Shawn N. Murphy

The GuideLine Interchange Format: A Model for Representing Guidelines

OBJECTIVE To allow exchange of clinical practice guidelines among institutions and computer-based applications. DESIGN The GuideLine Interchange Format (GLIF) specification consists of GLIF model and the GLIF syntax. The GLIF model is an object-oriented representation that consists of a set of classes for guideline entities, attributes for those classes, and data types for the attribute values. The GLIF syntax specifies the format of the test file that contains the encoding. METHODS Researchers from the InterMed Collaboratory at Columbia University, Harvard University (Brigham and Womens Hospital and Massachusetts General Hospital), and Stanford University analyzed four existing guideline systems to derive a set of requirements for guideline representation. The GLIF specification is a consensus representation developed through a brainstorming process. Four clinical guidelines were encoded in GLIF to assess its expressivity and to study the variability that occurs when two people from different sites encode the same guideline. RESULTS The encoders reported that GLIF was adequately expressive. A comparison of the encodings revealed substantial variability. CONCLUSION GLIF was sufficient to model the guidelines for the four conditions that were examined. GLIF needs improvement in standard representation of medical concepts, criterion logic, temporal information, and uncertainty.

The co-morbidity burden of children and young adults with autism spectrum disorders.

Objectives Use electronic health records Autism Spectrum Disorder (ASD) to assess the comorbidity burden of ASD in children and young adults. Study Design A retrospective prevalence study was performed using a distributed query system across three general hospitals and one pediatric hospital. Over 14,000 individuals under age 35 with ASD were characterized by their co-morbidities and conversely, the prevalence of ASD within these comorbidities was measured. The comorbidity prevalence of the younger (Age<18 years) and older (Age 18–34 years) individuals with ASD was compared. Results 19.44% of ASD patients had epilepsy as compared to 2.19% in the overall hospital population (95% confidence interval for difference in percentages 13.58–14.69%), 2.43% of ASD with schizophrenia vs. 0.24% in the hospital population (95% CI 1.89–2.39%), inflammatory bowel disease (IBD) 0.83% vs. 0.54% (95% CI 0.13–0.43%), bowel disorders (without IBD) 11.74% vs. 4.5% (95% CI 5.72–6.68%), CNS/cranial anomalies 12.45% vs. 1.19% (95% CI 9.41–10.38%), diabetes mellitus type I (DM1) 0.79% vs. 0.34% (95% CI 0.3–0.6%), muscular dystrophy 0.47% vs 0.05% (95% CI 0.26–0.49%), sleep disorders 1.12% vs. 0.14% (95% CI 0.79–1.14%). Autoimmune disorders (excluding DM1 and IBD) were not significantly different at 0.67% vs. 0.68% (95% CI −0.14-0.13%). Three of the studied comorbidities increased significantly when comparing ages 0–17 vs 18–34 with p<0.001: Schizophrenia (1.43% vs. 8.76%), diabetes mellitus type I (0.67% vs. 2.08%), IBD (0.68% vs. 1.99%) whereas sleeping disorders, bowel disorders (without IBD) and epilepsy did not change significantly. Conclusions The comorbidities of ASD encompass disease states that are significantly overrepresented in ASD with respect to even the patient populations of tertiary health centers. This burden of comorbidities goes well beyond those routinely managed in developmental medicine centers and requires broad multidisciplinary management that payors and providers will have to plan for.

The Shared Health Research Information Network (SHRINE): A Prototype Federated Query Tool for Clinical Data Repositories

The authors developed a prototype Shared Health Research Information Network (SHRINE) to identify the technical, regulatory, and political challenges of creating a federated query tool for clinical data repositories. Separate Institutional Review Boards (IRBs) at Harvards three largest affiliated health centers approved use of their data, and the Harvard Medical School IRB approved building a Query Aggregator Interface that can simultaneously send queries to each hospital and display aggregate counts of the number of matching patients. Our experience creating three local repositories using the open source Informatics for Integrating Biology and the Bedside (i2b2) platform can be used as a road map for other institutions. The authors are actively working with the IRBs and regulatory groups to develop procedures that will ultimately allow investigators to obtain identified patient data and biomaterials through SHRINE. This will guide us in creating a future technical architecture that is scalable to a national level, compliant with ethical guidelines, and protective of the interests of the participating hospitals.

Electronic medical records for discovery research in rheumatoid arthritis

Electronic medical records (EMRs) are a rich data source for discovery research but are underutilized due to the difficulty of extracting highly accurate clinical data. We assessed whether a classification algorithm incorporating narrative EMR data (typed physician notes) more accurately classifies subjects with rheumatoid arthritis (RA) compared with an algorithm using codified EMR data alone.

Aligning temporal data by sentinel events: discovering patterns in electronic health records

Electronic Health Records (EHRs) and other temporal databases contain hidden patterns that reveal important cause-and-effect phenomena. Finding these patterns is a challenge when using traditional query languages and tabular displays. We present an interactive visual tool that complements query formulation by providing operations to align, rank and filter the results, and to visualize estimates of the intervals of validity of the data. Display of patient histories aligned on sentinel events (such as a first heart attack) enables users to spot precursor, co-occurring, and aftereffect events. A controlled study demonstrates the benefits of providing alignment (with a 61% speed improvement for complex tasks). A qualitative study and interviews with medical professionals demonstrates that the interface can be learned quickly and seems to address their needs.

Detecting drug interactions from adverse-event reports: interaction between paroxetine and pravastatin increases blood glucose levels.

The lipid‐lowering agent pravastatin and the antidepressant paroxetine are among the most widely prescribed drugs in the world. Unexpected interactions between them could have important public health implications. We mined the US Food and Drug Administrations (FDAs) Adverse Event Reporting System (AERS) for side‐effect profiles involving glucose homeostasis and found a surprisingly strong signal for comedication with pravastatin and paroxetine. We retrospectively evaluated changes in blood glucose in 104 patients with diabetes and 135 without diabetes who had received comedication with these two drugs, using data in electronic medical record (EMR) systems of three geographically distinct sites. We assessed the mean random blood glucose levels before and after treatment with the drugs. We found that pravastatin and paroxetine, when administered together, had a synergistic effect on blood glucose. The average increase was 19 mg/dl (1.0 mmol/l) overall, and in those with diabetes it was 48 mg/dl (2.7 mmol/l). In contrast, neither drug administered singly was associated with such changes in glucose levels. An increase in glucose levels is not a general effect of combined therapy with selective serotonin reuptake inhibitors (SSRIs) and statins.

Normalization of plasma 25-hydroxy vitamin D is associated with reduced risk of surgery in Crohn's disease.

Background:Vitamin D may have an immunologic role in Crohn’s disease (CD) and ulcerative colitis (UC). Retrospective studies suggested a weak association between vitamin D status and disease activity but have significant limitations. Methods:Using a multi-institution inflammatory bowel disease cohort, we identified all patients with CD and UC who had at least one measured plasma 25-hydroxy vitamin D (25(OH)D). Plasma 25(OH)D was considered sufficient at levels ≥30 ng/mL. Logistic regression models adjusting for potential confounders were used to identify impact of measured plasma 25(OH)D on subsequent risk of inflammatory bowel disease–related surgery or hospitalization. In a subset of patients where multiple measures of 25(OH)D were available, we examined impact of normalization of vitamin D status on study outcomes. Results:Our study included 3217 patients (55% CD; mean age, 49 yr). The median lowest plasma 25(OH)D was 26 ng/mL (interquartile range, 17–35 ng/mL). In CD, on multivariable analysis, plasma 25(OH)D <20 ng/mL was associated with an increased risk of surgery (odds ratio, 1.76; 95% confidence interval, 1.24–2.51) and inflammatory bowel disease–related hospitalization (odds ratio, 2.07; 95% confidence interval, 1.59–2.68) compared with those with 25(OH)D ≥30 ng/mL. Similar estimates were also seen for UC. Furthermore, patients with CD who had initial levels <30 ng/mL but subsequently normalized their 25(OH)D had a reduced likelihood of surgery (odds ratio, 0.56; 95% confidence interval, 0.32–0.98) compared with those who remained deficient. Conclusion:Low plasma 25(OH)D is associated with increased risk of surgery and hospitalizations in both CD and UC, and normalization of 25(OH)D status is associated with a reduction in the risk of CD-related surgery.

Portability of an algorithm to identify rheumatoid arthritis in electronic health records.

OBJECTIVES Electronic health records (EHR) can allow for the generation of large cohorts of individuals with given diseases for clinical and genomic research. A rate-limiting step is the development of electronic phenotype selection algorithms to find such cohorts. This study evaluated the portability of a published phenotype algorithm to identify rheumatoid arthritis (RA) patients from EHR records at three institutions with different EHR systems. MATERIALS AND METHODS Physicians reviewed charts from three institutions to identify patients with RA. Each institution compiled attributes from various sources in the EHR, including codified data and clinical narratives, which were searched using one of two natural language processing (NLP) systems. The performance of the published model was compared with locally retrained models. RESULTS Applying the previously published model from Partners Healthcare to datasets from Northwestern and Vanderbilt Universities, the area under the receiver operating characteristic curve was found to be 92% for Northwestern and 95% for Vanderbilt, compared with 97% at Partners. Retraining the model improved the average sensitivity at a specificity of 97% to 72% from the original 65%. Both the original logistic regression models and locally retrained models were superior to simple billing code count thresholds. DISCUSSION These results show that a previously published algorithm for RA is portable to two external hospitals using different EHR systems, different NLP systems, and different target NLP vocabularies. Retraining the algorithm primarily increased the sensitivity at each site. CONCLUSION Electronic phenotype algorithms allow rapid identification of case populations in multiple sites with little retraining.

Instrumenting the health care enterprise for discovery research in the genomic era

Tens of thousands of subjects may be required to obtain reliable evidence relating disease characteristics to the weak effects typically reported from common genetic variants. The costs of assembling, phenotyping, and studying these large populations are substantial, recently estimated at three billion dollars for 500,000 individuals. They are also decade-long efforts. We hypothesized that automation and analytic tools can repurpose the informational byproducts of routine clinical care, bringing sample acquisition and phenotyping to the same high-throughput pace and commodity price-point as is currently true of genome-wide genotyping. Described here is a demonstration of the capability to acquire samples and data from densely phenotyped and genotyped individuals in the tens of thousands for common diseases (e.g., in a 1-yr period: N = 15,798 for rheumatoid arthritis; N = 42,238 for asthma; N = 34,535 for major depressive disorder) in one academic health center at an order of magnitude lower cost. Even for rare diseases caused by rare, highly penetrant mutations such as Huntington disease (N = 102) and autism (N = 756), these capabilities are also of interest.

Genetic Basis of Autoantibody Positive and Negative Rheumatoid Arthritis Risk in a Multi-ethnic Cohort Derived from Electronic Health Records

Discovering and following up on genetic associations with complex phenotypes require large patient cohorts. This is particularly true for patient cohorts of diverse ancestry and clinically relevant subsets of disease. The ability to mine the electronic health records (EHRs) of patients followed as part of routine clinical care provides a potential opportunity to efficiently identify affected cases and unaffected controls for appropriate-sized genetic studies. Here, we demonstrate proof-of-concept that it is possible to use EHR data linked with biospecimens to establish a multi-ethnic case-control cohort for genetic research of a complex disease, rheumatoid arthritis (RA). In 1,515 EHR-derived RA cases and 1,480 controls matched for both genetic ancestry and disease-specific autoantibodies (anti-citrullinated protein antibodies [ACPA]), we demonstrate that the odds ratios and aggregate genetic risk score (GRS) of known RA risk alleles measured in individuals of European ancestry within our EHR cohort are nearly identical to those derived from a genome-wide association study (GWAS) of 5,539 autoantibody-positive RA cases and 20,169 controls. We extend this approach to other ethnic groups and identify a large overlap in the GRS among individuals of European, African, East Asian, and Hispanic ancestry. We also demonstrate that the distribution of a GRS based on 28 non-HLA risk alleles in ACPA+ cases partially overlaps with ACPA- subgroup of RA cases. Our study demonstrates that the genetic basis of rheumatoid arthritis risk is similar among cases of diverse ancestry divided into subsets based on ACPA status and emphasizes the utility of linking EHR clinical data with biospecimens for genetic studies.