Continuous Markov Models for Analyzing the Effect of Environmental Personal Exposure on Multiple Sclerosis Progression.

Multiple sclerosis (MS) is an inflammatory autoimmune demyelinating disorder of the central nervous system, leading to progressive functional impairments. Predicting disease progression with a probabilistic and time-dependent approach might help suggest interventions for a better management of the disease. Recently, there has been increasing focus on the impact of air pollutants as environmental factors influencing disease progression. This study employs a Continuous-Time Markov Model (CMM) to explore the impact of air pollution measurements on MS progression using longitudinal data from MS patients in Italy between 2013 and 2022. Preliminary findings indicate a relationship between air pollution and MS progression, with pollutants like Particulate Matter with a diameter of 10 micrometers (PM10) or 2.5 micrometers (PM2.5), Nitrogen Dioxide (NO2), and Carbon Monoxide (CO) showing potential effects on disease activity.

Critical assessment of variant prioritization methods for rare disease diagnosis within the rare genomes project.

BACKGROUND: A major obstacle faced by families with rare diseases is obtaining a genetic diagnosis. The average "diagnostic odyssey" lasts over five years and causal variants are identified in under 50%, even when capturing variants genome-wide. To aid in the interpretation and prioritization of the vast number of variants detected, computational methods are proliferating. Knowing which tools are most effective remains unclear. To evaluate the performance of computational methods, and to encourage innovation in method development, we designed a Critical Assessment of Genome Interpretation (CAGI) community challenge to place variant prioritization models head-to-head in a real-life clinical diagnostic setting. METHODS: We utilized genome sequencing (GS) data from families sequenced in the Rare Genomes Project (RGP), a direct-to-participant research study on the utility of GS for rare disease diagnosis and gene discovery. Challenge predictors were provided with a dataset of variant calls and phenotype terms from 175 RGP individuals (65 families), including 35 solved training set families with causal variants specified, and 30 unlabeled test set families (14 solved, 16 unsolved). We tasked teams to identify causal variants in as many families as possible. Predictors submitted variant predictions with estimated probability of causal relationship (EPCR) values. Model performance was determined by two metrics, a weighted score based on the rank position of causal variants, and the maximum F-measure, based on precision and recall of causal variants across all EPCR values. RESULTS: Sixteen teams submitted predictions from 52 models, some with manual review incorporated. Top performers recalled causal variants in up to 13 of 14 solved families within the top 5 ranked variants. Newly discovered diagnostic variants were returned to two previously unsolved families following confirmatory RNA sequencing, and two novel disease gene candidates were entered into Matchmaker Exchange. In one example, RNA sequencing demonstrated aberrant splicing due to a deep intronic indel in ASNS, identified in trans with a frameshift variant in an unsolved proband with phenotypes consistent with asparagine synthetase deficiency. CONCLUSIONS: Model methodology and performance was highly variable. Models weighing call quality, allele frequency, predicted deleteriousness, segregation, and phenotype were effective in identifying causal variants, and models open to phenotype expansion and non-coding variants were able to capture more difficult diagnoses and discover new diagnoses. Overall, computational models can significantly aid variant prioritization. For use in diagnostics, detailed review and conservative assessment of prioritized variants against established criteria is needed.

Critical assessment of variant prioritization methods for rare disease diagnosis within the Rare Genomes Project.

Background: A major obstacle faced by rare disease families is obtaining a genetic diagnosis. The average "diagnostic odyssey" lasts over five years, and causal variants are identified in under 50%. The Rare Genomes Project (RGP) is a direct-to-participant research study on the utility of genome sequencing (GS) for diagnosis and gene discovery. Families are consented for sharing of sequence and phenotype data with researchers, allowing development of a Critical Assessment of Genome Interpretation (CAGI) community challenge, placing variant prioritization models head-to-head in a real-life clinical diagnostic setting. Methods: Predictors were provided a dataset of phenotype terms and variant calls from GS of 175 RGP individuals (65 families), including 35 solved training set families, with causal variants specified, and 30 test set families (14 solved, 16 unsolved). The challenge tasked teams with identifying the causal variants in as many test set families as possible. Ranked variant predictions were submitted with estimated probability of causal relationship (EPCR) values. Model performance was determined by two metrics, a weighted score based on rank position of true positive causal variants and maximum F-measure, based on precision and recall of causal variants across EPCR thresholds. Results: Sixteen teams submitted predictions from 52 models, some with manual review incorporated. Top performing teams recalled the causal variants in up to 13 of 14 solved families by prioritizing high quality variant calls that were rare, predicted deleterious, segregating correctly, and consistent with reported phenotype. In unsolved families, newly discovered diagnostic variants were returned to two families following confirmatory RNA sequencing, and two prioritized novel disease gene candidates were entered into Matchmaker Exchange. In one example, RNA sequencing demonstrated aberrant splicing due to a deep intronic indel in ASNS, identified in trans with a frameshift variant, in an unsolved proband with phenotype overlap with asparagine synthetase deficiency. Conclusions: By objective assessment of variant predictions, we provide insights into current state-of-the-art algorithms and platforms for genome sequencing analysis for rare disease diagnosis and explore areas for future optimization. Identification of diagnostic variants in unsolved families promotes synergy between researchers with clinical and computational expertise as a means of advancing the field of clinical genome interpretation.

Impact of COVID-19 lockdown on PM concentrations in an Italian Northern City: A year-by-year assessment.

In the last century, the increase in traffic, human activities and industrial production have led to a diffuse presence of air pollution, which causes an increase of risk of several health conditions such as respiratory diseases. In Europe, air pollution is a serious concern that affects several areas, one of the worst ones being northern Italy, and in particular the Po Valley, an area characterized by low air quality due to a combination of high population density, industrial activity, geographical factors and weather conditions. Public health authorities and local administrations are aware of this problem, and periodically intervene with temporary traffic limitations and other regulations, often insufficient to solve the problem. In February 2020, this area was the first in Europe to be severely hit by the SARS-CoV-2 virus causing the COVID-19 disease, to which the Italian government reacted with the establishment of a drastic lockdown. This situation created the condition to study how significant is the impact of car traffic and industrial activity on the pollution in the area, as these factors were strongly reduced during the lockdown. Differently from some areas in the world, a drastic decrease in pollution measured in terms of particulate matter (PM) was not observed in the Po Valley during the lockdown, suggesting that several external factors can play a role in determining the severity of pollution. In this study, we report the case study of the city of Pavia, where data coming from 23 air quality sensors were analyzed to compare the levels measured during the lockdown with the ones coming from the same period in 2019. Our results show that, on a global scale, there was a statistically significant reduction in terms of PM levels taking into account meteorological variables that can influence pollution such as wind, temperature, humidity, rain and solar radiation. Differences can be noticed analyzing daily pollution trends too, as-compared to the study period in 2019-during the study period in 2020 pollution was higher in the morning and lower in the remaining hours.

Digital Health during COVID-19: Informatics Dialogue with the World Health Organization.

BACKGROUND: On December 16, 2020 representatives of the International Medical Informatics Association (IMIA), a Non-Governmental Organization in official relations with the World Health Organization (WHO), along with its International Academy for Health Sciences Informatics (IAHSI), held an open dialogue with WHO Director General (WHO DG) Tedros Adhanom Ghebreyesus about the opportunities and challenges of digital health during the COVID-19 global pandemic. OBJECTIVES: The aim of this paper is to report the outcomes of the dialogue and discussions with more than 200 participants representing different civil society organizations (CSOs). METHODS: The dialogue was held in form of a webinar. After an initial address of the WHO DG, short presentations by the panelists, and live discussions between panelists, the WHO DG and WHO representatives took place. The audience was able to post questions in written. These written discussions were saved with participants' consent and summarized in this paper. RESULTS: The main themes that were brought up by the audience for discussion were: (a) opportunities and challenges in general; (b) ethics and artificial intelligence; (c) digital divide; (d) education. Proposed actions included the development of a roadmap based on the lessons learned from the COVID-19 pandemic. CONCLUSIONS: Decision making by policy makers needs to be evidence-based and health informatics research should be used to support decisions surrounding digital health, and we further propose next steps in the collaboration between IMIA and WHO such as future engagement in the World Health Assembly.

Spatial Enablement to Support Environmental, Demographic, Socioeconomics, and Health Data Integration and Analysis for Big Cities: A Case Study With Asthma Hospitalizations in New York City.

The percentage of the world's population living in urban areas is projected to increase in the next decades. Big cities are heterogeneous environments in which socioeconomic and environmental differences among the neighborhoods are often very pronounced. Each individual, during his/her life, is constantly subject to a mix of exposures that have an effect on their phenotype but are frequently difficult to identify, especially in an urban environment. Studying how the combination of environmental and socioeconomic factors which the population is exposed to influences pathological outcomes can help transforming public health from a reactive to a predictive system. Thanks to the application of state-of-the-art spatially enabled methods, patients can be stratified according to their characteristics and the geographical context they live in, optimizing healthcare processes and the reducing its costs. Some public health studies focusing specifically on urban areas have been conducted, but they usually consider a coarse spatial subdivision, as a consequence of scarce availability of well-integrated data regarding health and environmental exposure at a sufficient level of granularity to enable meaningful statistical analyses. In this paper, we present an application of highly fine-grained spatial resolution methods to New York City data. We investigated the link between asthma hospitalizations and a combination of air pollution and other environmental and socioeconomic factors. We first performed an explorative analysis using spatial clustering methods that shows that asthma is related to numerous factors whose level of influence varies considerably among neighborhoods. We then performed a Geographically Weighted Regression with different covariates and determined which environmental and socioeconomic factors can predict hospitalizations and how they vary throughout the city. These methods showed to be promising both for visualization and analysis of demographic and epidemiological urban dynamics, that can be used to organize targeted intervention and treatment policies to address the single citizens considering the factors he/she is exposed to. We found a link between asthma and several factors such as PM2.5, age, health insurance coverage, race, poverty, obesity, industrial areas, and recycling. This study has been conducted within the PULSE project, funded by the European Commission, briefly presented in this paper.

A Network-Based Data Integration Approach to Support Drug Repurposing and Multi-Target Therapies in Triple Negative Breast Cancer.

The integration of data and knowledge from heterogeneous sources can be a key success factor in drug design, drug repurposing and multi-target therapies. In this context, biological networks provide a useful instrument to highlight the relationships and to model the phenomena underlying therapeutic action in cancer. In our work, we applied network-based modeling within a novel bioinformatics pipeline to identify promising multi-target drugs. Given a certain tumor type/subtype, we derive a disease-specific Protein-Protein Interaction (PPI) network by combining different data-bases and knowledge repositories. Next, the application of suitable graph-based algorithms allows selecting a set of potentially interesting combinations of drug targets. A list of drug candidates is then extracted by applying a recent data fusion approach based on matrix tri-factorization. Available knowledge about selected drugs mechanisms of action is finally exploited to identify the most promising candidates for planning in vitro studies. We applied this approach to the case of Triple Negative Breast Cancer (TNBC), a subtype of breast cancer whose biology is poorly understood and that lacks of specific molecular targets. Our "in-silico" findings have been confirmed by a number of in vitro experiments, whose results demonstrated the ability of the method to select candidates for drug repurposing.

Big Data Technologies: New Opportunities for Diabetes Management.

The so-called big data revolution provides substantial opportunities to diabetes management. At least 3 important directions are currently of great interest. First, the integration of different sources of information, from primary and secondary care to administrative information, may allow depicting a novel view of patient's care processes and of single patient's behaviors, taking into account the multifaceted nature of chronic care. Second, the availability of novel diabetes technologies, able to gather large amounts of real-time data, requires the implementation of distributed platforms for data analysis and decision support. Finally, the inclusion of geographical and environmental information into such complex IT systems may further increase the capability of interpreting the data gathered and extract new knowledge from them. This article reviews the main concepts and definitions related to big data, it presents some efforts in health care, and discusses the potential role of big data in diabetes care. Finally, as an example, it describes the research efforts carried on in the MOSAIC project, funded by the European Commission.

Development and representation of health indicators with thematic maps.

Italian Local Health Care Agencies (ASLs) have the role of managing the public healthcare resources in their area of competence. To this end, the ASL of Pavia has implemented a data warehouse, which collects and integrates health data of more than 500,000 people since 2004. We have exploited such data repository to compute a variety of yearly health indicators, which have been represented on thematic maps of the area. Thanks to a Web-based application, the ASL decision-makers can monitor the area with a fine-grained spatial detail, dissecting the epidemiological, economical and pharmaceutical factors underlying citizens' health and patients' care. The implemented tool is currently up-and-running and has been evaluated with a usability questionnaire on a small number of users.

Forecast model for the evaluation of economic resources employed in the health care of patients with HIV infection.

BACKGROUND AND AIMS: The total health care cost for human immunodeficiency virus (HIV) patients has constantly grown in recent years. To date, there is no information about how this trend will behave over the next few years. The aim of the present study is to define a pharmacoeconomic model for the forecast of the costs of a group of chronically treated patients followed over the period 2004-2009. METHODS: A pharmacoeconomics model was built to describe the probability of transition among different health states and to modify the therapy over time. A Markov model was applied to evaluate the temporal evolution of the average cost. The health care resources exploited during hospitalization were analyzed by using an "activity-based costing" method. RESULTS: The Markov model showed that the mean total cost, after an initial increase, tended to remain stable. A total of 20 clinical records were examined. The average daily cost for each patient was EUR 484.42, with a cost for admission of EUR 6781.88. CONCLUSION: The treatment of HIV infection in compliance with the guidelines is also effective from the payer perspective, as it allows a good health condition to be maintained and reduces the need and the costs of hospitalizations.

Stochastic model search with binary outcomes for genome-wide association studies.

OBJECTIVE: The spread of case-control genome-wide association studies (GWASs) has stimulated the development of new variable selection methods and predictive models. We introduce a novel Bayesian model search algorithm, Binary Outcome Stochastic Search (BOSS), which addresses the model selection problem when the number of predictors far exceeds the number of binary responses. MATERIALS AND METHODS: Our method is based on a latent variable model that links the observed outcomes to the underlying genetic variables. A Markov Chain Monte Carlo approach is used for model search and to evaluate the posterior probability of each predictor. RESULTS: BOSS is compared with three established methods (stepwise regression, logistic lasso, and elastic net) in a simulated benchmark. Two real case studies are also investigated: a GWAS on the genetic bases of longevity, and the type 2 diabetes study from the Wellcome Trust Case Control Consortium. Simulations show that BOSS achieves higher precisions than the reference methods while preserving good recall rates. In both experimental studies, BOSS successfully detects genetic polymorphisms previously reported to be associated with the analyzed phenotypes. DISCUSSION: BOSS outperforms the other methods in terms of F-measure on simulated data. In the two real studies, BOSS successfully detects biologically relevant features, some of which are missed by univariate analysis and the three reference techniques. CONCLUSION: The proposed algorithm is an advance in the methodology for model selection with a large number of features. Our simulated and experimental results showed that BOSS proves effective in detecting relevant markers while providing a parsimonious model.

A methodology for the extraction of quantitative risk indexes from medical injuries compensation claims.

The prevention of adverse events and medical injuries due to malpractice or suboptimal delivery of health care services is one of the major concerns of citizens and Health Care Organizations. One way to understand adverse events is to analyze the compensation requests for medical injuries that are claimed to hospital or health care services. In this paper we describe the results obtained by applying a probabilistic model, called the actuarial model, to analyze 317 cases of injuries with compensation requests collected from 1999 to the first semester of 2007 by the Azienda Ospedaliera (A.O.) of Lodi, in the Northern part of Italy. The approach, adapted from operational and financial risk management, proved to be useful to understand the risk structure in terms of frequency, severity, expected and unexpected loss related to adverse events.

Temporal data mining for the assessment of the costs related to diabetes mellitus pharmacological treatment.

Diabetes care and chronic disease management represent data-intensive contexts which allow Local Healthcare Agencies (ASL) to collect a huge amount of information. Time is often an essential component of such information, given the strong importance of the temporal evolution of the considered disease and of its treatment. In this paper we show the application of a temporal data mining technique to extract temporal association rules over an integrated repository including both administrative and clinical data related to a sample of diabetic patients. We will show how the method can be used to highlight cases and conditions which lead to the highest pharmaceutical costs. Considering the perspective of a Regional Healthcare Agency, this method could be properly exploited to assess the overall standards and quality of care, while lowering costs.

Temporal data mining for the quality assessment of hemodialysis services.

OBJECTIVE: This paper describes the temporal data mining aspects of a research project that deals with the definition of methods and tools for the assessment of the clinical performance of hemodialysis (HD) services, on the basis of the time series automatically collected during hemodialysis sessions. METHODS: Intelligent data analysis and temporal data mining techniques are applied to gain insight and to discover knowledge on the causes of unsatisfactory clinical results. In particular, two new methods for association rule discovery and temporal rule discovery are applied to the time series. Such methods exploit several pre-processing techniques, comprising data reduction, multi-scale filtering and temporal abstractions. RESULTS: We have analyzed the data of more than 5800 dialysis sessions coming from 43 different patients monitored for 19 months. The qualitative rules associating the outcome parameters and the measured variables were examined by the domain experts, which were able to distinguish between rules confirming available background knowledge and unexpected but plausible rules. CONCLUSION: The new methods proposed in the paper are suitable tools for knowledge discovery in clinical time series. Their use in the context of an auditing system for dialysis management helped clinicians to improve their understanding of the patients' behavior.

Analysing Italian voluntary abortion data using a Bayesian approach to the time series decomposition.

After the approval of the law on voluntary abortion in Italy, the Italian health care system started to practice voluntary abortion before the third month of pregnancy. Since 1980, the Italian Institute of Statistics (ISTAT) has collected data on the abortion frequency per month and per administrative local areas. Although a preliminary analysis of the data showed that, after an initial increase, the number of abortions progressively lowered over years, there is no insight on the existence of periodicity in the time series and on the local effects related to the regional habits and social environments. The aim of our study is therefore to extract local trends and periodicity from the data collected by ISTAT, by combining a 'structural model' of the time series and Bayesian statistics. This paper describes both the adopted stochastic model and its Bayesian estimation through a Markov chain Monte Carlo approach on the Italian abortion data. Abortion data are analysed both at national level and in each of the 95 Italian local areas. At the national level this analysis allows extraction of a trend component that clearly shows that the voluntary abortion trend has decreased constantly since June-July 1983 until the end of the study. The periodic component shows an astonishing regularity too, suggesting that the Italian people have a seasonal preference for voluntary abortion. In particular, abortions are concentrated in the central part of the year (April-August). Finally, at the local level this analysis allows us to find similarities/differences between different areas in trends and/or in seasonal preferences.