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OBJECTIVE - Phenotyping algorithms applied to electronic health record (EHR) data enable investigators to identify large cohorts for clinical and genomic research. Algorithm development is often iterative, depends on fallible investigator intuition, and is time- and labor-intensive. We developed and evaluated 4 types of phenotyping algorithms and categories of EHR information to identify hypertensive individuals and controls and provide a portable module for implementation at other sites.
MATERIALS AND METHODS - We reviewed the EHRs of 631 individuals followed at Vanderbilt for hypertension status. We developed features and phenotyping algorithms of increasing complexity. Input categories included International Classification of Diseases, Ninth Revision (ICD9) codes, medications, vital signs, narrative-text search results, and Unified Medical Language System (UMLS) concepts extracted using natural language processing (NLP). We developed a module and tested portability by replicating 10 of the best-performing algorithms at the Marshfield Clinic.
RESULTS - Random forests using billing codes, medications, vitals, and concepts had the best performance with a median area under the receiver operator characteristic curve (AUC) of 0.976. Normalized sums of all 4 categories also performed well (0.959 AUC). The best non-NLP algorithm combined normalized ICD9 codes, medications, and blood pressure readings with a median AUC of 0.948. Blood pressure cutoffs or ICD9 code counts alone had AUCs of 0.854 and 0.908, respectively. Marshfield Clinic results were similar.
CONCLUSION - This work shows that billing codes or blood pressure readings alone yield good hypertension classification performance. However, even simple combinations of input categories improve performance. The most complex algorithms classified hypertension with excellent recall and precision.
© The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

We propose multi-atlas learner fusion (MLF), a framework for rapidly and accurately replicating the highly accurate, yet computationally expensive, multi-atlas segmentation framework based on fusing local learners. In the largest whole-brain multi-atlas study yet reported, multi-atlas segmentations are estimated for a training set of 3464 MR brain images. Using these multi-atlas estimates we (1) estimate a low-dimensional representation for selecting locally appropriate example images, and (2) build AdaBoost learners that map a weak initial segmentation to the multi-atlas segmentation result. Thus, to segment a new target image we project the image into the low-dimensional space, construct a weak initial segmentation, and fuse the trained, locally selected, learners. The MLF framework cuts the runtime on a modern computer from 36 h down to 3-8 min - a 270× speedup - by completely bypassing the need for deformable atlas-target registrations. Additionally, we (1) describe a technique for optimizing the weak initial segmentation and the AdaBoost learning parameters, (2) quantify the ability to replicate the multi-atlas result with mean accuracies approaching the multi-atlas intra-subject reproducibility on a testing set of 380 images, (3) demonstrate significant increases in the reproducibility of intra-subject segmentations when compared to a state-of-the-art multi-atlas framework on a separate reproducibility dataset, (4) show that under the MLF framework the large-scale data model significantly improve the segmentation over the small-scale model under the MLF framework, and (5) indicate that the MLF framework has comparable performance as state-of-the-art multi-atlas segmentation algorithms without using non-local information.
Copyright © 2015 Elsevier B.V. All rights reserved.

In clinical notes, physicians commonly describe reasons why certain treatments are given. However, this information is not typically available in a computable form. We describe a supervised learning system that is able to predict whether or not a treatment relation exists between any two medical concepts mentioned in clinical notes. To train our prediction model, we manually annotated 958 treatment relations in sentences selected from 6,864 discharge summaries. The features used to indicate the existence of a treatment relation between two medical concepts consisted of lexical and semantic information associated with the two concepts as well as information derived from the MEDication Indication (MEDI) resource and SemRep. The best F1-measure results of our supervised learning system (84.90) were significantly better than the F1-measure results achieved by SemRep (72.34).

OBJECTIVE - Data in electronic health records (EHRs) is being increasingly leveraged for secondary uses, ranging from biomedical association studies to comparative effectiveness. To perform studies at scale and transfer knowledge from one institution to another in a meaningful way, we need to harmonize the phenotypes in such systems. Traditionally, this has been accomplished through expert specification of phenotypes via standardized terminologies, such as billing codes. However, this approach may be biased by the experience and expectations of the experts, as well as the vocabulary used to describe such patients. The goal of this work is to develop a data-driven strategy to (1) infer phenotypic topics within patient populations and (2) assess the degree to which such topics facilitate a mapping across populations in disparate healthcare systems.
METHODS - We adapt a generative topic modeling strategy, based on latent Dirichlet allocation, to infer phenotypic topics. We utilize a variance analysis to assess the projection of a patient population from one healthcare system onto the topics learned from another system. The consistency of learned phenotypic topics was evaluated using (1) the similarity of topics, (2) the stability of a patient population across topics, and (3) the transferability of a topic across sites. We evaluated our approaches using four months of inpatient data from two geographically distinct healthcare systems: (1) Northwestern Memorial Hospital (NMH) and (2) Vanderbilt University Medical Center (VUMC).
RESULTS - The method learned 25 phenotypic topics from each healthcare system. The average cosine similarity between matched topics across the two sites was 0.39, a remarkably high value given the very high dimensionality of the feature space. The average stability of VUMC and NMH patients across the topics of two sites was 0.988 and 0.812, respectively, as measured by the Pearson correlation coefficient. Also the VUMC and NMH topics have smaller variance of characterizing patient population of two sites than standard clinical terminologies (e.g., ICD9), suggesting they may be more reliably transferred across hospital systems.
CONCLUSIONS - Phenotypic topics learned from EHR data can be more stable and transferable than billing codes for characterizing the general status of a patient population. This suggests that EHR-based research may be able to leverage such phenotypic topics as variables when pooling patient populations in predictive models.
Copyright © 2015 Elsevier Inc. All rights reserved.

OBJECTIVE - To evaluate the contribution of the MEDication Indication (MEDI) resource and SemRep for identifying treatment relations in clinical text.
MATERIALS AND METHODS - We first processed clinical documents with SemRep to extract the Unified Medical Language System (UMLS) concepts and the treatment relations between them. Then, we incorporated MEDI into a simple algorithm that identifies treatment relations between two concepts if they match a medication-indication pair in this resource. For a better coverage, we expanded MEDI using ontology relationships from RxNorm and UMLS Metathesaurus. We also developed two ensemble methods, which combined the predictions of SemRep and the MEDI algorithm. We evaluated our selected methods on two datasets, a Vanderbilt corpus of 6864 discharge summaries and the 2010 Informatics for Integrating Biology and the Bedside (i2b2)/Veteran's Affairs (VA) challenge dataset.
RESULTS - The Vanderbilt dataset included 958 manually annotated treatment relations. A double annotation was performed on 25% of relations with high agreement (Cohen's κ = 0.86). The evaluation consisted of comparing the manual annotated relations with the relations identified by SemRep, the MEDI algorithm, and the two ensemble methods. On the first dataset, the best F1-measure results achieved by the MEDI algorithm and the union of the two resources (78.7 and 80, respectively) were significantly higher than the SemRep results (72.3). On the second dataset, the MEDI algorithm achieved better precision and significantly lower recall values than the best system in the i2b2 challenge. The two systems obtained comparable F1-measure values on the subset of i2b2 relations with both arguments in MEDI.
CONCLUSIONS - Both SemRep and MEDI can be used to extract treatment relations from clinical text. Knowledge-based extraction with MEDI outperformed use of SemRep alone, but superior performance was achieved by integrating both systems. The integration of knowledge-based resources such as MEDI into information extraction systems such as SemRep and the i2b2 relation extractors may improve treatment relation extraction from clinical text.
© The Author 2014. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

OBJECTIVES - Drug repurposing, which finds new indications for existing drugs, has received great attention recently. The goal of our work is to assess the feasibility of using electronic health records (EHRs) and automated informatics methods to efficiently validate a recent drug repurposing association of metformin with reduced cancer mortality.
METHODS - By linking two large EHRs from Vanderbilt University Medical Center and Mayo Clinic to their tumor registries, we constructed a cohort including 32,415 adults with a cancer diagnosis at Vanderbilt and 79,258 cancer patients at Mayo from 1995 to 2010. Using automated informatics methods, we further identified type 2 diabetes patients within the cancer cohort and determined their drug exposure information, as well as other covariates such as smoking status. We then estimated HRs for all-cause mortality and their associated 95% CIs using stratified Cox proportional hazard models. HRs were estimated according to metformin exposure, adjusted for age at diagnosis, sex, race, body mass index, tobacco use, insulin use, cancer type, and non-cancer Charlson comorbidity index.
RESULTS - Among all Vanderbilt cancer patients, metformin was associated with a 22% decrease in overall mortality compared to other oral hypoglycemic medications (HR 0.78; 95% CI 0.69 to 0.88) and with a 39% decrease compared to type 2 diabetes patients on insulin only (HR 0.61; 95% CI 0.50 to 0.73). Diabetic patients on metformin also had a 23% improved survival compared with non-diabetic patients (HR 0.77; 95% CI 0.71 to 0.85). These associations were replicated using the Mayo Clinic EHR data. Many site-specific cancers including breast, colorectal, lung, and prostate demonstrated reduced mortality with metformin use in at least one EHR.
CONCLUSIONS - EHR data suggested that the use of metformin was associated with decreased mortality after a cancer diagnosis compared with diabetic and non-diabetic cancer patients not on metformin, indicating its potential as a chemotherapeutic regimen. This study serves as a model for robust and inexpensive validation studies for drug repurposing signals using EHR data.
© The Author 2014. Published by Oxford University Press on behalf of the American Medical Informatics Association.

Medical imaging analysis processes often involve the concatenation of many steps (e.g., multi-stage scripts) to integrate and realize advancements from image acquisition, image processing, and computational analysis. With the dramatic increase in data size for medical imaging studies (e.g., improved resolution, higher throughput acquisition, shared databases), interesting study designs are becoming intractable or impractical on individual workstations and servers. Modern pipeline environments provide control structures to distribute computational load in high performance computing (HPC) environments. However, high performance computing environments are often shared resources, and scheduling computation across these resources necessitates higher level modeling of resource utilization. Submission of 'jobs' requires an estimate of the CPU runtime and memory usage. The resource requirements for medical image processing algorithms are difficult to predict since the requirements can vary greatly between different machines, different execution instances, and different data inputs. Poor resource estimates can lead to wasted resources in high performance environments due to incomplete executions and extended queue wait times. Hence, resource estimation is becoming a major hurdle for medical image processing algorithms to efficiently leverage high performance computing environments. Herein, we present our implementation of a resource estimation system to overcome these difficulties and ultimately provide users with the ability to more efficiently utilize high performance computing resources.

Deep venous thrombosis and pulmonary embolism are diseases associated with significant morbidity and mortality. Known risk factors are attributed for only slight majority of venous thromboembolic disease (VTE) with the remainder of risk presumably related to unidentified genetic factors. We designed a general purpose Natural Language (NLP) algorithm to retrospectively capture both acute and historical cases of thromboembolic disease in a de-identified electronic health record. Applying the NLP algorithm to a separate evaluation set found a positive predictive value of 84.7% and sensitivity of 95.3% for an F-measure of 0.897, which was similar to the training set of 0.925. Use of the same algorithm on problem lists only in patients without VTE ICD-9s was found to be the best means of capturing historical cases with a PPV of 83%. NLP of VTE ICD-9 positive cases and non-ICD-9 positive problem lists provides an effective means for capture of both acute and historical cases of venous thromboembolic disease.

In shotgun proteomics, database search algorithms rely on fragmentation models to predict fragment ions that should be observed for a given peptide sequence. The most widely used strategy (Naive model) is oversimplified, cleaving all peptide bonds with equal probability to produce fragments of all charges below that of the precursor ion. More accurate models, based on fragmentation simulation, are too computationally intensive for on-the-fly use in database search algorithms. We have created an ordinal-regression-based model called Basophile that takes fragment size and basic residue distribution into account when determining the charge retention during CID/higher-energy collision induced dissociation (HCD) of charged peptides. This model improves the accuracy of predictions by reducing the number of unnecessary fragments that are routinely predicted for highly-charged precursors. Basophile increased the identification rates by 26% (on average) over the Naive model, when analyzing triply-charged precursors from ion trap data. Basophile achieves simplicity and speed by solving the prediction problem with an ordinal regression equation, which can be incorporated into any database search software for shotgun proteomic identification.
Copyright © 2013. Production and hosting by Elsevier Ltd.

The combination of improved genomic analysis methods, decreasing genotyping costs, and increasing computing resources has led to an explosion of clinical genomic knowledge in the last decade. Similarly, healthcare systems are increasingly adopting robust electronic health record (EHR) systems that not only can improve health care, but also contain a vast repository of disease and treatment data that could be mined for genomic research. Indeed, institutions are creating EHR-linked DNA biobanks to enable genomic and pharmacogenomic research, using EHR data for phenotypic information. However, EHRs are designed primarily for clinical care, not research, so reuse of clinical EHR data for research purposes can be challenging. Difficulties in use of EHR data include: data availability, missing data, incorrect data, and vast quantities of unstructured narrative text data. Structured information includes billing codes, most laboratory reports, and other variables such as physiologic measurements and demographic information. Significant information, however, remains locked within EHR narrative text documents, including clinical notes and certain categories of test results, such as pathology and radiology reports. For relatively rare observations, combinations of simple free-text searches and billing codes may prove adequate when followed by manual chart review. However, to extract the large cohorts necessary for genome-wide association studies, natural language processing methods to process narrative text data may be needed. Combinations of structured and unstructured textual data can be mined to generate high-validity collections of cases and controls for a given condition. Once high-quality cases and controls are identified, EHR-derived cases can be used for genomic discovery and validation. Since EHR data includes a broad sampling of clinically-relevant phenotypic information, it may enable multiple genomic investigations upon a single set of genotyped individuals. This chapter reviews several examples of phenotype extraction and their application to genetic research, demonstrating a viable future for genomic discovery using EHR-linked data.