MACE: model based analysis of ChIP-exo.

Understanding the role of a given transcription factor (TF) in regulating gene expression requires precise mapping of its binding sites in the genome. Chromatin immunoprecipitation-exo, an emerging technique using λ exonuclease to digest TF unbound DNA after ChIP, is designed to reveal transcription factor binding site (TFBS) boundaries with near-single nucleotide resolution. Although ChIP-exo promises deeper insights into transcription regulation, no dedicated bioinformatics tool exists to leverage its advantages. Most ChIP-seq and ChIP-chip analytic methods are not tailored for ChIP-exo, and thus cannot take full advantage of high-resolution ChIP-exo data. Here we describe a novel analysis framework, termed MACE (model-based analysis of ChIP-exo) dedicated to ChIP-exo data analysis. The MACE workflow consists of four steps: (i) sequencing data normalization and bias correction; (ii) signal consolidation and noise reduction; (iii) single-nucleotide resolution border peak detection using the Chebyshev Inequality and (iv) border matching using the Gale-Shapley stable matching algorithm. When applied to published human CTCF, yeast Reb1 and our own mouse ONECUT1/HNF6 ChIP-exo data, MACE is able to define TFBSs with high sensitivity, specificity and spatial resolution, as evidenced by multiple criteria including motif enrichment, sequence conservation, direct sequence pileup, nucleosome positioning and open chromatin states. In addition, we show that the fundamental advance of MACE is the identification of two boundaries of a TFBS with high resolution, whereas other methods only report a single location of the same event. The two boundaries help elucidate the in vivo binding structure of a given TF, e.g. whether the TF may bind as dimers or in a complex with other co-factors.

Tracking health disparities through natural-language processing.

Health disparities and solutions are heterogeneous within and among racial and ethnic groups, yet existing administrative databases lack the granularity to reflect important sociocultural distinctions. We measured the efficacy of a natural-language-processing algorithm to identify a specific immigrant group. The algorithm demonstrated accuracy and precision in identifying Somali patients from the electronic medical records at a single institution. This technology holds promise to identify and track immigrants and refugees in the United States in local health care settings.

Automated chart review for asthma cohort identification using natural language processing: an exploratory study.

BACKGROUND: A significant proportion of children with asthma have delayed diagnosis of asthma by health care providers. Manual chart review according to established criteria is more accurate than directly using diagnosis codes, which tend to under-identify asthmatics, but chart reviews are more costly and less timely. OBJECTIVE: To evaluate the accuracy of a computational approach to asthma ascertainment, characterizing its utility and feasibility toward large-scale deployment in electronic medical records. METHODS: A natural language processing (NLP) system was developed for extracting predetermined criteria for asthma from unstructured text in electronic medical records and then inferring asthma status based on these criteria. Using manual chart reviews as a gold standard, asthma status (yes vs no) and identification date (first date of a "yes" asthma status) were determined by the NLP system. RESULTS: Patients were a group of children (n = 112, 84% Caucasian, 49% girls) younger than 4 years (mean 2.0 years, standard deviation 1.03 years) who participated in previous studies. The NLP approach to asthma ascertainment showed sensitivity, specificity, positive predictive value, negative predictive value, and median delay in diagnosis of 84.6%, 96.5%, 88.0%, 95.4%, and 0 months, respectively; this compared favorably with diagnosis codes, at 30.8%, 93.2%, 57.1%, 82.2%, and 2.3 months, respectively. CONCLUSION: Automated asthma ascertainment from electronic medical records using NLP is feasible and more accurate than traditional approaches such as diagnosis codes. Considering the difficulty of labor-intensive manual record review, NLP approaches for asthma ascertainment should be considered for improving clinical care and research, especially in large-scale efforts.

Patient-level temporal aggregation for text-based asthma status ascertainment.

OBJECTIVE: To specify the problem of patient-level temporal aggregation from clinical text and introduce several probabilistic methods for addressing that problem. The patient-level perspective differs from the prevailing natural language processing (NLP) practice of evaluating at the term, event, sentence, document, or visit level. METHODS: We utilized an existing pediatric asthma cohort with manual annotations. After generating a basic feature set via standard clinical NLP methods, we introduce six methods of aggregating time-distributed features from the document level to the patient level. These aggregation methods are used to classify patients according to their asthma status in two hypothetical settings: retrospective epidemiology and clinical decision support. RESULTS: In both settings, solid patient classification performance was obtained with machine learning algorithms on a number of evidence aggregation methods, with Sum aggregation obtaining the highest F1 score of 85.71% on the retrospective epidemiological setting, and a probability density function-based method obtaining the highest F1 score of 74.63% on the clinical decision support setting. Multiple techniques also estimated the diagnosis date (index date) of asthma with promising accuracy. DISCUSSION: The clinical decision support setting is a more difficult problem. We rule out some aggregation methods rather than determining the best overall aggregation method, since our preliminary data set represented a practical setting in which manually annotated data were limited. CONCLUSION: Results contrasted the strengths of several aggregation algorithms in different settings. Multiple approaches exhibited good patient classification performance, and also predicted the timing of estimates with reasonable accuracy.

Open Source Clinical NLP - More than Any Single System.

The number of Natural Language Processing (NLP) tools and systems for processing clinical free-text has grown as interest and processing capability have surged. Unfortunately any two systems typically cannot simply interoperate, even when both are built upon a framework designed to facilitate the creation of pluggable components. We present two ongoing activities promoting open source clinical NLP. The Open Health Natural Language Processing (OHNLP) Consortium was originally founded to foster a collaborative community around clinical NLP, releasing UIMA-based open source software. OHNLP's mission currently includes maintaining a catalog of clinical NLP software and providing interfaces to simplify the interaction of NLP systems. Meanwhile, Apache cTAKES aims to integrate best-of-breed annotators, providing a world-class NLP system for accessing clinical information within free-text. These two activities are complementary. OHNLP promotes open source clinical NLP activities in the research community and Apache cTAKES bridges research to the health information technology (HIT) practice.

A common type system for clinical natural language processing.

BACKGROUND: One challenge in reusing clinical data stored in electronic medical records is that these data are heterogenous. Clinical Natural Language Processing (NLP) plays an important role in transforming information in clinical text to a standard representation that is comparable and interoperable. Information may be processed and shared when a type system specifies the allowable data structures. Therefore, we aim to define a common type system for clinical NLP that enables interoperability between structured and unstructured data generated in different clinical settings. RESULTS: We describe a common type system for clinical NLP that has an end target of deep semantics based on Clinical Element Models (CEMs), thus interoperating with structured data and accommodating diverse NLP approaches. The type system has been implemented in UIMA (Unstructured Information Management Architecture) and is fully functional in a popular open-source clinical NLP system, cTAKES (clinical Text Analysis and Knowledge Extraction System) versions 2.0 and later. CONCLUSIONS: We have created a type system that targets deep semantics, thereby allowing for NLP systems to encapsulate knowledge from text and share it alongside heterogenous clinical data sources. Rather than surface semantics that are typically the end product of NLP algorithms, CEM-based semantics explicitly build in deep clinical semantics as the point of interoperability with more structured data types.

Analysis of cross-institutional medication description patterns in clinical narratives.

A large amount of medication information resides in the unstructured text found in electronic medical records, which requires advanced techniques to be properly mined. In clinical notes, medication information follows certain semantic patterns (eg, medication, dosage, frequency, and mode). Some medication descriptions contain additional word(s) between medication attributes. Therefore, it is essential to understand the semantic patterns as well as the patterns of the context interspersed among them (ie, context patterns) to effectively extract comprehensive medication information. In this paper we examined both semantic and context patterns, and compared those found in Mayo Clinic and i2b2 challenge data. We found that some variations exist between the institutions but the dominant patterns are common.

An information extraction framework for cohort identification using electronic health records.

Information extraction (IE), a natural language processing (NLP) task that automatically extracts structured or semi-structured information from free text, has become popular in the clinical domain for supporting automated systems at point-of-care and enabling secondary use of electronic health records (EHRs) for clinical and translational research. However, a high performance IE system can be very challenging to construct due to the complexity and dynamic nature of human language. In this paper, we report an IE framework for cohort identification using EHRs that is a knowledge-driven framework developed under the Unstructured Information Management Architecture (UIMA). A system to extract specific information can be developed by subject matter experts through expert knowledge engineering of the externalized knowledge resources used in the framework.

Towards a semantic lexicon for clinical natural language processing.

A semantic lexicon which associates words and phrases in text to concepts is critical for extracting and encoding clinical information in free text and therefore achieving semantic interoperability between structured and unstructured data in Electronic Health Records (EHRs). Directly using existing standard terminologies may have limited coverage with respect to concepts and their corresponding mentions in text. In this paper, we analyze how tokens and phrases in a large corpus distribute and how well the UMLS captures the semantics. A corpus-driven semantic lexicon, MedLex, has been constructed where the semantics is based on the UMLS assisted with variants mined and usage information gathered from clinical text. The detailed corpus analysis of tokens, chunks, and concept mentions shows the UMLS is an invaluable source for natural language processing. Increasing the semantic coverage of tokens provides a good foundation in capturing clinical information comprehensively. The study also yields some insights in developing practical NLP systems.

Unified Medical Language System term occurrences in clinical notes: a large-scale corpus analysis.

OBJECTIVE: To characterise empirical instances of Unified Medical Language System (UMLS) Metathesaurus term strings in a large clinical corpus, and to illustrate what types of term characteristics are generalisable across data sources. DESIGN: Based on the occurrences of UMLS terms in a 51 million document corpus of Mayo Clinic clinical notes, this study computes statistics about the terms' string attributes, source terminologies, semantic types and syntactic categories. Term occurrences in 2010 i2b2/VA text were also mapped; eight example filters were designed from the Mayo-based statistics and applied to i2b2/VA data. RESULTS: For the corpus analysis, negligible numbers of mapped terms in the Mayo corpus had over six words or 55 characters. Of source terminologies in the UMLS, the Consumer Health Vocabulary and Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT) had the best coverage in Mayo clinical notes at 106426 and 94788 unique terms, respectively. Of 15 semantic groups in the UMLS, seven groups accounted for 92.08% of term occurrences in Mayo data. Syntactically, over 90% of matched terms were in noun phrases. For the cross-institutional analysis, using five example filters on i2b2/VA data reduces the actual lexicon to 19.13% of the size of the UMLS and only sees a 2% reduction in matched terms. CONCLUSION: The corpus statistics presented here are instructive for building lexicons from the UMLS. Features intrinsic to Metathesaurus terms (well formedness, length and language) generalise easily across clinical institutions, but term frequencies should be adapted with caution. The semantic groups of mapped terms may differ slightly from institution to institution, but they differ greatly when moving to the biomedical literature domain.