Joyce A. Mitchell

Using literature-based discovery to identify disease candidate genes

We present BITOLA, an interactive literature-based biomedical discovery support system. The goal of this system is to discover new, potentially meaningful relations between a given starting concept of interest and other concepts, by mining the bibliographic database MEDLINE. To make the system more suitable for disease candidate gene discovery and to decrease the number of candidate relations, we integrate background knowledge about the chromosomal location of the starting disease as well as the chromosomal location of the candidate genes from resources such as LocusLink and Human Genome Organization (HUGO). BITOLA can also be used as an alternative way of searching the MEDLINE database. The system is available at http://www.mf.uni-lj.si/bitola/.

Effect of physician profiling on utilization - Meta-analysis of randomized clinical trials

OBJECTIVES: An American Medical Association survey reported that more than half of physicians are subjects of either clinical or economic profiling. This multilevel meta-analysis was designed to assess the clinical effect of peer-comparison feedback intervention (profiles) in changing practice patterns.METHODS: Systematic computerized and manual searches were combined to retrieve articles on randomized controlled clinical trials testing profiling reports. Eligible studies were randomized, controlled clinical trials that tested peer-comparison feedback intervention and measured utilization of clinical procedures. To use all available information, data were abstracted and analyzed on three levels: (1) direction of effects, (2)p value from the statistical comparison, and (3) odds ratio (OR).MAIN RESULTS: In the 12 eligible trials, 553 physicians were profiled. The test result wasp<.05 for the vote-counting sign test of 12 studies (level 1) andp<.05 for the z-transformation test of 8 studies (level 2). There were 5 trials included in the OR analysis (level 3). The primary effect variable in two of the 5 trials had a nonsignificant OR. However, the overall OR calculated by the Mantel-Haenszel method was significant (1.091, confidence interval: 1.045 to 1.136).CONCLUSIONS: Profiling has a statistically significant, but minimal effect on the utilization of clinical procedures. The results of this study indicate a need for controlled clinical evaluations before subjecting large numbers of physicians to utilization management interventions.

Methods of Randomized Controlled Clinical Trials in Health Services Research

The randomized controlled clinical trial is an increasingly used method in health services research. Analysis of methodology is needed to accelerate practical implementation of trial results, select trials for meta-analysis, and improve trial quality in health services research. The objectives of this study are to explore the methodology of health services research trials, create and validate a streamlined quality evaluation tool, and identify frequent quality defects and confounding effects on quality. The authors developed a quality questionnaire that contained 20 evaluation criteria for health services research trials. One hundred one trials from the Columbia Registry of Controlled Clinical Trials were evaluated using the new quality tool. The overall agreement between independent reviewers, Cohens kappa, was 0.94 (±0.01). Of a possible score of 100, the trials received an average score of 54.8 (±12.5). Five evaluation criteria indicated significant quality deficiencies (sample size, description of case selection, data on possible adverse effects, analysis of secondary effect variables, and retrospective analysis). The quality of study characteristics was significantly weaker than the quality of reporting characteristics (P <0.001). The total average scores of Medline-indexed journals were better than the non-Medline-indexed journals (P < 0.001). There was a positive correlation between the overall quality and year of publication (R = 0.21, P < 0.05). The authors conclude that the new quality evaluation tool leads to replicable results and there is an urgent need to improve several study characteristics of clinical trials. In comparison to drug trials, site selection, randomization, and blinding often require different approaches in health services research.

Comparison of compliance for colorectal cancer screening and surveillance by colonoscopy based on risk.

Purpose: To compare colonoscopy screening/surveillance rates by level of risk for colorectal cancer based on age, personal history of adenomatous polyps or colorectal cancer, or family history of colorectal cancer.Methods: Participants were aged 30–90 years, were seen within 5 years at Intermountain Healthcare, and had family history in the Utah Population Database. Colonoscopy rates were measured for those with/without risk factors.Results: Among those aged 60–69 years, 48.4% had colonoscopy in the last 10 years, with rates declining after age 70 years. Percentages of those having had a colonoscopy in the last 10 years generally increased by risk level from 38.5% in those with a familial relative risk <1.0 to 47.6% in those with a familial relative risk >3.0. Compared with those with no family history, the odds ratio for being screened according to guidelines was higher for those with one first-degree relative diagnosed with colorectal cancer ≥ 60 years or two affected second-degree relatives (1.54, 95% confidence interval: 1.46–1.61) than those with one affected first-degree relative diagnosed <60 years or ≥2 affected first-degree relatives (1.25, 95% confidence interval: 1.14–1.37).Conclusions: Compliance with colonoscopy guidelines was higher for those with familial risk but did not correspond with the degree of risk.

CHARGE Syndrome. Part II. Hearing loss

CHARGE is a mnemonic for a syndrome with multiple congenital anomalies that occurs with normal chromosomes. The unique external ear anomalies have been described in CHARGE Syndrome Part I in this journal. This report describes the distinctive middle ear and sensorineural losses that occur in the syndrome, both of which can be progressive and, in most cases, are moderate to severe. There is evidence to indicate that these losses are due to congenital ossicular anomalies, eustachian tube dysfunction from craniofacial malformation, and cochlear involvement that is greatest for high frequencies.

Evaluating the informatics for integrating biology and the bedside system for clinical research

BackgroundSelecting patient cohorts is a critical, iterative, and often time-consuming aspect of studies involving human subjects; informatics tools for helping streamline the process have been identified as important infrastructure components for enabling clinical and translational research. We describe the evaluation of a free and open source cohort selection tool from the Informatics for Integrating Biology and the Bedside (i2b2) group: the i2b2 hive.MethodsOur evaluation included the usability and functionality of the i2b2 hive using several real world examples of research data requests received electronically at the University of Utah Health Sciences Center between 2006 - 2008. The hive server component and the visual query tool application were evaluated for their suitability as a cohort selection tool on the basis of the types of data elements requested, as well as the effort required to fulfill each research data request using the i2b2 hive alone.ResultsWe found the i2b2 hive to be suitable for obtaining estimates of cohort sizes and generating research cohorts based on simple inclusion/exclusion criteria, which consisted of about 44% of the clinical research data requests sampled at our institution. Data requests that relied on post-coordinated clinical concepts, aggregate values of clinical findings, or temporal conditions in their inclusion/exclusion criteria could not be fulfilled using the i2b2 hive alone, and required one or more intermediate data steps in the form of pre- or post-processing, modifications to the hive metadata, etc.ConclusionThe i2b2 hive was found to be a useful cohort-selection tool for fulfilling common types of requests for research data, and especially in the estimation of initial cohort sizes. For another institution that might want to use the i2b2 hive for clinical research, we recommend that the institution would need to have structured, coded clinical data and metadata available that can be transformed to fit the logical data models of the i2b2 hive, strategies for extracting relevant clinical data from source systems, and the ability to perform substantial pre- and post-processing of these data.

Countering imbalanced datasets to improve adverse drug event predictive models in labor and delivery

BACKGROUND The IOM report, Preventing Medication Errors, emphasizes the overall lack of knowledge of the incidence of adverse drug events (ADE). Operating rooms, emergency departments and intensive care units are known to have a higher incidence of ADE. Labor and delivery (L&D) is an emergency care unit that could have an increased risk of ADE, where reported rates remain low and under-reporting is suspected. Risk factor identification with electronic pattern recognition techniques could improve ADE detection rates. OBJECTIVE The objective of the present study is to apply Synthetic Minority Over Sampling Technique (SMOTE) as an enhanced sampling method in a sparse dataset to generate prediction models to identify ADE in women admitted for labor and delivery based on patient risk factors and comorbidities. RESULTS By creating synthetic cases with the SMOTE algorithm and using a 10-fold cross-validation technique, we demonstrated improved performance of the Naïve Bayes and the decision tree algorithms. The true positive rate (TPR) of 0.32 in the raw dataset increased to 0.67 in the 800% over-sampled dataset. CONCLUSION Enhanced performance from classification algorithms can be attained with the use of synthetic minority class oversampling techniques in sparse clinical datasets. Predictive models created in this manner can be used to develop evidence based ADE monitoring systems.

Nanoinformatics: a new area of research in nanomedicine

Over a decade ago, nanotechnologists began research on applications of nanomaterials for medicine. This research has revealed a wide range of different challenges, as well as many opportunities. Some of these challenges are strongly related to informatics issues, dealing, for instance, with the management and integration of heterogeneous information, defining nomenclatures, taxonomies and classifications for various types of nanomaterials, and research on new modeling and simulation techniques for nanoparticles. Nanoinformatics has recently emerged in the USA and Europe to address these issues. In this paper, we present a review of nanoinformatics, describing its origins, the problems it addresses, areas of interest, and examples of current research initiatives and informatics resources. We suggest that nanoinformatics could accelerate research and development in nanomedicine, as has occurred in the past in other fields. For instance, biomedical informatics served as a fundamental catalyst for the Human Genome Project, and other genomic and –omics projects, as well as the translational efforts that link resulting molecular-level research to clinical problems and findings.

Predicting phenotypic severity of uncertain gene variants in the RET proto-oncogene.

Although reported gene variants in the RET oncogene have been directly associated with multiple endocrine neoplasia type 2 and hereditary medullary thyroid carcinoma, other mutations are classified as variants of uncertain significance (VUS) until the associated clinical phenotype is made clear. Currently, some 46 non-synonymous VUS entries exist in curated archives. In the absence of a gold standard method for predicting phenotype outcomes, this follow up study applies feature selected amino acid physical and chemical properties feeding a Bayes classifier to predict disease association of uncertain gene variants into categories of benign and pathogenic. Algorithm performance and VUS predictions were compared to established phylogenetic based mutation prediction algorithms. Curated outcomes and unpublished RET gene variants with known disease association were used to benchmark predictor performance. Reliable classification of RET uncertain gene variants will augment current clinical information of RET mutations and assist in improving prediction algorithms as knowledge increases.

In Search of Controlled Evidence for Health Care Quality Improvement

The purpose of this study was to measure the efficiency of simple searches in retrieving controlled evidence about specific primary health care quality improvement interventions and their effects. Searches were conducted to retrieve evidence on seven interventions and seven effect variables. Specific words and the closest Medical Subject Headings (MeSH) recommended by professional librarians were used to search the MEDLINE database. Searches were restricted to the MeSH publication type “randomized controlled trial.” Two reviewers independently judged retrieved citations for relevancy to the selected interventions and effects. In selecting MeSH terms, the average agreement among librarians was 64.3% (±26.1) for interventions and 57.1% (±19.9) for effects. Analysis of the 755 retrieved reports showed that MeSH term searches had an overall recall rate of 58% while the same rate for textword searches was significantly lower (11%, p < .001). The difference in overall precision rates was nonsignificant (26% versus 33%, p = .15). In the group of MeSH searches, overall precision and recall was significantly lower for effects than for interventions (12% versus 52%, p < .001 and 41% versus 69%, p < .001). Two textwords appeared in more than 25% of the benchmark collection: reminder (25.7%) and cost (25.0%). The results of this study indicate that information needs for health care quality improvement cannot be met by simple literature searches. Certain MeSH terms and combinations of textwords yield moderately efficient recall and precision in literature searches for health care quality improvement. Clinicians and physician executives gaining direct access to bibliographic database could probably be better served by structured indexing of critical aspects of randomized controlled clinical trials: design, sample, interventions, and effects.