Adler J. Perotte

NONCONVULSIVE SEIZURES AFTER SUBARACHNOID HEMORRHAGE: MULTIMODAL DETECTION AND OUTCOMES

Seizures have been implicated as a cause of secondary brain injury, but the systemic and cerebral physiologic effects of seizures after acute brain injury are poorly understood.

A collaborative approach to developing an electronic health record phenotyping algorithm for drug-induced liver injury

OBJECTIVE To describe a collaborative approach for developing an electronic health record (EHR) phenotyping algorithm for drug-induced liver injury (DILI). METHODS We analyzed types and causes of differences in DILI case definitions provided by two institutions-Columbia University and Mayo Clinic; harmonized two EHR phenotyping algorithms; and assessed the performance, measured by sensitivity, specificity, positive predictive value, and negative predictive value, of the resulting algorithm at three institutions except that sensitivity was measured only at Columbia University. RESULTS Although these sites had the same case definition, their phenotyping methods differed by selection of liver injury diagnoses, inclusion of drugs cited in DILI cases, laboratory tests assessed, laboratory thresholds for liver injury, exclusion criteria, and approaches to validating phenotypes. We reached consensus on a DILI phenotyping algorithm and implemented it at three institutions. The algorithm was adapted locally to account for differences in populations and data access. Implementations collectively yielded 117 algorithm-selected cases and 23 confirmed true positive cases. DISCUSSION Phenotyping for rare conditions benefits significantly from pooling data across institutions. Despite the heterogeneity of EHRs and varied algorithm implementations, we demonstrated the portability of this algorithm across three institutions. The performance of this algorithm for identifying DILI was comparable with other computerized approaches to identify adverse drug events. CONCLUSIONS Phenotyping algorithms developed for rare and complex conditions are likely to require adaptive implementation at multiple institutions. Better approaches are also needed to share algorithms. Early agreement on goals, data sources, and validation methods may improve the portability of the algorithms.

Diagnosis code assignment: models and evaluation metrics

Background and objective The volume of healthcare data is growing rapidly with the adoption of health information technology. We focus on automated ICD9 code assignment from discharge summary content and methods for evaluating such assignments. Methods We study ICD9 diagnosis codes and discharge summaries from the publicly available Multiparameter Intelligent Monitoring in Intensive Care II (MIMIC II) repository. We experiment with two coding approaches: one that treats each ICD9 code independently of each other (flat classifier), and one that leverages the hierarchical nature of ICD9 codes into its modeling (hierarchy-based classifier). We propose novel evaluation metrics, which reflect the distances among gold-standard and predicted codes and their locations in the ICD9 tree. Experimental setup, code for modeling, and evaluation scripts are made available to the research community. Results The hierarchy-based classifier outperforms the flat classifier with F-measures of 39.5% and 27.6%, respectively, when trained on 20 533 documents and tested on 2282 documents. While recall is improved at the expense of precision, our novel evaluation metrics show a more refined assessment: for instance, the hierarchy-based classifier identifies the correct sub-tree of gold-standard codes more often than the flat classifier. Error analysis reveals that gold-standard codes are not perfect, and as such the recall and precision are likely underestimated. Conclusions Hierarchy-based classification yields better ICD9 coding than flat classification for MIMIC patients. Automated ICD9 coding is an example of a task for which data and tools can be shared and for which the research community can work together to build on shared models and advance the state of the art.

Characterizing treatment pathways at scale using the OHDSI network

Observational research promises to complement experimental research by providing large, diverse populations that would be infeasible for an experiment. Observational research can test its own clinical hypotheses, and observational studies also can contribute to the design of experiments and inform the generalizability of experimental research. Understanding the diversity of populations and the variance in care is one component. In this study, the Observational Health Data Sciences and Informatics (OHDSI) collaboration created an international data network with 11 data sources from four countries, including electronic health records and administrative claims data on 250 million patients. All data were mapped to common data standards, patient privacy was maintained by using a distributed model, and results were aggregated centrally. Treatment pathways were elucidated for type 2 diabetes mellitus, hypertension, and depression. The pathways revealed that the world is moving toward more consistent therapy over time across diseases and across locations, but significant heterogeneity remains among sources, pointing to challenges in generalizing clinical trial results. Diabetes favored a single first-line medication, metformin, to a much greater extent than hypertension or depression. About 10% of diabetes and depression patients and almost 25% of hypertension patients followed a treatment pathway that was unique within the cohort. Aside from factors such as sample size and underlying population (academic medical center versus general population), electronic health records data and administrative claims data revealed similar results. Large-scale international observational research is feasible.

Parameterizing time in electronic health record studies

Abstract Background Fields like nonlinear physics offer methods for analyzing time series, but many methods require that the time series be stationary—no change in properties over time. Objective Medicine is far from stationary, but the challenge may be able to be ameliorated by reparameterizing time because clinicians tend to measure patients more frequently when they are ill and are more likely to vary. Methods We compared time parameterizations, measuring variability of rate of change and magnitude of change, and looking for homogeneity of bins of temporal separation between pairs of time points. We studied four common laboratory tests drawn from 25 years of electronic health records on 4 million patients. Results We found that sequence time—that is, simply counting the number of measurements from some start—produced more stationary time series, better explained the variation in values, and had more homogeneous bins than either traditional clock time or a recently proposed intermediate parameterization. Sequence time produced more accurate predictions in a single Gaussian process model experiment. Conclusions Of the three parameterizations, sequence time appeared to produce the most stationary series, possibly because clinicians adjust their sampling to the acuity of the patient. Parameterizing by sequence time may be applicable to association and clustering experiments on electronic health record data. A limitation of this study is that laboratory data were derived from only one institution. Sequence time appears to be an important potential parameterization.

Risk prediction for chronic kidney disease progression using heterogeneous electronic health record data and time series analysis.

Abstract Background As adoption of electronic health records continues to increase, there is an opportunity to incorporate clinical documentation as well as laboratory values and demographics into risk prediction modeling. Objective The authors develop a risk prediction model for chronic kidney disease (CKD) progression from stage III to stage IV that includes longitudinal data and features drawn from clinical documentation. Methods The study cohort consisted of 2908 primary-care clinic patients who had at least three visits prior to January 1, 2013 and developed CKD stage III during their documented history. Development and validation cohorts were randomly selected from this cohort and the study datasets included longitudinal inpatient and outpatient data from these populations. Time series analysis (Kalman filter) and survival analysis (Cox proportional hazards) were combined to produce a range of risk models. These models were evaluated using concordance, a discriminatory statistic. Results A risk model incorporating longitudinal data on clinical documentation and laboratory test results (concordance 0.849) predicts progression from state III CKD to stage IV CKD more accurately when compared to a similar model without laboratory test results (concordance 0.733, P<.001), a model that only considers the most recent laboratory test results (concordance 0.819, P < .031) and a model based on estimated glomerular filtration rate (concordance 0.779, P < .001). Conclusions A risk prediction model that takes longitudinal laboratory test results and clinical documentation into consideration can predict CKD progression from stage III to stage IV more accurately than three models that do not take all of these variables into consideration.

Temporal Properties of Diagnosis Code Time Series in Aggregate

Time series are essential to health data research and data mining. We aim to study the properties of one of the more commonly available but historically unreliable types of data: administrative diagnoses in the form of the International Classification of Diseases, Ninth Revision (ICD9) codes. We use differential entropy of ICD9 code time series as a surrogate measure for disease time course and also explore Gaussian kernel smoothing to characterize the time course of diseases in a more fine-grained way. Compared to a gold standard created by a panel of clinicians, the first model classified diseases into acute and chronic groups with a receiver operating characteristic area under curve of 0.83. In the second model, several characteristic temporal profiles were observed including permanent, chronic, and acute. In addition, condition dynamics such as the refractory period for giving birth following childbirth were observed. These models demonstrate that ICD9 codes, despite well-documented concerns, contain valid and potentially valuable temporal information.

Dynamical Phenotyping: Using Temporal Analysis of Clinically Collected Physiologic Data to Stratify Populations

Using glucose time series data from a well measured population drawn from an electronic health record (EHR) repository, the variation in predictability of glucose values quantified by the time-delayed mutual information (TDMI) was explained using a mechanistic endocrine model and manual and automated review of written patient records. The results suggest that predictability of glucose varies with health state where the relationship (e.g., linear or inverse) depends on the source of the acuity. It was found that on a fine scale in parameter variation, the less insulin required to process glucose, a condition that correlates with good health, the more predictable glucose values were. Nevertheless, the most powerful effect on predictability in the EHR subpopulation was the presence or absence of variation in health state, specifically, in- and out-of-control glucose versus in-control glucose. Both of these results are clinically and scientifically relevant because the magnitude of glucose is the most commonly used indicator of health as opposed to glucose dynamics, thus providing for a connection between a mechanistic endocrine model and direct insight to human health via clinically collected data.

Elevated GM3 plasma concentration in idiopathic Parkinson’s disease: A lipidomic analysis

Parkinson’s disease (PD) is a common neurodegenerative disease whose pathological hallmark is the accumulation of intracellular α-synuclein aggregates in Lewy bodies. Lipid metabolism dysregulation may play a significant role in PD pathogenesis; however, large plasma lipidomic studies in PD are lacking. In the current study, we analyzed the lipidomic profile of plasma obtained from 150 idiopathic PD patients and 100 controls, taken from the ‘Spot’ study at Columbia University Medical Center in New York. Our mass spectrometry based analytical panel consisted of 520 lipid species from 39 lipid subclasses including all major classes of glycerophospholipids, sphingolipids, glycerolipids and sterols. Each lipid species was analyzed using a logistic regression model. The plasma concentrations of two lipid subclasses, triglycerides and monosialodihexosylganglioside (GM3), were different between PD and control participants. GM3 ganglioside concentration had the most significant difference between PD and controls (1.531±0.037 pmol/μl versus 1.337±0.040 pmol/μl respectively; p-value = 5.96E-04; q-value = 0.048; when normalized to total lipid: p-value = 2.890E-05; q-value = 2.933E-03). Next, we used a collection of 20 GM3 and glucosylceramide (GlcCer) species concentrations normalized to total lipid to perform a ROC curve analysis, and found that these lipids compare favorably with biomarkers reported in previous studies (AUC = 0.742 for males, AUC = 0.644 for females). Our results suggest that higher plasma GM3 levels are associated with PD. GM3 lies in the same glycosphingolipid metabolic pathway as GlcCer, a substrate of the enzyme glucocerebrosidase, which has been associated with PD. These findings are consistent with previous reports implicating lower glucocerebrosidase activity with PD risk.

Vulnerable atherosclerotic plaque detection by resonance Raman spectroscopy

Abstract. A clear correlation has been observed between the resonance Raman (RR) spectra of plaques in the aortic tunica intimal wall of a human corpse and three states of plaque evolution: fibrolipid plaques, calcified and ossified plaques, and vulnerable atherosclerotic plaques (VPs). These three states of atherosclerotic plaque lesions demonstrated unique RR molecular fingerprints from key molecules, rendering their spectra unique with respect to one another. The vibrational modes of lipids, cholesterol, carotenoids, tryptophan and heme proteins, the amide I, II, III bands, and methyl/methylene groups from the intrinsic atherosclerotic VPs in tissues were studied. The salient outcome of the investigation was demonstrating the correlation between RR measurements of VPs and the thickness measurements of fibrous caps on VPs using standard histopathology methods, an important metric in evaluating the stability of a VP. The RR results show that VPs undergo a structural change when their caps thin to 66  μm, very close to the 65-μm empirical medical definition of a thin cap fibroatheroma plaque, the most unstable type of VP.