Clinical validity assessment of genes frequently tested on intellectual disability/autism sequencing panels.

PURPOSE: Neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and autism spectrum disorder (ASD), exhibit genetic and phenotypic heterogeneity, making them difficult to differentiate without a molecular diagnosis. The Clinical Genome Resource Intellectual Disability/Autism Gene Curation Expert Panel (GCEP) uses systematic curation to distinguish ID/ASD genes that are appropriate for clinical testing (ie, with substantial evidence supporting their relationship to disease) from those that are not. METHODS: Using the Clinical Genome Resource gene-disease validity curation framework, the ID/Autism GCEP classified genes frequently included on clinical ID/ASD testing panels as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship. RESULTS: As of September 2021, 156 gene-disease pairs have been evaluated. Although most (75%) were determined to have definitive roles in NDDs, 22 (14%) genes evaluated had either Limited or Disputed evidence. Such genes are currently not recommended for use in clinical testing owing to the limited ability to assess the effect of identified variants. CONCLUSION: Our understanding of gene-disease relationships evolves over time; new relationships are discovered and previously-held conclusions may be questioned. Without periodic re-examination, inaccurate gene-disease claims may be perpetuated. The ID/Autism GCEP will continue to evaluate these claims to improve diagnosis and clinical care for NDDs.

Breast Density Status Changes: Frequency, Sequence, and Practice Implications.

OBJECTIVE: Changes in a patient's reported breast density status (dense vs nondense) trigger modifications in their cancer risk profile and supplemental screening recommendations. This study tracked the frequency and longitudinal sequence of breast density status changes among patients who received serial mammograms. METHODS: This IRB-approved, HIPAA-compliant retrospective cohort study tracked breast density changes among patients who received at least 2 mammograms over an 8-year study period. BI-RADS density assessment categories A through D, visually determined at the time of screening, were abstracted from electronic medical records and dichotomized into either nondense (categories A or B) or dense (categories C or D) status. A sequence analysis of longitudinal changes in density status was performed using Microsoft SQL. RESULTS: A total of 58 895 patients underwent 231 997 screening mammograms. Most patients maintained the same BI-RADS density category A through D (87.35% [51 444/58 895]) and density status (93.35% [54 978/58 859]) throughout the study period. Among patients whose density status changed, the majority (97% [3800/3917]) had either scattered or heterogeneously dense tissue, and over half (57% [2235/3917]) alternated between dense and nondense status multiple times. CONCLUSION: Our results suggest that many cases of density status change may be attributable to intra- and interradiologist variability rather than to true underlying changes in density. These results lend support to consideration of automated density assessment because breast density status changes can significantly impact cancer risk assessment and supplemental screening recommendations.

Performance of International Classification of Disease-10 codes in detecting emergency department patients with opioid misuse.

BACKGROUND AND AIMS: Accurate case discovery is critical for disease surveillance, resource allocation and research. International Classification of Disease (ICD) diagnosis codes are commonly used for this purpose. We aimed to determine the sensitivity, specificity and positive predictive value (PPV) of ICD-10 codes for opioid misuse case discovery in the emergency department (ED) setting. DESIGN AND SETTING: Retrospective cohort study of ED encounters from January 2018 to December 2020 at an urban academic hospital in the United States. A sample of ED encounters enriched for opioid misuse was developed by oversampling ED encounters with positive urine opiate screens or pre-existing opioid-related diagnosis codes in addition to other opioid misuse risk factors. CASES: A total of 1200 randomly selected encounters were annotated by research staff for the presence of opioid misuse within health record documentation using a 5-point scale for likelihood of opioid misuse and dichotomized into cohorts of opioid misuse and no opioid misuse. MEASUREMENTS: Using manual annotation as ground truth, the sensitivity and specificity of ICD-10 codes entered during the encounter were determined with PPV adjusted for oversampled data. Metrics were also determined by disposition subgroup: discharged home or admitted. FINDINGS: There were 541 encounters annotated as opioid misuse and 617 with no opioid misuse. The majority were males (54.4%), average age was 47 years and 68.5% were discharged directly from the ED. The sensitivity of ICD-10 codes was 0.56 (95% confidence interval [CI], 0.51-0.60), specificity 0.99 (95% CI, 0.97-0.99) and adjusted PPV 0.78 (95% CI, 0.65-0.92). The sensitivity was higher for patients discharged from the ED (0.65; 95% CI, 0.60-0.69) than those admitted (0.31; 95% CI, 0.24-0.39). CONCLUSIONS: International Classification of Disease-10 codes appear to have low sensitivity but high specificity and positive predictive value in detecting opioid misuse among emergency department patients in the United States.

The Identification of Subphenotypes and Associations with Health Outcomes in Patients with Opioid-Related Emergency Department Encounters Using Latent Class Analysis.

The emergency department (ED) is a critical setting for the treatment of patients with opioid misuse. Detecting relevant clinical profiles allows for tailored treatment approaches. We sought to identify and characterize subphenotypes of ED patients with opioid-related encounters. A latent class analysis was conducted using 14,057,302 opioid-related encounters from 2016 through 2017 using the National Emergency Department Sample (NEDS), the largest all-payer ED database in the United States. The optimal model was determined by face validity and information criteria-based metrics. A three-step approach assessed class structure, assigned individuals to classes, and examined characteristics between classes. Class associations were determined for hospitalization, in-hospital death, and ED charges. The final five-class model consisted of the following subphenotypes: Chronic pain (class 1); Alcohol use (class 2); Depression and pain (class 3); Psychosis, liver disease, and polysubstance use (class 4); and Pregnancy (class 5). Using class 1 as the reference, the greatest odds for hospitalization occurred in classes 3 and 4 (Ors 5.24 and 5.33, p < 0.001) and for in-hospital death in class 4 (OR 3.44, p < 0.001). Median ED charges ranged from USD 2177 (class 1) to USD 2881 (class 4). These subphenotypes provide a basis for examining patient-tailored approaches for this patient population.

In vivo femoral head damage and its effect on polyethylene wear.

The purposes of this study were to determine the spectrum of femoral head damage in patients undergoing revision total hip arthroplasty and to determine the impact of that damage on polyethylene wear. One hundred eight consecutive modular metal femoral heads were retrieved at revision surgery. The mean roughness (Ra) value was 0.18 +/- 0.18 microm. The roughest femoral heads (mean Ra, 0.56 microm) were from retrievals correlated with mode 2 wear (recurrent dislocation and complete wear through of the polyethylene liner). Five million cycles of wear tests were performed using retrieved femoral heads against both new conventional and highly cross-linked polyethylene. The mean wear rate of conventional polyethylene was 15.9 +/- 4.3 mg and that of highly cross-linked polyethylene was 0.04 +/- 0.14 mg per 1 million cycles (P < .001). Highly cross-linked polyethylene was more resistant to wear than conventional polyethylene, even when mated against roughened femoral heads.