drugs. The current study aims to build predictive models of risk of DILI for chemical compounds using multiple sources of information. Methods: Using several supervised machine learning algorithms, we built predictive models for several alternative splits of compounds between DILI and non-DILI classes. To this end, we used chemical properties of the given compounds, their effects on gene expression levels in six human cell lines treated with them, as well as their toxicological profiles. First, we identified the most informative variables in all data sets. Then, these variables were used to build machine learning models. Finally, composite models were built with the Super Learner approach. All modeling was performed using multiple repeats of cross-validation for unbiased and precise estimates of performance. Results: With one exception, gene expression profiles of human cell lines were non-informative and resulted in random models. Toxicological reports were not useful for prediction of DILI. The best results were obtained for models discerning between harmless compounds and those for which any level of DILI was observed (AUC = 0.75). These models were built with Random Forest algorithm that used molecular descriptors.

Integration of human cell lines gene expression and chemical properties of drugs for Drug Induced Liver Injury prediction.

MOTIVATION: Drug-induced liver injury (DILI) is one of the primary problems in drug development. Early prediction of DILI can bring a significant reduction in the cost of clinical trials. In this work we examined whether occurrence of DILI can be predicted using gene expression profile in cancer cell lines and chemical properties of drugs. METHODS: We used gene expression profiles from 13 human cell lines, as well as molecular properties of drugs to build Machine Learning models of DILI. To this end, we have used a robust cross-validated protocol based on feature selection and Random Forest algorithm. In this protocol we first identify the most informative variables and then use them to build predictive models. The models are first built using data from single cell lines, and chemical properties. Then they are integrated using Super Learner method with several underlying methods for integration. The entire modelling process is performed using nested cross-validation. RESULTS: We have obtained weakly predictive ML models when using either molecular descriptors, or some individual cell lines (AUC ∈(0.55-0.61)). Models obtained with the Super Learner approach have a significantly improved accuracy (AUC=0.73), which allows to divide substances in two categories: low-risk and high-risk.

Sensitivity analysis based on the random forest machine learning algorithm identifies candidate genes for regulation of innate and adaptive immune response of chicken.

Two categories of immune responses-innate and adaptive immunity-have both polygenic backgrounds and a significant environmental component. The goal of the reported study was to define candidate genes and mutations for the immune traits of interest in chickens using machine learning-based sensitivity analysis for single-nucleotide polymorphisms (SNPs) located in candidate genes defined in quantitative trait loci regions. Here the adaptive immunity is represented by the specific antibody response toward keyhole limpet hemocyanin (KLH), whereas the innate immunity was represented by natural antibodies toward lipopolysaccharide (LPS) and lipoteichoic acid (LTA). The analysis consisted of 3 basic steps: an identification of candidate SNPs via feature selection, an optimisation of the feature set using recursive feature elimination, and finally a gene-level sensitivity analysis for final selection of models. The predictive model based on 5 genes (MAPK8IP3 CRLF3, UNC13D, ILR9, and PRCKB) explains 14.9% of variance for KLH adaptive response. The models obtained for LTA and LPS use more genes and have lower predictive power, explaining respectively 7.8 and 4.5% of total variance. In comparison, the linear models built on genes identified by a standard statistical analysis explain 1.5, 0.5, and 0.3% of variance for KLH, LTA, and LPS response, respectively. The present study shows that machine learning methods applied to systems with a complex interaction network can discover phenotype-genotype associations with much higher sensitivity than traditional statistical models. It adds contribution to evidence suggesting a role of MAPK8IP3 in the adaptive immune response. It also indicates that CRLF3 is involved in this process as well. Both findings need additional verification.

Integration of multiple types of genetic markers for neuroblastoma may contribute to improved prediction of the overall survival.

BACKGROUND: Modern experimental techniques deliver data sets containing profiles of tens of thousands of potential molecular and genetic markers that can be used to improve medical diagnostics. Previous studies performed with three different experimental methods for the same set of neuroblastoma patients create opportunity to examine whether augmenting gene expression profiles with information on copy number variation can lead to improved predictions of patients survival. We propose methodology based on comprehensive cross-validation protocol, that includes feature selection within cross-validation loop and classification using machine learning. We also test dependence of results on the feature selection process using four different feature selection methods. RESULTS: The models utilising features selected based on information entropy are slightly, but significantly, better than those using features obtained with t-test. The synergy between data on genetic variation and gene expression is possible, but not confirmed. A slight, but statistically significant, increase of the predictive power of machine learning models has been observed for models built on combined data sets. It was found while using both out of bag estimate and in cross-validation performed on a single set of variables. However, the improvement was smaller and non-significant when models were built within full cross-validation procedure that included feature selection within cross-validation loop. Good correlation between performance of the models in the internal and external cross-validation was observed, confirming the robustness of the proposed protocol and results. CONCLUSIONS: We have developed a protocol for building predictive machine learning models. The protocol can provide robust estimates of the model performance on unseen data. It is particularly well-suited for small data sets. We have applied this protocol to develop prognostic models for neuroblastoma, using data on copy number variation and gene expression. We have shown that combining these two sources of information may increase the quality of the models. Nevertheless, the increase is small and larger samples are required to reduce noise and bias arising due to overfitting. REVIEWERS: This article was reviewed by Lan Hu, Tim Beissbarth and Dimitar Vassilev.