Transcriptomics in Toxicogenomics, Part III: Data Modelling for Risk Assessment.

Transcriptomics data are relevant to address a number of challenges in Toxicogenomics (TGx). After careful planning of exposure conditions and data preprocessing, the TGx data can be used in predictive toxicology, where more advanced modelling techniques are applied. The large volume of molecular profiles produced by omics-based technologies allows the development and application of artificial intelligence (AI) methods in TGx. Indeed, the publicly available omics datasets are constantly increasing together with a plethora of different methods that are made available to facilitate their analysis, interpretation and the generation of accurate and stable predictive models. In this review, we present the state-of-the-art of data modelling applied to transcriptomics data in TGx. We show how the benchmark dose (BMD) analysis can be applied to TGx data. We review read across and adverse outcome pathways (AOP) modelling methodologies. We discuss how network-based approaches can be successfully employed to clarify the mechanism of action (MOA) or specific biomarkers of exposure. We also describe the main AI methodologies applied to TGx data to create predictive classification and regression models and we address current challenges. Finally, we present a short description of deep learning (DL) and data integration methodologies applied in these contexts. Modelling of TGx data represents a valuable tool for more accurate chemical safety assessment. This review is the third part of a three-article series on Transcriptomics in Toxicogenomics.

Predictive Performance of a Fall Risk Assessment Tool for Community-Dwelling Older People (FRAT-up) in 4 European Cohorts.

BACKGROUND AND OBJECTIVE: The fall risk assessment tool (FRAT-up) is a tool for predicting falls in community-dwelling older people based on a meta-analysis of fall risk factors. Based on the fall risk factor profile, this tool calculates the individual risk of falling over the next year. The objective of this study is to evaluate the performance of FRAT-up in predicting future falls in multiple cohorts. METHODS: Information about fall risk factors in 4 European cohorts of older people [Activity and Function in the Elderly (ActiFE), Germany; English Longitudinal Study of Aging (ELSA), England; Invecchiare nel Chianti (InCHIANTI), Italy; Irish Longitudinal Study on Aging (TILDA), Ireland] was used to calculate the FRAT-up risk score in individual participants. Information about falls that occurred after the assessment of the risk factors was collected from subsequent longitudinal follow-ups. We compared the performance of FRAT-up against those of other prediction models specifically fitted in each cohort by calculation of the area under the receiver operating characteristic curve (AUC). RESULTS: The AUC attained by FRAT-up is 0.562 [95% confidence interval (CI) 0.530-0.594] for ActiFE, 0.699 (95% CI 0.680-0.718) for ELSA, 0.636 (95% CI 0.594-0.681) for InCHIANTI, and 0.685 (95% CI 0.660-0.709) for TILDA. Mean FRAT-up AUC as estimated from meta-analysis is 0.646 (95% CI 0.584-0.708), with substantial heterogeneity between studies. In each cohort, FRAT-up discriminant ability is surpassed, at most, by the cohort-specific risk model fitted on that same cohort. CONCLUSIONS: We conclude that FRAT-up is a valid approach to estimate risk of falls in populations of community-dwelling older people. However, further studies should be performed to better understand the reasons for the observed heterogeneity across studies and to refine a tool that performs homogeneously with higher accuracy measures across different populations.

FRAT-up, a Web-based fall-risk assessment tool for elderly people living in the community.

BACKGROUND: About 30% of people over 65 are subject to at least one unintentional fall a year. Fall prevention protocols and interventions can decrease the number of falls. To be effective, a prevention strategy requires a prior step to evaluate the fall risk of the subjects. Despite extensive research, existing assessment tools for fall risk have been insufficient for predicting falls. OBJECTIVE: The goal of this study is to present a novel web-based fall-risk assessment tool (FRAT-up) and to evaluate its accuracy in predicting falls, within a context of community-dwelling persons aged 65 and up. METHODS: FRAT-up is based on the assumption that a subject's fall risk is given by the contribution of their exposure to each of the known fall-risk factors. Many scientific studies have investigated the relationship between falls and risk factors. The majority of these studies adopted statistical approaches, usually providing quantitative information such as odds ratios. FRAT-up exploits these numerical results to compute how each single factor contributes to the overall fall risk. FRAT-up is based on a formal ontology that enlists a number of known risk factors, together with quantitative findings in terms of odds ratios. From such information, an automatic algorithm generates a rule-based probabilistic logic program, that is, a set of rules for each risk factor. The rule-based program takes the health profile of the subject (in terms of exposure to the risk factors) and computes the fall risk. A Web-based interface allows users to input health profiles and to visualize the risk assessment for the given subject. FRAT-up has been evaluated on the InCHIANTI Study dataset, a representative population-based study of older persons living in the Chianti area (Tuscany, Italy). We compared reported falls with predicted ones and computed performance indicators. RESULTS: The obtained area under curve of the receiver operating characteristic was 0.642 (95% CI 0.614-0.669), while the Brier score was 0.174. The Hosmer-Lemeshow test indicated statistical significance of miscalibration. CONCLUSIONS: FRAT-up is a web-based tool for evaluating the fall risk of people aged 65 or up living in the community. Validation results of fall risks computed by FRAT-up show that its performance is comparable to externally validated state-of-the-art tools. A prototype is freely available through a web-based interface. TRIAL REGISTRATION: ClinicalTrials.gov NCT01331512 (The InChianti Follow-Up Study); http://clinicaltrials.gov/show/NCT01331512 (Archived by WebCite at http://www.webcitation.org/6UDrrRuaR).