The Human Phenotype Ontology in 2017 Köhler, Sebastian; Vasilevsky, Nicole A; Engelstad, Mark ...
Nucleic acids research,
01/2017, Volume:
45, Issue:
D1
Journal Article
Peer reviewed
Open access
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.
RATIONALE:Disruption in subcellular targeting of Ca signaling complexes secondary to changes in cardiac myocyte structure may contribute to the pathophysiology of a variety of cardiac diseases, ...including heart failure (HF) and certain arrhythmias.
OBJECTIVE:To explore microdomain-targeted remodeling of ventricular L-type Ca channels (LTCCs) in HF.
METHODS AND RESULTS:Super-resolution scanning patch-clamp, confocal and fluorescence microscopy were used to explore the distribution of single LTCCs in different membrane microdomains of nonfailing and failing human and rat ventricular myocytes. Disruption of membrane structure in both species led to the redistribution of functional LTCCs from their canonical location in transversal tubules (T-tubules) to the non-native crest of the sarcolemma, where their open probability was dramatically increased (0.034±0.011 versus 0.154±0.027, P<0.001). High open probability was linked to enhance calcium–calmodulin kinase II–mediated phosphorylation in non-native microdomains and resulted in an elevated ICa,L window current, which contributed to the development of early afterdepolarizations. A novel model of LTCC function in HF was developed; after its validation with experimental data, the model was used to ascertain how HF-induced T-tubule loss led to altered LTCC function and early afterdepolarizations. The HF myocyte model was then implemented in a 3-dimensional left ventricle model, demonstrating that such early afterdepolarizations can propagate and initiate reentrant arrhythmias.
CONCLUSIONS:Microdomain-targeted remodeling of LTCC properties is an important event in pathways that may contribute to ventricular arrhythmogenesis in the settings of HF-associated remodeling. This extends beyond the classical concept of electric remodeling in HF and adds a new dimension to cardiovascular disease.
Cohort studies have consistently shown underground miners exposed to high levels of radon to be at excess risk of lung cancer, and extrapolations based on those results indicate that residential ...radon may be responsible for nearly 10-15% of all lung cancer deaths per year in the United States. However, case-control studies of residential radon and lung cancer have provided ambiguous evidence of radon lung cancer risks. Regardless, alpha-particle emissions from the short-lived radioactive radon decay products can damage cellular DNA. The possibility that a demonstrated lung carcinogen may be present in large numbers of homes raises a serious public health concern. Thus, a systematic analysis of pooled data from all North American residential radon studies was undertaken to provide a more direct characterization of the public health risk posed by prolonged radon exposure. To evaluate the risk associated with prolonged residential radon exposure, a combined analysis of the primary data from seven large scale case-control studies of residential radon and lung cancer risk was conducted. The combined data set included a total of 4081 cases and 5281 controls, representing the largest aggregation of data on residential radon and lung cancer conducted to date. Residential radon concentrations were determined primarily by α-track detectors placed in the living areas of homes of the study subjects in order to obtain an integrated 1-yr average radon concentration in indoor air. Conditional likelihood regression was used to estimate the excess risk of lung cancer due to residential radon exposure, with adjustment for attained age, sex, study, smoking factors, residential mobility, and completeness of radon measurements. Although the main analyses were based on the combined data set as a whole, we also considered subsets of the data considered to have more accurate radon dosimetry. This included a subset of the data involving 3662 cases and 4966 controls with α-track radon measurements within the exposure time window (ETW) 5-30 yr prior to the index date considered previously by
Krewski et al. (2005)
. Additional restrictions focused on subjects for which a greater proportion of the ETW was covered by measured rather than imputed radon concentrations, and on subjects who occupied at most two residences. The estimated odds ratio (OR) of lung cancer generally increased with radon concentration. The OR trend was consistent with linearity (p = .10), and the excess OR (EOR) was 0.10 per Bq/m
3
with 95% confidence limits (−0.01, 0.26). For the subset of the data considered previously by
Krewski et al. (2005)
, the EOR was 0.11 (0.00, 0.28). Further limiting subjects based on our criteria (residential stability and completeness of radon monitoring) expected to improve radon dosimetry led to increased estimates of the EOR. For example, for subjects who had resided in only one or two houses in the 5-30 ETW and who had α-track radon measurements for at least 20 yr of this 25-yr period, the EOR was 0.18 (0.02, 0.43) per 100 Bq/m
3
. Both estimates are compatible with the EOR of 0.12 (0.02, 0.25) per 100 Bq/m
3
predicted by downward extrapolation of the miner data. Collectively, these results provide direct evidence of an association between residential radon and lung cancer risk, a finding predicted by extrapolation of results from occupational studies of radon-exposed underground miners.
E. G. Létourneau and J. B. Schoenberg have retired; J. A. Stolwijk holds an emeritus position.
We acknowledge the helpful input of the following individuals who served on the International Steering Committee for the North American combined analysis: Ken Chadwick (CEC Radiation Protection Program), Susan Conrath (U.S. Environmental Protection Agency), Sarah Darby (Oxford University), Evan Douple (U.S. National Academy of Sciences), Colin Muirhead (UK National Radiation Protection Board), and Susan Rose (U.S. Department of Energy). Salary support for Drs. Field, Lynch, and Steck was provided in part by grant numbers R01 ES05653 and P30 ES05605 from the National Institute of Environmental Health Sciences, NIH and grant number R01 CA85942 from the National Cancer Institute, NIH. This research was supported by grants from the Canadian Institutes of Health Research (formerly the Medical Research Council of Canada) and the Natural Sciences and Engineering Research Council of Canada to D. Krewski, who currently holds the NSERC/SSHRC/McLaughlin Chair in Population Health Risk Assessment at the University of Ottawa. Financial support for the meetings of the Analysis Team and the Steering Committee was also provided by Health Canada and the U.S. Department of Energy. We are grateful to Dr. Huixia Jiang for assistance with the combined analysis, and to Jackie Monaghan for technical assistance in preparing this report.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
OBJECTIVE:Ethnicity has been associated with clinical and experimental pain responses. Whereas ethnic disparities in pain in other minority groups compared with whites are well described, pain in ...Asian Americans remains poorly understood. The purpose of this study was to characterize differences in clinical pain intensity and experimental pain sensitivity among older Asian American and non-Hispanic white (NHW) participants with knee osteoarthritis (OA).
METHODS:Data were collected from 50 Asian Americans ages 45 to 85 (28 Korean, 9 Chinese, 7 Japanese, 5 Filipino, and 1 Indian) and compared with 50 age-matched and sex-matched NHW individuals with symptomatic knee OA pain. The Western Ontario and McMaster Universities Osteoarthritis Index and Graded Chronic Pain Scale were used to assess the intensity of clinical knee pain. In addition, quantitative sensory testing was used to measure experimental sensitivity to heat-induced and mechanically induced pain.
RESULTS:Asian American participants had significantly higher levels of clinical pain intensity than NHW participants with knee OA. In addition, Asian American participants had significantly higher experimental pain sensitivity than NHW participants with knee OA.
DISCUSSION:These findings add to the growing literature regarding ethnic and racial differences in clinical pain intensity and experimental pain sensitivity. Asian Americans in particular may be at risk for clinical pain and heightened experimental pain sensitivity. Further investigation is needed to identify the mechanisms underlying ethnic group differences in pain between Asian Americans and NHWs, and to ensure that ethnic group disparities in pain are ameliorated.
A compact quasi-poloidally symmetric stellarator (QPS) plasma and coil configuration is described that has desirable physics properties and engineering feasibility with a very low aspect ratio plasma ...bounded by good magnetic flux surfaces both in vacuum and at β = 2%. The plasma is robust with respect to variations of pressure and the resulting bootstrap current, which leave the bounding flux surface approximately unchanged and thus reduce active positional control requirements. This configuration was developed by reconfiguring the QPS modular coils and applying a new computational method that maximizes the volume of good (integrable) vacuum flux surfaces as a measure of robustness. The stellarator plasma and coil design code STELLOPT is used to vary the coil geometry to determine the plasma geometry and profiles that optimize plasma performance with respect to neoclassical transport, infinite-n ballooning stability up to β = 2%, and coil engineering parameters. The normal component of the vacuum magnetic field is simultaneously minimized at the full-beta plasma boundary.
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The feasibility of predicting pH, color, shear force, and sensory characteristics of chicken breasts deboned at 2, 4, 6, and 24 h postmortem by visible/near infrared reflectance spectroscopy (NIRS) ...in the 400 to 1850 nm region was determined. Prediction of physical attributes of Commission Internationale de l'Eclairage (CIE) color values (L*, a*, and b*), pH, and shear force had better accuracies than those of individual sensory attributes. Calibration and validation statistics for shear force and sensory traits indicated that visible/near infrared models were not significantly improved for cooked muscles compared with predictions based on raw muscle characteristics. On the basis of predicted shear values from the partial least squares (PLS) model, breast samples were classified into "tender" and "tough" classes with a correct classification of 74.0% if the boundary was set at 7.5 kg. The model developed from measured shears using soft independent modeling of class analogy/principal components analysis (SIMCA/PCA) showed nearly the same classification success.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Toxoplasmosis (TXP) is a life-threatening complication of allogeneic haematopoietic stem cell transplantation (AHSCT). Little is known about the risk factors and there is no consensus on prophylactic ...measures. To investigate the risk factors, we conducted a single-centre, retrospective matched case–control study among adults who underwent AHSCT from January 2006 to March 2015 in our hospital. TXP cases were identified from the prospectively maintained hospital's database. The 1:2 control population consisted of the two patients who received an AHSCT immediately before and after each case with similar donor relationship (related, unrelated) but who did not develop TXP. Risk factors were identified by conditional logistic regression. Clinical features and outcome of TXP were examined. Twenty-three (3.9%) cases of TXP (20 diseases, three infections) were identified among 588 AHSCT recipients. Twenty (87%) cases had a positive pre-transplant Toxoplasma gondii serology. In comparison with 46 matched control patients, risk factors were the absence of effective anti-Toxoplasma prophylaxis (odds ratio (OR) 11.95; 95% CI 3.04–46.88; p <0.001), high-grade (III–IV) acute graft-versus-host-disease (OR 3.1; 95% CI 1.04–9.23; p 0.042) and receipt of the tumour necrosis factor-α blocker etanercept (OR 12.02; 95% CI 1.33–108.6; p 0.027). Mortality attributable to TXP was 43.5% (n = 10). Non-relapse mortality rates during the study period of cases and controls were 69.6% (n = 16) and 17.4% (n = 8), respectively. Lung involvement was the dominant clinical feature (n = 14). Two cases were associated with graft failure, one preceded by haemophagocytic syndrome. Given TXP-related morbidity and attributable mortality, anti-Toxoplasma prophylaxis is essential for optimized management of seropositive AHSCT recipients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Invasive fungal infections are a major cause of morbidity and mortality among solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients, but few data have been ...reported on the epidemiology of endemic fungal infections in these populations.
Methods
Fifteen institutions belonging to the Transplant‐Associated Infection Surveillance Network prospectively enrolled SOT and HCT recipients with histoplasmosis, blastomycosis, or coccidioidomycosis occurring between March 2001 and March 2006.
Results
A total of 70 patients (64 SOT recipients and 6 HCT recipients) had infection with an endemic mycosis, including 52 with histoplasmosis, 9 with blastomycosis, and 9 with coccidioidomycosis. The 12‐month cumulative incidence rate among SOT recipients for histoplasmosis was 0.102%. Occurrence of infection was bimodal; 28 (40%) infections occurred in the first 6 months post transplantation, and 24 (34%) occurred between 2 and 11 years post transplantation. Three patients were documented to have acquired infection from the donor organ. Seven SOT recipients with histoplasmosis and 3 with coccidioidomycosis died (16%); no HCT recipient died.
Conclusions
This 5‐year multicenter prospective surveillance study found that endemic mycoses occur uncommonly in SOT and HCT recipients, and that the period at risk extends for years after transplantation.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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