On Path to Informing Hierarchy of Eplet Mismatches as Determinants of Kidney Transplant Loss.

INTRODUCTION: To mitigate risks related to human leukocyte antigen (HLA) incompatibility, we assessed whether certain structurally defined HLA targets present in donors but absent from recipients, known as eplet mismatches (EMM), are associated with death-censored graft failure (DCGF). METHODS: We studied a cohort of 118,313 American 0% panel reactive antibodies (PRA) first kidney transplant recipients (2000 to 2015) from the Scientific Registry of Transplant Recipients. Imputed allele-level donor and recipient HLA-A, -B, -C, -DRB1, and -DQB1 genotypes were converted to the repertoire of EMM. We fit survival models for each EMM with significance thresholds corrected for false discovery rate and validated those in an independent PRA > 0% cohort. We conducted network-based analyses to model relationships among EMM and developed models to select the subset of EMM most predictive of DCGF. RESULTS: Of 412 EMM observed, 119 class I and 118 class II EMM were associated with DCGF. Network analysis showed that although 210 eplets formed profiles of 2 to 12 simultaneously occurring EMMs, 202 were singleton EMMs that were not involved in any profile. A variable selection procedure identified 55 single HLA class I and II EMMs in 70% of the dataset; of those, 15 EMMs (9 singleton and 6 involved in profiles) were predictive of DCGF in the remaining dataset. CONCLUSION: Our analysis distinguished increasingly smaller subsets of EMMs associated with increased risk of DCGF. Validation of these EMMs as important predictors of transplant outcomes (in contrast to acceptable EMMs) in datasets with measured allele-level genotypes will support their role as immunodominant EMMs worthy of consideration in organ allocation schemes.

Matchmaker, matchmaker make me a match: Opportunities and challenges in optimizing compatibility of HLA eplets in transplantation.

The development of donor-specific antibodies (DSAs) is a major complication in transplantation, which is associated with inferior graft survival, impaired quality of life, and increased healthcare costs. DSA develop upon recognition of nonself HLA by the recipient's immune system. HLA molecules contain epitopes, which are the surface regions of HLA molecules recognized by antibodies. HLAMatchmaker is an algorithm for assessing donor:recipient HLA compatibility at the level of structurally defined HLA targets called eplets. The consideration of eplets, rather than the whole HLA molecule, could offer some advantages when classifying the immune risk associated with particular donor:recipient pairs. Assessing compatibility at the level of HLA eplets could decrease misclassification of post-transplant immune risk by improving specificity, when antibodies are confirmed to be directed against donor eplets missing from the recipient's repertoire of eplets. Consideration of eplets may also increase the sensitivity of immune risk assessment, when identifying mismatched eplets that could give rise to new, not previously detected, donor-specific antibodies post-transplant. Eplet matching can serve as a rational strategy for immune risk mitigation. Herein, we review the evolution of HLA (in) compatibility assessment for organ allocation. We outline challenges in the implementation of eplet-based donor:recipient matching, including unavailability of allele-level donor genotypes for 11 HLA loci at the time of organ allocation and difficulty in assessing the hierarchy of immune risk associated with particular HLA eplet mismatches. Opportunities to address some of the current shortcomings of donor genotyping and HLAMatchmaker are also discussed. While there is a demonstrated benefit in the application of HLAMatchmaker for donor: recipient HLA (in)compatibility assessment, evolving long-read genotyping methods, compilation of large data sets with allele-level genotypes, and standardization of methods to verify eplets as determinants of immune-mediated injuries are required before HLA eplet matching is implemented in organ allocation to improve upon transplant outcomes.

Correction: Using Natural Language Processing to Examine the Uptake, Content, and Readability of Media Coverage of a Pan-Canadian Drug Safety Research Project: Cross-Sectional Observational Study.

[This corrects the article DOI: 10.2196/13296.].

Using Natural Language Processing to Examine the Uptake, Content, and Readability of Media Coverage of a Pan-Canadian Drug Safety Research Project: Cross-Sectional Observational Study.

BACKGROUND: Isotretinoin, for treating cystic acne, increases the risk of miscarriage and fetal abnormalities when taken during pregnancy. The Health Canada-approved product monograph for isotretinoin includes pregnancy prevention guidelines. A recent study by the Canadian Network for Observational Drug Effect Studies (CNODES) on the occurrence of pregnancy and pregnancy outcomes during isotretinoin therapy estimated poor adherence to these guidelines. Media uptake of this study was unknown; awareness of this uptake could help improve drug safety communication. OBJECTIVE: The aim of this study was to understand how the media present pharmacoepidemiological research using the CNODES isotretinoin study as a case study. METHODS: Google News was searched (April 25-May 6, 2016), using a predefined set of terms, for mention of the CNODES study. In total, 26 articles and 3 CNODES publications (original article, press release, and podcast) were identified. The article texts were cleaned (eg, advertisements and links removed), and the podcast was transcribed. A dictionary of 1295 unique words was created using natural language processing (NLP) techniques (term frequency-inverse document frequency, Porter stemming, and stop-word filtering) to identify common words and phrases. Similarity between the articles and reference publications was calculated using Euclidian distance; articles were grouped using hierarchical agglomerative clustering. Nine readability scales were applied to measure text readability based on factors such as number of words, difficult words, syllables, sentence counts, and other textual metrics. RESULTS: The top 5 dictionary words were pregnancy (250 appearances), isotretinoin (220), study (209), drug (201), and women (185). Three distinct clusters were identified: Clusters 2 (5 articles) and 3 (4 articles) were from health-related websites and media, respectively; Cluster 1 (18 articles) contained largely media sources; 2 articles fell outside these clusters. Use of the term isotretinoin versus Accutane (a brand name of isotretinoin), discussion of pregnancy complications, and assignment of responsibility for guideline adherence varied between clusters. For example, the term pregnanc appeared most often in Clusters 1 (14.6 average times per article) and 2 (11.4) and relatively infrequently in Cluster 3 (1.8). Average readability for all articles was high (eg, Flesch-Kincaid, 13; Gunning Fog, 15; SMOG Index, 10; Coleman Liau Index, 15; Linsear Write Index, 13; and Text Standard, 13). Readability increased from Cluster 2 (Gunning Fog of 16.9) to 3 (12.2). It varied between clusters (average 13th-15th grade) but exceeded the recommended health information reading level (grade 6th to 8th), overall. CONCLUSIONS: Media interpretation of the CNODES study varied, with differences in synonym usage and areas of focus. All articles were written above the recommended health information reading level. Analyzing media using NLP techniques can help determine drug safety communication effectiveness. This project is important for understanding how drug safety studies are taken up and redistributed in the media.

Semantics-based plausible reasoning to extend the knowledge coverage of medical knowledge bases for improved clinical decision support.

BACKGROUND: Capturing complete medical knowledge is challenging-often due to incomplete patient Electronic Health Records (EHR), but also because of valuable, tacit medical knowledge hidden away in physicians' experiences. To extend the coverage of incomplete medical knowledge-based systems beyond their deductive closure, and thus enhance their decision-support capabilities, we argue that innovative, multi-strategy reasoning approaches should be applied. In particular, plausible reasoning mechanisms apply patterns from human thought processes, such as generalization, similarity and interpolation, based on attributional, hierarchical, and relational knowledge. Plausible reasoning mechanisms include inductive reasoning, which generalizes the commonalities among the data to induce new rules, and analogical reasoning, which is guided by data similarities to infer new facts. By further leveraging rich, biomedical Semantic Web ontologies to represent medical knowledge, both known and tentative, we increase the accuracy and expressivity of plausible reasoning, and cope with issues such as data heterogeneity, inconsistency and interoperability. In this paper, we present a Semantic Web-based, multi-strategy reasoning approach, which integrates deductive and plausible reasoning and exploits Semantic Web technology to solve complex clinical decision support queries. RESULTS: We evaluated our system using a real-world medical dataset of patients with hepatitis, from which we randomly removed different percentages of data (5%, 10%, 15%, and 20%) to reflect scenarios with increasing amounts of incomplete medical knowledge. To increase the reliability of the results, we generated 5 independent datasets for each percentage of missing values, which resulted in 20 experimental datasets (in addition to the original dataset). The results show that plausibly inferred knowledge extends the coverage of the knowledge base by, on average, 2%, 7%, 12%, and 16% for datasets with, respectively, 5%, 10%, 15%, and 20% of missing values. This expansion in the KB coverage allowed solving complex disease diagnostic queries that were previously unresolvable, without losing the correctness of the answers. However, compared to deductive reasoning, data-intensive plausible reasoning mechanisms yield a significant performance overhead. CONCLUSIONS: We observed that plausible reasoning approaches, by generating tentative inferences and leveraging domain knowledge of experts, allow us to extend the coverage of medical knowledge bases, resulting in improved clinical decision support. Second, by leveraging OWL ontological knowledge, we are able to increase the expressivity and accuracy of plausible reasoning methods. Third, our approach is applicable to clinical decision support systems for a range of chronic diseases.