Mark Engelstad

The Human Phenotype Ontology in 2017

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.

The Monarch Initiative: an integrative data and analytic platform connecting phenotypes to genotypes across species.

The correlation of phenotypic outcomes with genetic variation and environmental factors is a core pursuit in biology and biomedicine. Numerous challenges impede our progress: patient phenotypes may not match known diseases, candidate variants may be in genes that have not been characterized, model organisms may not recapitulate human or veterinary diseases, filling evolutionary gaps is difficult, and many resources must be queried to find potentially significant genotype–phenotype associations. Non-human organisms have proven instrumental in revealing biological mechanisms. Advanced informatics tools can identify phenotypically relevant disease models in research and diagnostic contexts. Large-scale integration of model organism and clinical research data can provide a breadth of knowledge not available from individual sources and can provide contextualization of data back to these sources. The Monarch Initiative (monarchinitiative.org) is a collaborative, open science effort that aims to semantically integrate genotype–phenotype data from many species and sources in order to support precision medicine, disease modeling, and mechanistic exploration. Our integrated knowledge graph, analytic tools, and web services enable diverse users to explore relationships between phenotypes and genotypes across species.

Anterior Iliac Crest, Posterior Iliac Crest, and Proximal Tibia Donor Sites: A Comparison of Cancellous Bone Volumes in Fresh Cadavers

PURPOSE The anterior iliac crest, posterior iliac crest, and proximal tibia are common cancellous donor sites used for autogenous bone grafting. Donor site selection is partly dependent on the expected volume of available bone, but reports of cancellous bone volumes at each of these sites are variable. The goal of this study was to compare the volumes of cancellous bone harvested from donor sites within the same cadaver. MATERIALS AND METHODS Within each of 10 fresh frozen cadavers, cancellous bone was harvested from 3 donor sites-anterior iliac crest, posterior iliac crest, and proximal tibia-using established surgical techniques. Bone volumes were measured by fluid displacement. Mean compressed cancellous bone volumes from the 3 donor sites were compared among cadavers. Within each cadaver, the 3 donor sites were given a volume rank score from 1 (least volume) to 3 (most volume). RESULTS Among cadavers, mean compressed cancellous bone volumes from the proximal tibia (11.3 mL) and posterior iliac crest (10.1 mL) were significantly greater than the anterior iliac crest (7.0 mL). Within cadavers, the mean volume rank score of the proximal tibia (mean rank, 2.7) was statistically greater than that for the posterior iliac crest (mean rank, 2.0), which was statistically greater than that for the anterior iliac crest (mean rank, 1.2). Strong correlations in bone volume existed between the proximal tibia and iliac crests (r = 0.67) and between the anterior iliac crest and posterior iliac crest (r = 0.93). CONCLUSION The proximal tibia and posterior iliac crest yielded a significantly greater mean volume of compressed cancellous bone than the anterior iliac crest. Within individual cadaver skeletons, the proximal tibia was most likely to yield the largest cancellous volume, whereas the anterior iliac crest was most likely to yield the smallest cancellous volume. Although the proximal tibia contains relatively large volumes of cancellous bone, further investigation is required to determine how much cancellous bone can safely be harvested.

Prevalence of Loss of All Teeth (Edentulism) and Associated Factors in Older Adults in China, Ghana, India, Mexico, Russia and South Africa †

Little information exists about the loss of all one’s teeth (edentulism) among older adults in low- and middle-income countries. This study examines the prevalence of edentulism and associated factors among older adults in a cross-sectional study across six such countries. Data from the World Health Organization (WHO’s) Study on global AGEing and adult health (SAGE) Wave 1 was used for this study with adults aged 50-plus from China (N = 13,367), Ghana (N = 4724), India (N = 7150), Mexico (N = 2315), Russian Federation (N = 3938) and South Africa (N = 3840). Multivariate regression was used to assess predictors of edentulism. The overall prevalence of edentulism was 11.7% in the six countries, with India, Mexico, and Russia has higher prevalence rates (16.3%–21.7%) than China, Ghana, and South Africa (3.0%–9.0%). In multivariate logistic analysis sociodemographic factors (older age, lower education), chronic conditions (arthritis, asthma), health risk behaviour (former daily tobacco use, inadequate fruits and vegetable consumption) and other health related variables (functional disability and low social cohesion) were associated with edentulism. The national estimates and identified factors associated with edentulism among older adults across the six countries helps to identify areas for further exploration and targets for intervention.

Navigating the Phenotype Frontier: The Monarch Initiative

The principles of genetics apply across the entire tree of life. At the cellular level we share biological mechanisms with species from which we diverged millions, even billions of years ago. We can exploit this common ancestry to learn about health and disease, by analyzing DNA and protein sequences, but also through the observable outcomes of genetic differences, i.e. phenotypes. To solve challenging disease problems we need to unify the heterogeneous data that relates genomics to disease traits. Without a big-picture view of phenotypic data, many questions in genetics are difficult or impossible to answer. The Monarch Initiative (https://monarchinitiative.org) provides tools for genotype-phenotype analysis, genomic diagnostics, and precision medicine across broad areas of disease.

Embrasure wires for intraoperative maxillomandibular fixation are rapid and effective

PURPOSE The management of some mandible fractures requires maxillomandibular fixation (MMF) intraoperatively but not postoperatively. Intraoperative MMF with arch bars has significant disadvantages, including duration of application and risk of disease transmission. Some surgeons have sought to minimize these disadvantages, improve efficiency, and decrease cost by omitting formal MMF altogether and manually stabilizing the occlusion. Embrasure wires are a method of intraoperative MMF with significant potential advantages. The purpose of this investigation was to compare embrasure wires with Erich arch bars (Karl Leibinger Co, Mulheim, Germany) for intraoperative stabilization of mandible fractures. PATIENTS AND METHODS This retrospective case review comprised 50 patients with a primary diagnosis of mandible fracture requiring open reduction-internal fixation with intraoperative MMF. Patients were categorized into 2 groups: intraoperative MMF using embrasure wires (group A) or intraoperative MMF using arch bars (group B). In each group the time required to place the MMF was recorded in whole minutes. The success or failure of the technique to maintain stable MMF throughout the procedure was assessed. RESULTS Intraoperative MMF was used with embrasure wires in 27 of 50 patients (54%) and with arch bars in 23 of 50 (46%). The mean time required for placement of embrasure wire MMF (2.51 minutes) was significantly (P < .001) less than the mean time required for placement of arch bar MMF (25.47 minutes). The quality of MMF was judged to be stable for the duration of fixation in 24 of 27 patients (89%) in the embrasure wire MMF group and 22 of the 23 patients (96%) in the arch bar group. This difference was not significant (P = .61). CONCLUSION Embrasure wires can be placed in significantly less time than arch bars, and they provide a reliable form of intraoperative MMF during mandible fracture repair. For intraoperative MMF, embrasure wires offer significant advantages compared with arch bars by reducing application time. In addition, embrasure wires may reduce the risk of disease transmission by decreasing the number of wires required for MMF.

Medial canthopexy using transcaruncular barb and miniplate: Technique and cadaver study

Traditional medial canthopexy techniques require transnasal access, periorbital skin incision, and/or direct canthal suturing, often yielding unpredictable outcomes. The transcaruncular canthal barb and miniplate technique is a simplified method of canthopexy that avoids these manoeuvres. 10 transcaruncular medial canthopexies were performed on cadavers with simulated naso-orbito-ethmoid (NOE) injury. Differences in mean pre-injury and post-canthopexy intercanthal distance (ICD) and palpebral aperture width (PAW) measurements were compared using a matched paired t test. Reliability between pre-injury and post-injury intercanthal distance and PAW was compared with intraclass correlation coefficients. Canalicular distortion and final implant position were assessed with post-canthopexy computed tomography (CT). There was no difference in mean palpebral aperture width (32.32 and 32.43 mm) or mean intercanthal distance (29.18 and 29.06 mm) between pre-injury and post-canthopexy groups (both p>0.05). All intercanthal distance and PAW intraclass correlation coefficients were >0.97 (p<0.05). Post-canthopexy, CT scans showed canaliculus distortion in 4/10 of upper and 0/10 of lower canaliculi with all canthal barbs in the correct position relative to the plate. In a cadaver telecanthus model, medial canthopexy using the transcaruncular barb and miniplate technique reliably reduces the medial canthus and did not distort the lower lacrimal canaliculus, but may distort the upper canaliculus.

Deidentification of Facial Images Using Composites

PURPOSE Maxillofacial surgeons rely on photography for education and documentation. Photographs of the face, unlike those of other body regions, are readily identifiable. Traditional methods of facial image deidentification decrease educational quality or fail to adequately conceal identity. In the present study, a method that uses blended facial composites to deidentify original facial images was developed. This method allows significant components of the original face to be visualized while concealing its identity. MATERIALS AND METHODS The method was used to develop 20 different composite facial images that were viewed by student subjects. Ten of these images contained at least one third of a face that was familiar to the subjects. Subjects viewed the composite faces twice--first unaware that the faces were composites, and then primed to the presence of composites. Subjects later rated the efficacy of this method for image deidentification. RESULTS When unaware that they were viewing composite images, no subjects recognized the familiar faces within the composites or rated them as familiar (0/120 total views, 0%). When later primed to the potential presence of familiar faces within composites, the identification rate increased significantly (74/120, 62%; P < .001). Results were similar no matter which portion of the familiar face (upper, 67%; mid, 54%; lower, 67%) was present. Subjects rated all composites as clinically realistic patient images. They also rated composites as more effective at deidentification than traditional methods. CONCLUSION The use of composites appears to be a promising concept for facial image deidentification. Further larger-scale studies are needed to validate these findings.

Enhancing the human phenotype ontology for use by the layperson

In rare or undiagnosed diseases, physicians rely upon genotype and phenotype information in order to compare abnormalities to other known cases and to inform diagnoses. Patients are often the best sources of information about their symptoms and phenotypes. The Human Phenotype Ontology (HPO) contains over 12,000 terms describing abnormal human phenotypes. However, the labels and synonyms in the HPO primarily use medical terminology, which can be difficult for patients and their families to understand. In order to make the HPO more accessible to non-medical experts, we systematically added new synonyms using non-expert terminology (i.e., layperson terms) to the existing HPO classes or tagged existing synonyms as layperson. As a result, the HPO contains over 6,000 classes with layperson synonyms. Keywords—Human Phenotype Ontology, Synonyms, Rare Disease, Patient phenotypes

The Monarch Initiative: Insights across species reveal human disease mechanisms

The principles of genetics apply across the whole tree of life: on a cellular level, we share mechanisms with species from which we diverged millions or even billions of years ago. We can exploit this common ancestry at the level of sequences, but also in terms of observable outcomes (phenotypes), to learn more about health and disease for humans and all other species. Applying the range of available knowledge to solve challenging disease problems requires unified data relating genomics, phenotypes, and disease; it also requires computational tools that leverage these multimodal data to inform interpretations by geneticists and to suggest experiments. However, the distribution and heterogeneity of databases is a major impediment: databases tend to focus either on a single data type across species, or on single species across data types. Although each database provides rich, high-quality information, no single one provides unified data that is comprehensive across species, biological scales, and data types. Without a big-picture view of the data, many questions in genetics are difficult or impossible to answer. The Monarch Initiative (https://monarchinitiative.org) is an international consortium dedicated to providing computational tools that leverage a computational representation of phenotypic data for genotype-phenotype analysis, genomic diagnostics, and precision medicine on the basis of a large-scale platform of multimodal data that is deeply integrated across species and covering broad areas of disease.The principles of genetics apply across the whole tree of life: on a cellular level, we share mechanisms with species from which we diverged millions or even billions of years ago. We can exploit this common ancestry at the level of sequences, but also in terms of observable outcomes (phenotypes), to learn more about health and disease for humans and all other species. Applying the range of available knowledge to solve challenging disease problems requires unified data relating genomics, phenotypes, and disease; it also requires computational tools that leverage these multimodal data to inform interpretations by geneticists and to suggest experiments. However, the distribution and heterogeneity of databases is a major impediment: databases tend to focus either on a single data type across species, or on single species across data types. Although each database provides rich, high-quality information, no single one provides unified data that is comprehensive across species, biological scales, and data types. Without a big-picture view of the data, many questions in genetics are difficult or impossible to answer. The Monarch Initiative (https://monarchinitiative.org) is an international consortium dedicated to providing computational tools that leverage a computational representation of phenotypic data for genotype-phenotype analysis, genomic diagnostics, and precision medicine on the basis of a large-scale platform of multimodal data that is deeply integrated across species and covering broad areas of disease.