The Human Phenotype Ontology in 2021 Köhler, Sebastian; Gargano, Michael; Matentzoglu, Nicolas ...
Nucleic acids research,
01/2021, Volume:
49, Issue:
D1
Journal Article
Peer reviewed
Open access
Abstract
The Human Phenotype Ontology (HPO, https://hpo.jax.org) was launched in 2008 to provide a comprehensive logical standard to describe and computationally analyze phenotypic abnormalities ...found in human disease. The HPO is now a worldwide standard for phenotype exchange. The HPO has grown steadily since its inception due to considerable contributions from clinical experts and researchers from a diverse range of disciplines. Here, we present recent major extensions of the HPO for neurology, nephrology, immunology, pulmonology, newborn screening, and other areas. For example, the seizure subontology now reflects the International League Against Epilepsy (ILAE) guidelines and these enhancements have already shown clinical validity. We present new efforts to harmonize computational definitions of phenotypic abnormalities across the HPO and multiple phenotype ontologies used for animal models of disease. These efforts will benefit software such as Exomiser by improving the accuracy and scope of cross-species phenotype matching. The computational modeling strategy used by the HPO to define disease entities and phenotypic features and distinguish between them is explained in detail.We also report on recent efforts to translate the HPO into indigenous languages. Finally, we summarize recent advances in the use of HPO in electronic health record systems.
To assess the rapid implementation of child neurology telehealth outpatient care with the onset of the coronavirus disease 2019 (COVID-19) pandemic in March 2020.
This was a cohort study with ...retrospective comparison of 14,780 in-person encounters and 2,589 telehealth encounters, including 2,093 audio-video telemedicine and 496 scheduled telephone encounters, between October 1, 2019 and April 24, 2020. We compared in-person and telehealth encounters for patient demographics and diagnoses. For audio-video telemedicine encounters, we analyzed questionnaire responses addressing provider experience, follow-up plans, technical quality, need for in-person assessment, and parent/caregiver satisfaction. We performed manual reviews of encounters flagged as concerning by providers.
There were no differences in patient age and major ICD-10 codes before and after transition. Clinicians considered telemedicine satisfactory in 93% (1,200 of 1,286) of encounters and suggested telemedicine as a component for follow-up care in 89% (1,144 of 1,286) of encounters. Technical challenges were reported in 40% (519 of 1,314) of encounters. In-person assessment was considered warranted after 5% (65 of 1,285) of encounters. Patients/caregivers indicated interest in telemedicine for future care in 86% (187 of 217) of encounters. Participation in telemedicine encounters compared to telephone encounters was less frequent among patients in racial or ethnic minority groups.
We effectively converted most of our outpatient care to telehealth encounters, including mostly audio-video telemedicine encounters. Providers rated the vast majority of telemedicine encounters to be satisfactory, and only a small proportion of encounters required short-term in-person follow-up. These findings suggest that telemedicine is feasible and effective for a large proportion of child neurology care. Additional strategies are needed to ensure equitable telemedicine use.
Disease-causing variants in STXBP1 are among the most common genetic causes of neurodevelopmental disorders. However, the phenotypic spectrum in STXBP1-related disorders is wide and clear ...correlations between variant type and clinical features have not been observed so far. Here, we harmonized clinical data across 534 individuals with STXBP1-related disorders and analysed 19 973 derived phenotypic terms, including phenotypes of 253 individuals previously unreported in the scientific literature. The overall phenotypic landscape in STXBP1-related disorders is characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of individuals, including focal-onset seizures as the most common seizure type (47%). More than 88% of individuals with STXBP1-related disorders have seizure onset in the first year of life, including neonatal seizure onset in 47%. Individuals with protein-truncating variants and deletions in STXBP1 (n = 261) were almost twice as likely to present with West syndrome and were more phenotypically similar than expected by chance. Five genetic hotspots with recurrent variants were identified in more than 10 individuals, including p.Arg406Cys/His (n = 40), p.Arg292Cys/His/Leu/Pro (n = 30), p.Arg551Cys/Gly/His/Leu (n = 24), p.Pro139Leu (n = 12), and p.Arg190Trp (n = 11). None of the recurrent variants were significantly associated with distinct electroclinical syndromes, single phenotypic features, or showed overall clinical similarity, indicating that the baseline variability in STXBP1-related disorders is too high for discrete phenotypic subgroups to emerge. We then reconstructed the seizure history in 62 individuals with STXBP1-related disorders in detail, retrospectively assigning seizure type and seizure frequency monthly across 4433 time intervals, and retrieved 251 anti-seizure medication prescriptions from the electronic medical records. We demonstrate a dynamic pattern of seizure control and complex interplay with response to specific medications particularly in the first year of life when seizures in STXBP1-related disorders are the most prominent. Adrenocorticotropic hormone and phenobarbital were more likely to initially reduce seizure frequency in infantile spasms and focal seizures compared to other treatment options, while the ketogenic diet was most effective in maintaining seizure freedom. In summary, we demonstrate how the multidimensional spectrum of phenotypic features in STXBP1-related disorders can be assessed using a computational phenotype framework to facilitate the development of future precision-medicine approaches.
Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled ...CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice.
Febrile infection-related epilepsy syndrome (FIRES) is a severe childhood epilepsy with refractory status epilepticus after a typically mild febrile infection. The etiology of FIRES is largely ...unknown, and outcomes in most individuals with FIRES are poor.
Here, we reviewed the current state-of-the art genetic testing strategies in individuals with FIRES. We performed a systematic computational analysis to identify individuals with FIRES and characterize the clinical landscape using the Electronic Medical Records (EMR). Among 25 individuals with a confirmed FIRES diagnosis over the last decade, we performed a comprehensive review of genetic testing and other diagnostic testing.
Management included use of steroids and intravenous immunoglobulin (IVIG) in most individuals, with an increased use of immunomodulatory agents, including IVIG, plasma exchange (PLEX) and immunosuppressants such as cytokine inhibitors, and the ketogenic diet after 2014. Genetic testing was performed on a clinical basis in almost all individuals and was non-diagnostic in all patients. We compared FIRES with both status epilepticus (SE) and refractory status epilepticus (RSE) as a broader comparison cohort and identified genetic causes in 36% of patients with RSE. The difference in genetic signatures between FIRES and RSE suggest distinct underlying etiologies. In summary, despite the absence of any identifiable etiologies in FIRES, we performed an unbiased analysis of the clinical landscape, identifying a heterogeneous range of treatment strategies and characterized real-world clinical practice.
FIRES remains one of the most enigmatic conditions in child neurology without any known etiologies to date despite significant efforts in the field, suggesting a clear need for further studies and novel diagnostic and treatment approaches.
Objective
STXBP1‐related disorders are rare genetic epilepsies and neurodevelopmental disorders, but the impact of symptoms across clinical domains is poorly understood. Disease concept models are ...formal frameworks to assess the lived experience of individuals and their families and provide a basis for generating outcome measures.
Methods
We conducted semistructured, qualitative interviews with 19 caregivers of 16 individuals with STXBP1‐related disorders and 7 healthcare professionals. We systematically coded themes using NVivo software and grouped concepts into the domains of symptoms, symptom impact, and caregiver impact. We quantified the frequency of concepts throughout the lifespan and across clinical subgroups stratified by seizure history and developmental trajectories.
Results
Over 25 hours of interviews, we coded a total of 3626 references to 38 distinct concepts. In addition to well‐recognized clinical features such as developmental delay (n = 240 references), behavior (n = 201), and seizures (n = 147), we identified previously underrepresented symptoms including gastrointestinal (n = 68) and respiratory symptoms (n = 24) and pain (n = 30). The most frequently referenced symptom impacts were autonomy (n = 96), socialization (n = 64), and schooling (n = 61). Emotional impact (n = 354), support (n = 200), and daily life & activities (n = 108) were highly cited caregiver impacts. We found that seizures were more commonly referenced in infancy than in other age groups, while behavior and socialization were more likely to be referred to in childhood. We found that caregivers of individuals with ongoing seizures were less likely to reference developmental delay, possibly due to the relatively high impact of seizures.
Significance
STXBP1‐related disorders are complex conditions affecting a wide range of clinical and social domains. We comprehensively mapped symptoms and their impact on families to generate a comprehensive disease model as a foundation for clinical endpoints in future trials.
Febrile infection‐related epilepsy syndrome (FIRES) is a devastating epilepsy characterized by new‐onset refractory status epilepticus with a prior febrile infection. We performed exome sequencing in ...50 individuals with FIRES, including 27 patient–parent trios and 23 single probands, none of whom had pathogenic variants in established genes for epilepsies or neurodevelopmental disorders. We also performed HLA sequencing in 29 individuals with FIRES and 529 controls, which failed to identify prominent HLA alleles. The genetic architecture of FIRES is substantially different from other developmental and epileptic encephalopathies, and the underlying etiology remains elusive, requiring novel approaches to identify the underlying causative factors.
In this review, we aim to analyse the progress in understanding the genetic basis of the epilepsies, as well as ongoing efforts to define the increasingly diverse and novel presentations, phenotypes ...and divergences from the expected that have continually characterized the field.
A genetic workup is now considered to be standard of care for individuals with an unexplained epilepsy, due to mounting evidence that genetic diagnoses significantly influence treatment choices, prognostication, community support, and increasingly, access to clinical trials. As more individuals with epilepsy are tested, novel presentations of known epilepsy genes are being discovered, and more individuals with self-limited epilepsy are able to attain genetic diagnoses. In addition, new genes causative of epilepsy are being uncovered through both traditional and novel methods, including large international data-sharing collaborations and massive sequencing efforts as well as computational methods and analyses driven by the Human Phenotype Ontology (HPO).
New approaches to gene discovery and characterization are advancing rapidly our understanding of the genetic and phenotypic architecture of the epilepsies. This review highlights relevant and groundbreaking studies published recently that have pushed forward the field of epilepsy genetics.
Making a specific diagnosis in neurodevelopmental disorders is traditionally based on recognizing clinical features of a distinct syndrome, which guides testing of its possible genetic etiologies. ...Scalable frameworks for genomic diagnostics, however, have struggled to integrate meaningful measurements of clinical phenotypic features. While standardization has enabled generation and interpretation of genomic data for clinical diagnostics at unprecedented scale, making the equivalent breakthrough for clinical data has proven challenging. However, increasingly clinical features are being recorded using controlled dictionaries with machine readable formats such as the Human Phenotype Ontology (HPO), which greatly facilitates their use in the diagnostic space. Improving the tractability of large‐scale clinical information will present new opportunities to inform genomic research and diagnostics from a clinical perspective. Here, we describe novel approaches for computational phenotyping to harmonize clinical features, improve data translation through revising domain‐specific dictionaries, quantify phenotypic features, and determine clinical relatedness. We demonstrate how these concepts can be applied to longitudinal phenotypic information, which represents a critical element of developmental disorders and pediatric conditions. Finally, we expand our discussion to clinical data derived from electronic medical records, a largely untapped resource of deep clinical information with distinct strengths and weaknesses.
Visits of concern in child neurology telemedicine Prelack, Marisa; Fridinger, Sara; Gonzalez, Alexander K. ...
Developmental medicine and child neurology,
November 2022, Volume:
64, Issue:
11
Journal Article
Peer reviewed
Open access
Aim
To characterize child neurology telemedicine visits flagged as requiring in‐person evaluation during the COVID‐19 pandemic.
Method
We analyzed 7130 audio‐video telemedicine visits between March ...and November 2020. Visits of concern (VOCs) were defined as telemedicine visits where the clinical scenario necessitated in‐person follow‐up evaluation sooner than if the visit had been conducted in‐person.
Results
VOCs occurred in 5% (333/7130) of visits for 292 individuals (148 females, 144 males). Providers noted technical challenges more often in VOCs (40%; 133/333) than visits without concern (non‐VOCs) (28%; 1922/6797) (p < 0.05). The median age was younger in VOCs (9 years 3 months, interquartile range IQR 2 years 0 months–14 years 3 months) than non‐VOCs (11 years 3 months, IQR 5 years 10 months–15 years 10 months) (p < 0.05). Median household income was lower for patients with VOCs ($74 K, IQR $55 K–$97 K) compared to non‐VOCs ($80 K, IQR $61 K–$100 K) (p < 0.05). Compared with all other race categories, families who self‐identified as Black were more likely to have a VOC (odds ratio 1.53, 95% confidence interval 1.21–2.06). Epilepsy and headache represented the highest percentages of VOCs, while neuromuscular disorders and developmental delay had a higher proportion of VOCs than other neurological disorders.
Interpretation
These findings suggest that telemedicine is an effective platform for most child neurology visits. Younger children and those with neuromuscular disorders or developmental delays are more likely to require in‐person evaluation.
What this paper adds
It is possible to successfully flag patients who need in‐person assessment.
Providers can manage issues arising during telemedicine in 95% of visits.
Visits flagged as concerning were likely unrelated to modality of patient care.
Provider concern was independent of technical difficulties for most telehealth visits.
Younger age may be correlated with need for in‐person assessment.
What this paper adds
It is possible to successfully flag patients who need in‐person assessment.
Providers can manage issues arising during telemedicine in 95% of visits.
Visits flagged as concerning were likely unrelated to modality of patient care.
Provider concern was independent of technical difficulties for most telehealth visits.
Younger age may be correlated with need for in‐person assessment.
This study tracks pediatric neurology telemedicine visits and finds that telemedicine can be used in most encounters, and it is possible to successfully track and adjust for visits flagged as in need of an in‐person evaluation.
This original article is commented on by Wac on pages 1315–1316 of this issue.
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