A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk.

Although countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. By mining the medical records of over 110 million patients, we examine the extent to which Mendelian variation contributes to complex disease risk. We detect thousands of associations between Mendelian and complex diseases, revealing a nondegenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated with complex diseases are enriched in the genes indicated by this "Mendelian code." Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute nonadditively to the risk for a subset of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases.

Is the crowd better as an assistant or a replacement in ontology engineering? An exploration through the lens of the Gene Ontology.

Biomedical ontologies contain errors. Crowdsourcing, defined as taking a job traditionally performed by a designated agent and outsourcing it to an undefined large group of people, provides scalable access to humans. Therefore, the crowd has the potential to overcome the limited accuracy and scalability found in current ontology quality assurance approaches. Crowd-based methods have identified errors in SNOMED CT, a large, clinical ontology, with an accuracy similar to that of experts, suggesting that crowdsourcing is indeed a feasible approach for identifying ontology errors. This work uses that same crowd-based methodology, as well as a panel of experts, to verify a subset of the Gene Ontology (200 relationships). Experts identified 16 errors, generally in relationships referencing acids and metals. The crowd performed poorly in identifying those errors, with an area under the receiver operating characteristic curve ranging from 0.44 to 0.73, depending on the methods configuration. However, when the crowd verified what experts considered to be easy relationships with useful definitions, they performed reasonably well. Notably, there are significantly fewer Google search results for Gene Ontology concepts than SNOMED CT concepts. This disparity may account for the difference in performance - fewer search results indicate a more difficult task for the worker. The number of Internet search results could serve as a method to assess which tasks are appropriate for the crowd. These results suggest that the crowd fits better as an expert assistant, helping experts with their verification by completing the easy tasks and allowing experts to focus on the difficult tasks, rather than an expert replacement.

Interpretation of biological experiments changes with evolution of the Gene Ontology and its annotations.

Gene Ontology (GO) enrichment analysis is ubiquitously used for interpreting high throughput molecular data and generating hypotheses about underlying biological phenomena of experiments. However, the two building blocks of this analysis - the ontology and the annotations - evolve rapidly. We used gene signatures derived from 104 disease analyses to systematically evaluate how enrichment analysis results were affected by evolution of the GO over a decade. We found low consistency between enrichment analyses results obtained with early and more recent GO versions. Furthermore, there continues to be a strong annotation bias in the GO annotations where 58% of the annotations are for 16% of the human genes. Our analysis suggests that GO evolution may have affected the interpretation and possibly reproducibility of experiments over time. Hence, researchers must exercise caution when interpreting GO enrichment analyses and should reexamine previous analyses with the most recent GO version.

Using description logics to evaluate the consistency of drug-class membership relations in NDF-RT.

BACKGROUND: The NDF-RT (National Drug File Reference Terminology) is an ontology, which describes drugs and their properties and supports computerized physician order entry systems. NDF-RT's classes are mostly specified using only necessary conditions and lack sufficient conditions, making its use limited until recently, when asserted drug-class relations were added. The addition of these asserted drug-class relations presents an opportunity to compare them with drug-class relations that can be inferred using the properties of drugs and drug classes in NDF-RT. METHODS: We enriched NDF-RT's drug-classes with sufficient conditions, added property equivalences, and then used an OWL reasoner to infer drug-class membership relations. We compared the inferred class relations to the recently added asserted relations derived from FDA Structured Product Labels. RESULTS: The inferred and asserted relations only match in about 50% of the cases, due to incompleteness of the drug descriptions and quality issues in the class definitions. CONCLUSIONS: This investigation quantifies and categorizes the disparities between asserted and inferred drug-class relations and illustrates issues with class definitions and drug descriptions. In addition, it serves as an example of the benefits DL can add to ontology development and evaluation.

Using the wisdom of the crowds to find critical errors in biomedical ontologies: a study of SNOMED CT.

OBJECTIVES: The verification of biomedical ontologies is an arduous process that typically involves peer review by subject-matter experts. This work evaluated the ability of crowdsourcing methods to detect errors in SNOMED CT (Systematized Nomenclature of Medicine Clinical Terms) and to address the challenges of scalable ontology verification. METHODS: We developed a methodology to crowdsource ontology verification that uses micro-tasking combined with a Bayesian classifier. We then conducted a prospective study in which both the crowd and domain experts verified a subset of SNOMED CT comprising 200 taxonomic relationships. RESULTS: The crowd identified errors as well as any single expert at about one-quarter of the cost. The inter-rater agreement (κ) between the crowd and the experts was 0.58; the inter-rater agreement between experts themselves was 0.59, suggesting that the crowd is nearly indistinguishable from any one expert. Furthermore, the crowd identified 39 previously undiscovered, critical errors in SNOMED CT (eg, 'septic shock is a soft-tissue infection'). DISCUSSION: The results show that the crowd can indeed identify errors in SNOMED CT that experts also find, and the results suggest that our method will likely perform well on similar ontologies. The crowd may be particularly useful in situations where an expert is unavailable, budget is limited, or an ontology is too large for manual error checking. Finally, our results suggest that the online anonymous crowd could successfully complete other domain-specific tasks. CONCLUSIONS: We have demonstrated that the crowd can address the challenges of scalable ontology verification, completing not only intuitive, common-sense tasks, but also expert-level, knowledge-intensive tasks.

An empirically derived taxonomy of errors in SNOMED CT.

Ontologies underpin methods throughout biomedicine and biomedical informatics. However, as ontologies increase in size and complexity, so does the likelihood that they contain errors. Effective methods that identify errors are typically manual and expert-driven; however, automated methods are essential for the size of modern biomedical ontologies. The effect of ontology errors on their application is unclear, creating a challenge in differentiating salient, relevant errors with those that have no discernable effect. As a first step in understanding the challenge of identifying salient, common errors at a large scale, we asked 5 experts to verify a random subset of complex relations in the SNOMED CT CORE Problem List Subset. The experts found 39 errors that followed several common patterns. Initially, the experts disagreed about errors almost entirely, indicating that ontology verification is very difficult and requires many eyes on the task. It is clear that additional empirically-based, application-focused ontology verification method development is necessary. Toward that end, we developed a taxonomy that can serve as a checklist to consult during ontology quality assurance.

Crowdsourcing the verification of relationships in biomedical ontologies.

Biomedical ontologies are often large and complex, making ontology development and maintenance a challenge. To address this challenge, scientists use automated techniques to alleviate the difficulty of ontology development. However, for many ontology-engineering tasks, human judgment is still necessary. Microtask crowdsourcing, wherein human workers receive remuneration to complete simple, short tasks, is one method to obtain contributions by humans at a large scale. Previously, we developed and refined an effective method to verify ontology hierarchy using microtask crowdsourcing. In this work, we report on applying this method to find errors in the SNOMED CT CORE subset. By using crowdsourcing via Amazon Mechanical Turk with a Bayesian inference model, we correctly verified 86% of the relations from the CORE subset of SNOMED CT in which Rector and colleagues previously identified errors via manual inspection. Our results demonstrate that an ontology developer could deploy this method in order to audit large-scale ontologies quickly and relatively cheaply.

Applications of ontology design patterns in biomedical ontologies.

Ontology design patterns (ODPs) are a proposed solution to facilitate ontology development, and to help users avoid some of the most frequent modeling mistakes. ODPs originate from similar approaches in software engineering, where software design patterns have become a critical aspect of software development. There is little empirical evidence for ODP prevalence or effectiveness thus far. In this work, we determine the use and applicability of ODPs in a case study of biomedical ontologies. We encoded ontology design patterns from two ODP catalogs. We then searched for these patterns in a set of eight ontologies. We found five patterns of the 69 patterns. Two of the eight ontologies contained these patterns. While ontology design patterns provide a vehicle for capturing formally reoccurring models and best practices in ontology design, we show that today their use in a case study of widely used biomedical ontologies is limited.