Multidisciplinary and Evidence-based Method for Prioritizing Diseases of Food-producing Animals and Zoonoses

To prioritize 100 animal diseases and zoonoses in Europe, we used a multicriteria decision-making procedure based on opinions of experts and evidence-based data. Forty international experts performed intracategory and intercategory weighting of 57 prioritization criteria. Two methods (deterministic with mean of each weight and probabilistic with distribution functions of weights by using Monte Carlo simulation) were used to calculate a score for each disease. Consecutive ranking was established. Few differences were observed between each method. Compared with previous prioritization methods, our procedure is evidence based, includes a range of fields and criteria while considering uncertainty, and will be useful for analyzing diseases that affect public health.     

Incidence of and risk factors for diabetic retinopathy in Isfahan,Iran

Background Evidence on the incidence of and risk factors for diabetic retinopathy is mainly derived from studies in developed countries. Locally derived evidence is required for planning a well-coordinated approach to this public health problem in developing countries. Objective The objectives of the present study were to estimate the incidence of and risk factors for the development of diabetic retinopathy using routinely collected data from a clinical information system at the Isfahan Endocrinology and Metabolism Research Center, Iran, for non-insulin-dependent (insulin-treated and non-insulin-treated) diabetes. Method During the mean (standard deviation (SD)) follow-up period of 5.1 (2.1) (range 1–9) years, 549 diabetic patients (161 male and 388 female) from the Isfahan Endocrinology and Metabolism Research Center outpatient clinics at Amin University Hospital, Iran, were examined. The mean (SD) age of the participants was 45.7 (9.3) years with a mean (SD) duration of diabetes of 6.9 (5.7) years at initial registration. Results Among the 549 patients free of retinopathy at initial registration with at least one follow-up visit between 1992 and 2001, the incidence of any retinopathy was 89.4 (95% confidence interval (CI): 79.0, 101.0) [96.1 (95% CI: 76.7, 118.0) in males and 86.6 (95% CI: 74.5, 99.9) in females] per 1000 person-years based on 2786 person-years of follow-up. The incidence rate of retinopathy was 60% greater among insulin-treated than non-insulin-treated non-insulin-dependent diabetes mellitus (NIDDM) clinic attenders. The incidence of any retinopathy was greater with older age, longer duration of diabetes, higher diastolic blood pressure and poor metabolic control. Using a Cox's Proportional Hazards Model for insulin-treated and non-insulin-treated NIDDM diabetes separately, poor metabolic control was a significant independent predictor of retinopathy for insulin-treated and non-insulin-treated NIDDM patients. When all variables were entered in the model, age, poor metabolic control and fasting blood glucose were significant predictors of retinopathy. In the insulin-treated group, fasting blood glucose was also a significant predictor of retinopathy. Systolic and diastolic blood pressure, gender, smoking, proteinuria, body mass index and creatinine had no significant independent association with retinopathy when other covariates were considered. Conclusion These data suggest that diabetic retinopathy in this population of Iranian non-insulin-dependent diabetic patients is common, being found in almost half of the patients after a mean 5-year follow-up. Poor metabolic control is the major risk factor.     

Analysis of susceptible genes and chromosome loci for lung cancers by automated gene prediction tools and genome scanning meta-analysis

Genome-wide scanning of susceptible loci and genes for medical diseases is important in current post-genome era. To date, a variety of studies have been focused on the experimental validation or genome-wide linkage scans across multiple populations hunting for susceptibility genes in lung cancer. In the present study, we used two gene prediction tools (PROSPECTR and SUSPECTS, Gen Wanderer) to analyze eight previously identified susceptibility loci for lung tumors, which are selected from literature searching. Our results showed that there was a subset of 26 likely candidate susceptible genes related to lung cancer in each chromosomal region. For potential susceptible chromosome loci, the genome-wide scanning meta-analysis using bins of 60 cM width predicted a group of potential regions associated with lung cancer. Locus 15q21-26 (P=0.000606) is strongly evidenced, which has been confirmed in previous work. In contrast, another potential locus 10q11.2-q23.3 (P=0.0435223) is suggestively evidenced, which was never identified before. Ac compared to previous known regions, the latter one is the new detected one in our study. In conclusion, our study may be useful to contribute to further experimental tests of susceptibility genes/loci related to lung cancer.     

eDiVA—Classification and prioritization of pathogenic variants for clinical diagnostics

Mendelian diseases have shown to be an and efficient model for connecting genotypes to phenotypes and for elucidating the function of genes. Whole‐exome sequencing (WES) accelerated the study of rare Mendelian diseases in families, allowing for directly pinpointing rare causal mutations in genic regions without the need for linkage analysis. However, the low diagnostic rates of 20–30% reported for multiple WES disease studies point to the need for improved variant pathogenicity classification and causal variant prioritization methods. Here, we present the exome Disease Variant Analysis (eDiVA; http://ediva.crg.eu ), an automated computational framework for identification of causal genetic variants (coding/splicing single‐nucleotide variants and small insertions and deletions) for rare diseases using WES of families or parent–child trios. eDiVA combines next‐generation sequencing data analysis, comprehensive functional annotation, and causal variant prioritization optimized for familial genetic disease studies. eDiVA features a machine learning‐based variant pathogenicity predictor combining various genomic and evolutionary signatures. Clinical information, such as disease phenotype or mode of inheritance, is incorporated to improve the precision of the prioritization algorithm. Benchmarking against state‐of‐the‐art competitors demonstrates that eDiVA consistently performed as a good or better than existing approach in terms of detection rate and precision. Moreover, we applied eDiVA to several familial disease cases to demonstrate its clinical applicability.     

SARS‐CoV‐2 infection in patients with a normal or abnormal liver

Severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), a novel coronavirus causing coronavirus disease 19 (COVID‐19), with an estimated 22 million people infected worldwide so far although involving primarily the respiratory tract, has a remarkable tropism for the liver and the biliary tract. Patients with SARS‐CoV‐2 infection and no antecedent liver disease may display evidence of cytolytic liver damage, proportional to the severity of COVID‐19 but rarely of clinical significance. The mechanism of hepatocellular injury is unclear and possibly multifactorial. The clinical impact of SARS‐CoV‐2 infection in patients with underlying chronic liver disease, a cohort whose global size is difficult to estimate, has been assessed appropriately only recently and data are still evolving. Patients with cirrhosis are at higher risk of developing severe COVID‐19 and worse liver‐related outcomes as compared to those with non‐cirrhotic liver disease. OLT patients have an intermediate risk. Specific interventions in order to reduce the risk of transmission of infection among this high‐risk population have been outlined by international societies, together with recommendations for modified treatment and follow‐up regimens during the COVID‐19 pandemic. When a vaccine against SARS‐CoV‐2 becomes available, patients with fibrotic liver disease and those with OLT should be considered as prime targets for prophylaxis of COVID‐19, as all other highly susceptible subjects.     

mirVAFC: A Web Server for Prioritizations of Pathogenic Sequence Variants from Exome Sequencing Data via Classifications

Exome sequencing has been widely used to identify the genetic variants underlying human genetic disorders for clinical diagnoses, but the identification of pathogenic sequence variants among the huge amounts of benign ones is complicated and challenging. Here, we describe a new Web server named mirVAFC for pathogenic sequence variants prioritizations from clinical exome sequencing (CES) variant data of single individual or family. The mirVAFC is able to comprehensively annotate sequence variants, filter out most irrelevant variants using custom criteria, classify variants into different categories as for estimated pathogenicity, and lastly provide pathogenic variants prioritizations based on classifications and mutation effects. Case studies using different types of datasets for different diseases from publication and our in‐house data have revealed that mirVAFC can efficiently identify the right pathogenic candidates as in original work in each case. Overall, the Web server mirVAFC is specifically developed for pathogenic sequence variant identifications from family‐based CES variants using classification‐based prioritizations. The mirVAFC Web server is freely accessible at https://www.wzgenomics.cn/mirVAFC/ .     

Use of in vitro fertilization—ethical issues

This report is an ethical analysis based on both facts and values. In in vitro fertilization (IVF), there is an intricate interaction between rapid scientific development and changing societal values. In most countries, the ethical discussion is no longer on whether or not IVF in itself is ethically justifiable. Therefore, in this review, I discuss other ethical aspects that have emerged since IVF was first introduced, such as upper age limits, ‘ownership’ of gametes and embryos, IVF in single women and same-sex couples, preimplantatory genetic testing, social egg freezing, commercialization, public funding, and prioritization of IVF. Despite secularization, since religion still plays an important role in regulation and practices of IVF in many countries, positions on IVF among the world religions are summarized. Decision-making concerning IVF cannot be based only on clinical and economic considerations; these cannot be disentangled from ethical principles. Many concerns regarding the costs, effects, and safety of IVF subtly transcend into more complex questions about what it means to society to bear and give birth to children.     

Criteria for fairly allocating scarce health-care resources to genetic tests: which matter most?

The use of genetic tests is expanding rapidly. Given limited health-care budgets throughout Europe and few national coverage decisions specifically for genetic tests, decisions about allocating scarce resources to genetic tests are frequently ad hoc and left to lower-level decision makers. This study assesses substantive ethical and economic criteria to prioritize genetic services in a reasonable and fair manner. Principles for allocating health-care resources can be classified into four categories: need-based allocation; maximizing total benefits; treating people equally; and promoting and rewarding social usefulness. In the face of scarcity, the degree of an individual''s need for medical intervention is an important criterion. Also, different economic concepts of efficiency are of relevance in the theory and practice of prioritizing genetic tests. Equity concerns are most likely to be relevant in terms of avoiding undesirable inequities, which may also set boundaries to the use of efficiency as a prioritization criterion. The aim of promoting and rewarding social usefulness is unlikely to be relevant to the question of what priority a genetic test should have in clinical practice. Further work is needed to select an appropriate set of criteria; operationalize them; and assign weights before some kind of standardized priority information can be added to information sources for genetic services. Besides the substantive criteria, formal considerations like those pointed out in the framework of accountability for reasonableness need to be considered in decision making.