Generating Clinical-Grade Gene-Disease Validity Classifications Through the ClinGen Data Platforms.

Clinical genetic laboratories must have access to clinically validated biomedical data for precision medicine. A lack of accessibility, normalized structure, and consistency in evaluation complicates interpretation of disease causality, resulting in confusion in assessing the clinical validity of genes and genetic variants for diagnosis. A key goal of the Clinical Genome Resource (ClinGen) is to fill the knowledge gap concerning the strength of evidence supporting the role of a gene in a monogenic disease, which is achieved through a process known as Gene-Disease Validity curation. Here we review the work of ClinGen in developing a curation infrastructure that supports the standardization, harmonization, and dissemination of Gene-Disease Validity data through the creation of frameworks and the utilization of common data standards. This infrastructure is based on several applications, including the ClinGen GeneTracker, Gene Curation Interface, Data Exchange, GeneGraph, and website.

Cost, Utilization, and Patient and Family Experience With ACO-Based Pediatric Care Management.

BACKGROUND AND OBJECTIVES: Children and Youth with Special Health Care Needs have high healthcare utilization, fragmented care, and unmet health needs. Accountable Care Organizations (ACOs) increasingly use pediatric care management to improve quality and reduce unnecessary utilization. We evaluated effects of pediatric care management on total medical expense (TME) and utilization; perceived quality of care coordination, unmet needs, and patient and family experience; and differential impact by payor, risk score, care manager discipline, and behavioral health diagnosis. METHODS: Mixed-methods analysis including claims using quasi-stepped-wedge design pre and postenrollment to estimate difference-in-differences, participant survey, and semistructured interviews. Participants included 1321 patients with medical, behavioral, or social needs, high utilization, in Medicaid or commercial ACOs, and enrolled in multidisciplinary, primary care-embedded care management. RESULTS: TME significantly declined 1 to 6 months postenrollment and continued through 19 to 24 months (-$645.48 per member per month, P < .001). Emergency department and inpatient utilization significantly decreased 7 to 12 months post-enrollment and persisted through 19 to 24 months (-29% emergency department, P = .012; -82% inpatient, P < .001). Of respondents, 87.2% of survey respondents were somewhat or very satisfied with care coordination, 56.1% received education coordination when needed, and 81.5% had no unmet health needs. Emergency department or inpatient utilization decreases were consistent across payors and care manager disciplines, occurred sooner with behavioral health diagnoses, and were significant among children with above-median risk scores. Satisfaction and experience were equivalent across groups, with more unmet needs and frustration with above-median risk scores. CONCLUSIONS: Pediatric care management in multipayor ACOs may effectively reduce TME and utilization and clinically provide high-quality care coordination, including education and family stress, with high participant satisfaction.

Outcomes in PIC-Related CNV: Pooled Analysis of Individual Participant Data.

Choroidal neovascularization (CNV) affects 64-75% of eyes with punctate inner choroidopathy (PIC). Although anti-VEGF agents are considered first-line therapy, there is controversy regarding other modalities, such as immunosuppression. We performed a systematic review of individual participant data (IPD) and generated a dataset of 278 eyes with PIC-related CNV from 45 studies. Forty-two percent presented with moderate visual loss (MVL) or worse. Four different treatment modalities (anti-VEGF, photodynamic therapy, local immunosuppression, and systemic immunosuppression) and most combinations among them were represented. Anti-VEGF injections decreased the likelihood of MVL (Odds Ratio 0.3, p = .027), an effect moderated by presenting visual acuity and patient age. Eyes receiving more than 3 injections were more likely to receive additional therapeutic modalities. Increasing number of modalities was associated with longer follow-up time and did not improve vision. The beneficial effect of anti-VEGF injections persisted when controlling for presenting visual acuity and follow-up time.

Accessing clinical-grade genomic classification data through the ClinGen Data Platform.

The Clinical Genome Resource (ClinGen) serves as an authoritative resource on the clinical relevance of genes and variants. In order to support our curation activities and to disseminate our findings to the community, we have developed a Data Platform of informatics resources backed by standardized data models. In this workshop we demonstrate our publicly available resources including curation interfaces, (Variant Curation Interface, CIViC), supporting infrastructure (Allele Registry, Genegraph), and data models (SEPIO, GA4GH VRS, VA).

ClinGen Variant Curation Interface: a variant classification platform for the application of evidence criteria from ACMG/AMP guidelines.

BACKGROUND: Identification of clinically significant genetic alterations involved in human disease has been dramatically accelerated by developments in next-generation sequencing technologies. However, the infrastructure and accessible comprehensive curation tools necessary for analyzing an individual patient genome and interpreting genetic variants to inform healthcare management have been lacking. RESULTS: Here we present the ClinGen Variant Curation Interface (VCI), a global open-source variant classification platform for supporting the application of evidence criteria and classification of variants based on the ACMG/AMP variant classification guidelines. The VCI is among a suite of tools developed by the NIH-funded Clinical Genome Resource (ClinGen) Consortium and supports an FDA-recognized human variant curation process. Essential to this is the ability to enable collaboration and peer review across ClinGen Expert Panels supporting users in comprehensively identifying, annotating, and sharing relevant evidence while making variant pathogenicity assertions. To facilitate evidence-based improvements in human variant classification, the VCI is publicly available to the genomics community. Navigation workflows support users providing guidance to comprehensively apply the ACMG/AMP evidence criteria and document provenance for asserting variant classifications. CONCLUSIONS: The VCI offers a central platform for clinical variant classification that fills a gap in the learning healthcare system, facilitates widespread adoption of standards for clinical curation, and is available at https://curation.clinicalgenome.org.

Impact of a State Law on Physician Practice in Sports-Related Concussions.

OBJECTIVE: To determine physician-reported adherence to and support of the 2010 Massachusetts youth concussion law, as well as barriers to care and clinical practice in the context of legislation. STUDY DESIGN: Primary care physicians (n = 272) in a large pediatric network were eligible for a cross-sectional survey in 2014. Survey questions addressed key policy and practice provisions: concussion knowledge, state regulations and training, practice patterns, referrals, patient characteristics, and barriers to care. Analyses explored relationships between practice and policy, adjusting for physician demographic and practice characteristics. RESULTS: The survey response rate was 64% among all responders (173 of 272). A total of 146 respondents who had evaluated, treated, or referred patients with a suspected sports-related concussion in the previous year were eligible for analysis. The vast majority (90%) of providers agreed that the current Massachusetts laws regarding sports concussions are necessary and support the major provisions. Three-quarters (74%) had taken a required clinician training course on concussions. Those who took training courses were significantly more likely to develop individualized treatment plans (OR, 3.6; 95% CI, 1.1-11.0). Physician training did not improve screening of youth with concussion for depression or substance use. Most physicians (77%) advised patients to refrain from computer, telephone, or television for various time periods. Physicians reported limited communication with schools. CONCLUSIONS: Primary care physicians report being comfortable with the diagnosis and management of concussions, and support statewide regulations; however, adherence to mandated training and specific legal requirements varied. Broader and more frequent training may be necessary to align current best evidence with clinical care and state-mandated practice.

Predictors of treatment failure for pneumatic retinopexy.

OBJECTIVE: The purpose of this study was to define the overall anatomic success rate in pneumatic retinopexy and to identify morphologic features that may be predictive of treatment failure in pneumatic retinopexy. DESIGN AND PARTICIPANTS: Prospective consecutive interventional case series of patients with new-onset primary rhegmatogenous retinal detachments treated with pneumatic retinopexy. METHODS: In this interventional case series, consecutive patients with new-onset primary rhegmatogenous retinal detachments were treated with pneumatic retinopexy and followed prospectively. Morphologic data were collected on 3-colour fundus drawings. The primary outcome measure was treatment failure, defined as requirement for scleral buckle or vitrectomy within the follow-up period. Rates of failure for each morphologic feature were compared and a logistic regression model was fit. RESULTS: A total of 113 eyes were included in the study. Anatomic success was achieved in 69.6% of patients. Morphologic criteria including the position and number of breaks, position and extent of lattice degeneration, size of the detached area, and macular status were all found not to be significantly related to failure. In multivariate analysis, only 3 predictors, pseudophakic status (p < 0.05, odds ratio [OR] 2.9, 95% CI, 1.06-7.88), presence of retinal break greater than 1 clock-hour (p < 0.05, OR 3.41, 1.06-11.02), and presence of grade C or D proliferative vitreoretinopathy (PVR) (p < 0.01, OR 31.83, 95% CI, 3.59-282.24), gained statistical significance. CONCLUSIONS: Only pseudophakia, a large retinal break, and/or PVR was associated with an increased likelihood of failure.

Small ciliary body tumors: ultrasound biomicroscopic assessment and follow-up of 42 patients.

PURPOSE: Detecting and following small tumors of the ciliary body is a particular challenge because of their location. Recently high-frequency ultrasound biomicroscopy (UBM) has been used to assist in this task. The aim of this study was to evaluate this subset of small ciliary body tumors through the use of UBM. DESIGN: Retrospective, noncomparative case series. METHODS: Forty-two patients with small ciliary body tumors (less than 4 mm) from our institution were included in the study with a median follow-up of 4.3 years. UBM was used to assess tumor characteristics including height, location, and internal and external features. The data were collected longitudinally, and statistical analysis was performed. RESULTS: Median initial tumor height was 2.05 mm (range 1.1 to 3.8 mm) as measured by UBM. By 5 years after diagnosis, five tumors (12%) exhibited growth. The overall mean growth rate was 0.026 mm per year (P = .00007). The most rapid period of growth was in the first year after diagnosis (growth rate 0.128 mm per year), after which the mean tumor size appeared to stabilize. CONCLUSIONS: UBM is a valuable tool for detecting and following small ciliary body tumors (less than 4 mm), as these lesions may go undetected by other methods. Despite the potential for local extension into the iris or choroid, few of the tumors in this study exhibited growth, suggesting that many of these tumors can be managed conservatively. UBM can be used to assess various internal tumor features; however, arriving at a specific diagnosis without histologic correlation is difficult.

Prevalence of traumatic hip and pelvic fractures in patients with suspected hip fracture and negative initial standard radiographs--a study of emergency department patients.

OBJECTIVES: To determine the prevalence of hip and pelvic fractures in emergency department (ED) patients with hip pain and negative standard initial radiographs. METHODS: This was a retrospective, cohort study at an academic, community-based ED. ED patients presenting during a one-year period with hip pain for whom a plain-film radiograph was obtained were included. Eligible patients were identified by query of electronic records. Plain radiographs and magnetic resonance images (MRIs) were ordered at the discretion of the treating physician. Initial plain radiographs were read at the point of care by board-certified radiologists. MRI images were reviewed by radiologists with fellowship training in musculoskeletal imaging. Structured follow-up at more than one month postvisit was conducted to rule out a subsequent diagnosis of hip fracture. Ninety-five-percent confidence intervals (95% CIs) and kappa (kappa) were calculated as appropriate. RESULTS: Seven hundred sixty-four of 895 patients (85.3%) had follow-up completed (study group). Within the study group, 219 patients (29%) had evidence of fracture on initial radiographs. Of the 545 patients with negative initial radiographs, 62 patients (11.4%) underwent hip MRI during the ED visit. MRI identified 24 additional patients with hip fractures. Interobserver agreement for the presence of fracture on MRI was very good (kappa = 0.847). For patients with negative initial plain radiographs who did not have a hip MRI, follow-up did not identify any of these patients as having a subsequent diagnosis of fracture. Thus, 24 of 545 (4.4%; 95% CI = 3.0% to 6.5%) patients with negative initial plain radiographs had a hip fracture. CONCLUSIONS: In this cohort of ED patients with symptoms suspicious for hip fracture who had negative standard radiographs, the authors found that 4.4% were subsequently diagnosed as having fracture. Further studies are warranted to identify characteristics of patients requiring advanced hip imaging studies.

Electrocardiographic findings in Emergency Department patients with pulmonary embolism.

To assess the pre-study, null hypothesis that there is no difference in the electrocardiogram (EKG) findings for Emergency Department (ED) patients who rule in vs. rule out for suspected pulmonary embolism, a retrospective review of a cohort of patients with pulmonary embolism and their controls was conducted in an academic, suburban ED. Patients who were evaluated in the ED during a one-year study period for symptoms suggestive of pulmonary embolism were eligible for inclusion. All patients with pulmonary embolism and sex- and age-matched controls comprised the final study groups. Two board-certified cardiologists reviewed each patient's EKG. There were 350 eligible patients identified; 49 patients with pulmonary embolism and 49 controls were entered into the study. The most common rhythm observed in both groups was normal sinus rhythm (67.3% cases vs. 68.6 % controls; p = 1.0). Abnormalities believed to be associated with pulmonary embolism occurred with similar frequency in both case and control groups (sinus tachycardia [18.8 % vs. 11.8%, respectively; p = 0.40]), incomplete right bundle branch block (4.2% vs. 0.0%, respectively; p = 0.24), complete right bundle branch block (4.2% vs. 6.0, respectively; p = 1.0), S1Q3T3 pattern (2.1 vs. 0.0, respectively; p = 0.49), S1Q3 pattern (0.0 vs. 0.0), and extreme right axis (0.0 vs. 0.0). New EKG changes were identified more frequently for patients with pulmonary embolism (33.3% vs. 12.5% controls; p = 0.03), but specific findings were rarely different between cases and controls. In our cohort of ED patients, we did not identify EKG features that are likely to help distinguish patients with pulmonary embolism from those who rule out for the disease.

Anterior chamber depth in plateau iris syndrome and pupillary block as measured by ultrasound biomicroscopy.

PURPOSE: To quantitatively analyze the anterior chamber depth (ACD) in patients with pupillary block and plateau iris syndrome. DESIGN: Retrospective, consecutive, observational case series. METHODS: We measured the ACD in 318 eyes of 318 patients who had been diagnosed by ultrasound biomicroscopy as having either pupillary block or plateau iris syndrome. Pupillary block patients were all preiridotomy and plateau iris patients were all postiridotomy. Anterior chamber depth was measured axially from the internal corneal surface to the lens surface using the ultrasound instrument's internal measuring capability. RESULTS: The mean ACD in patients with plateau iris syndrome (n = 181) was significantly smaller than the hypothesized normal ACD (2.04 +/- 0.30 mm vs 3.0 mm, P =.0001). The mean ACD in patients with pupillary block (n = 137) was also significantly smaller than the hypothesized normal ACD (2.17 +/- 0.30 mm vs 3.0 mm, P =.0001). The mean ACD in patients with plateau iris syndrome was significantly smaller than the ACD in patients with pupillary block (2.04 +/- 0.30 mm vs 2.17 +/- 0.30 mm, P =.001). CONCLUSIONS: Review of the literature suggests that patients with plateau iris have a normal or deeper axial ACD compared with pupillary block. This study found that the ACD associated with plateau iris syndrome is shallower than normal and also shallower than in pupillary block.

Can emergency department triage nurses appropriately utilize the Ottawa Knee Rules to order radiographs?-An implementation trial.

OBJECTIVE: To determine whether triage nurses can successfully interpret the Ottawa Knee Rule (OKR) and order knee radiographs according to the OKR. METHODS: This was a prospective implementation trial of a clinical decision rule, set in a suburban, community emergency department (ED), evaluating a convenience sample of ED patients aged > 17 years with acute knee injuries. Patients were excluded for altered mental status, distracting injuries, and knee lacerations. Triage nurses and attending emergency physicians (EPs) were trained in appropriate use of the OKR. The triage nurses evaluated eligible patients and radiographs were ordered according to their interpretation of the OKR. EPs who were initially blinded to the triage assessments also evaluated the patients. EPs could add an x-ray order if, according to their assessment of the OKR, one was indicated and a radiograph had not been ordered by the nurse. Nurses and EPs recorded their blinded assessments on standardized data collection instruments. Kappa values were calculated to assess interobserver agreement (IOA) between nurses and EPs; sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were calculated as appropriate. RESULTS: One hundred three patients were enrolled; 53% were female; 10 fractures were identified (9.7%). The IOAs between the nurses and EPs for each of the criteria were moderate to almost perfect: age-0.94; fibular head tenderness-0.4; isolated patellar tenderness-0.68; inability to bend knee to 90 degrees-0.73; inability to bear weight-0.76. The IOA was moderate (0.52) for the overall interpretation of the OKR by nurses and EPs. Sensitivity of nurse interpretation of the OKR for fracture was 70%, specificity 33%, NPV 91%, PPV 10%. Sensitivity of EP interpretation of the OKR for fracture was 100%, specificity 25%, NPV 100%, PPV 13%. CONCLUSIONS: Triage nurses showed fair to good ability to appropriately apply the OKR to pre-order knee radiographs.

Do ED patients with migraine headaches meet internationally accepted criteria?

A recent editorial criticized emergency medicine researchers who study the treatment of acute migraine for failing to standardize patients according to definitions provided by the International Headache Society (IHS). In fact, most emergency medicine-based studies of migraine therapies have not used IHS Criteria (IHSC) for patient inclusion and are not uniform in the definition of acute migraine. The purpose of this study was to determine the percentage of patients with complaint of headache who present to the emergency department with a prior diagnosis of migraine and/or emergency department discharge diagnosis of acute migraine that meet IHSC. The study was a prospective observational study performed in a community-based and consisted of consecutive patients with a chief complaint of headache who presented to any 1 of 6 study investigators. Patients recorded historical data on a standard form; Clinical data were recorded by the investigators. Ninety-five percent confidence intervals and the Fisher exact test were calculated as appropriate. One hundred eighty-five patients were enrolled (study group): 70% were women, 43% had prior imaging studies to diagnose the etiology of the headache, and 26% had a diagnostic workup during the current emergency department visit; the probable headache etiology was found in 12 of these cases. Only 3 patients that had an ED workup that fit IHSC. Forty-nine percent of all patients had a prior diagnosis of migraines; 41 of these patients (45%) met IHSC. Forty-two percent of all patients had an emergency discharge diagnosis of acute migraine; of these, 43 (56%) met IHSC. Forty-four out of 96 (46%; 95% confidence interval = 35%-57%) patients with a prior diagnosis of migraine and/or discharge diagnosis of acute migraine met IHSC. Modification of the IHSC, by removing restrictions for headache duration and number of prior episodes, would have markedly increased the percentage of patients with a previous migraine and/or emergency discharge diagnosis of acute migraine that met other qualitative IHSC (94%). Of the patients with prior migraine diagnosis and/or emergency department diagnosis of acute migraine, men and women were equally as likely to meet IHSC (41% v 48%, P = 0.79). Less than half of patients with a prior diagnosis and/or final emergency discharge diagnosis of acute migraine met IHSC. Our findings raise concerns about the external validity of prior emergency department-based research of acute migraine therapy and the utility of the IHSC for future research. Modification of the IHSC for emergency medicine research should be considered.

Parental use and misuse of antibiotics: are there differences in urban vs. suburban settings?

OBJECTIVE: To compare the frequencies with which suburban and urban parents give their children antibiotics without first consulting a physician. METHODS: This was a prospective, comparative survey of a suburban emergency department (ED) patient population in New Jersey with an annual patient census of 60,000 visits and an urban ED in Connecticut with 58,000 annual visits. A convenience sample of parents with children <18 years of age were enrolled. Patients who were critically ill and/or not oriented were excluded. Subjects provided written answers to a series of closed questions regarding their knowledge and use of antibiotics for their children over the previous 12 months. Categorical data were analyzed by chi-square and Fisher's exact test; continuous data were analyzed by t-tests. All tests were two-tailed with alpha set at 0.05. The primary endpoint, antibiotic "misuse," was defined as parental administration of antibiotics to a child during the previous 12 months without the consultation of a physician. RESULTS: Eight hundred one parents were enrolled; 424 at the suburban site. Parents in the suburban site were significantly different with regard to mean age (39 +/- 7.2 vs. 32 +/- 9.0, p < 0.001), percentage female sex (63% vs. 81%, p < 0.001), percentage white race (78% vs. 34%, p < 0.001), and percentage with private insurance (89% vs. 56%, p < 0.001). A higher percentage of parents at the suburban site had misused antibiotics (12.1% vs. 4.0%; p < 0.001). Using logistic regression, this significant difference in the rate of antibiotic misuse between the two groups remained after adjustment for demographic variables and insurance status of the parents (p < 0.001). Parents at the suburban site were significantly less likely to have been previously discharged with their child from an office or ED setting without antibiotics only to go soon afterwards to another health facility in order to obtain such medications (5% vs. 48%; p < 0.001). CONCLUSIONS: Parents in the suburban setting were more likely to have misused antibiotics for their children. On the other hand, parents in the urban setting were more likely to have been discharged by a physician at one health facility and gone to another physician's office or ED in order to obtain antibiotics for their children.