OBJECTIVE: Phenotypic misclassification in genetic association analyses can impact the accuracy of PRS-based prediction models. The bias reduction method proposed by Tong et al. (2019) has demonstrated its efficacy in reducing the effects of bias on the estimation of association parameters between genotype and phenotype while minimizing variance by employing chart reviews on a subset of the data for validating phenotypes, however its improvement of subsequent PRS prediction accuracy remains unclear. Our study aims to fill this gap by assessing the performance of simulated PRS models and estimating the optimal number of chart reviews needed for validation.
METHODS: To comprehensively assess the efficacy of the bias reduction method proposed by Tong et al. in enhancing the accuracy of PRS-based prediction models, we simulated each phenotype under different correlation structures (an independent model, a weakly correlated model, a strongly correlated model) and introduced error-prone phenotypes using two distinct error mechanisms (differential and non-differential phenotyping errors). To facilitate this, we used genotype and phenotype data from 12 case-control datasets in the Alzheimer\'s Disease Genetics Consortium (ADGC) to produce simulated phenotypes. The evaluation included analyses across various misclassification rates of original phenotypes as well as quantities of validation set. Additionally, we determined the median threshold, identifying the minimal validation size required for a meaningful improvement in the accuracy of PRS-based predictions across a broad spectrum.
RESULTS: This simulation study demonstrated that incorporating chart review does not universally guarantee enhanced performance of PRS-based prediction models. Specifically, in scenarios with minimal misclassification rates and limited validation sizes, PRS models utilizing debiased regression coefficients demonstrated inferior predictive capabilities compared to models using error-prone phenotypes. Put differently, the effectiveness of the bias reduction method is contingent upon the misclassification rates of phenotypes and the size of the validation set employed during chart reviews. Notably, when dealing with datasets featuring higher misclassification rates, the advantages of utilizing this bias reduction method become more evident, requiring a smaller validation set to achieve better performance.
CONCLUSIONS: This study highlights the importance of choosing an appropriate validation set size to balance between the efforts of chart review and the gain in PRS prediction accuracy. Consequently, our study establishes a valuable guidance for validation planning, across a diverse array of sensitivity and specificity combinations.

OBJECTIVE: The phase 3 REGAIN study and its open-label extension demonstrated the efficacy of the complement C5 inhibitor eculizumab in patients with treatment-refractory, acetylcholine receptor antibody-positive generalized myasthenia gravis (gMG). The aim of the ELEVATE study was to assess the effectiveness of eculizumab in clinical practice in adults with MG in the United States.
METHODS: A retrospective chart review was conducted in adults with MG who initiated eculizumab treatment between October 23, 2017 and December 31, 2019. Outcomes assessed before and during eculizumab treatment using a pre- versus post-treatment study design included Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores; minimal symptom expression (MSE); physician impression of clinical change; minimal manifestation status (MMS); and concomitant medication use.
RESULTS: In total, 119 patients were included in the study. A significant reduction was observed in mean MG-ADL total score, from 8.0 before eculizumab initiation to 5.4 at 3 months and to 4.7 at 24 months after eculizumab initiation (both p < 0.001). At 24 months after eculizumab initiation, MSE was achieved by 19% of patients. MMS or better was achieved by 30% of patients at 24 months. Additionally, 64% of patients receiving prednisone at eculizumab initiation had their prednisone dosage reduced during eculizumab treatment and 13% discontinued prednisone; 32% were able to discontinue nonsteroidal immunosuppressant therapy.
CONCLUSIONS: Eculizumab treatment was associated with sustained improvements in MG-ADL total scores through 24 months in adults with MG. Prednisone dosage was reduced in approximately two-thirds of patients, suggesting a steroid-sparing effect for eculizumab.

Purpose: Improvements in outcomes for adolescent and young adult (AYA) oncology patients have lagged behind those of other age-specific cancer populations. Research has indicated that low availability of clinical trials, biological differences of this age-group, and several psychosocial factors including higher emotional distress impact outcomes. To improve care and survival rates for these patients, hospitals have implemented AYA oncology programs. The current study evaluated documentation of care in an AYA program housed in an academic medical center based on three areas emphasized in the National Comprehensive Cancer Network\'s Clinical Practice Guidelines in Oncology for AYAs: clinical trial enrollment, fertility, and psychosocial care. Methods: Retrospective chart reviews were conducted for 45 patients treated before the start of the AYA oncology program and 45 patients treated after program initiation. Patients aged 15-39 years with a diagnosis of a malignant tumor were included. Variables evaluated included documentation of clinical trial enrollment, fertility preservation and sexual health considerations, and behavioral health referrals. Results: Documentation of most clinical trial and fertility variables did not significantly improve from pre- to post-program, although a higher number of patients had these variables documented post-program. Behavioral health referrals increased significantly from 52.8% pre-program to 95.4% post-program. Conclusion: Access to behavioral health care improved the most following implementation of our AYA program, which is likely because of the integration of a dedicated psychologist for AYAs when the program began. The practice of guideline-based care for this population can be better assessed and improved with designated behavioral health providers and more systematic documentation processes.

UNASSIGNED: Long COVID, marked by persistent, recurring, or new symptoms post-COVID-19 infection, impacts children\'s well-being yet lacks a unified clinical definition. This study evaluates the performance of an empirically derived Long COVID case identification algorithm, or computable phenotype, with manual chart review in a pediatric sample. This approach aims to facilitate large-scale research efforts to understand this condition better.
UNASSIGNED: The algorithm, composed of diagnostic codes empirically associated with Long COVID, was applied to a cohort of pediatric patients with SARS-CoV-2 infection in the RECOVER PCORnet EHR database. The algorithm classified 31,781 patients with conclusive, probable, or possible Long COVID and 307,686 patients without evidence of Long COVID. A chart review was performed on a subset of patients (n=651) to determine the overlap between the two methods. Instances of discordance were reviewed to understand the reasons for differences.
UNASSIGNED: The sample comprised 651 pediatric patients (339 females, M age = 10.10 years) across 16 hospital systems. Results showed moderate overlap between phenotype and chart review Long COVID identification (accuracy = 0.62, PPV = 0.49, NPV = 0.75); however, there were also numerous cases of disagreement. No notable differences were found when the analyses were stratified by age at infection or era of infection. Further examination of the discordant cases revealed that the most common cause of disagreement was the clinician reviewers\' tendency to attribute Long COVID-like symptoms to prior medical conditions. The performance of the phenotype improved when prior medical conditions were considered (accuracy = 0.71, PPV = 0.65, NPV = 0.74).
UNASSIGNED: Although there was moderate overlap between the two methods, the discrepancies between the two sources are likely attributed to the lack of consensus on a Long COVID clinical definition. It is essential to consider the strengths and limitations of each method when developing Long COVID classification algorithms.

BACKGROUND: Up to 50% of antibiotic prescriptions for upper respiratory infections (URIs) are inappropriate. Clinical decision support (CDS) systems to mitigate unnecessary antibiotic prescriptions have been implemented into electronic health records, but their use by providers has been limited.
OBJECTIVE: As a delegation protocol, we adapted a validated electronic health record-integrated clinical prediction rule (iCPR) CDS-based intervention for registered nurses (RNs), consisting of triage to identify patients with low-acuity URI followed by CDS-guided RN visits. It was implemented in February 2022 as a randomized controlled stepped-wedge trial in 43 primary and urgent care practices within 4 academic health systems in New York, Wisconsin, and Utah. While issues were pragmatically addressed as they arose, a systematic assessment of the barriers to implementation is needed to better understand and address these barriers.
METHODS: We performed a retrospective case study, collecting quantitative and qualitative data regarding clinical workflows and triage-template use from expert interviews, study surveys, routine check-ins with practice personnel, and chart reviews over the first year of implementation of the iCPR intervention. Guided by the updated CFIR (Consolidated Framework for Implementation Research), we characterized the initial barriers to implementing a URI iCPR intervention for RNs in ambulatory care. CFIR constructs were coded as missing, neutral, weak, or strong implementation factors.
RESULTS: Barriers were identified within all implementation domains. The strongest barriers were found in the outer setting, with those factors trickling down to impact the inner setting. Local conditions driven by COVID-19 served as one of the strongest barriers, impacting attitudes among practice staff and ultimately contributing to a work infrastructure characterized by staff changes, RN shortages and turnover, and competing responsibilities. Policies and laws regarding scope of practice of RNs varied by state and institutional application of those laws, with some allowing more clinical autonomy for RNs. This necessitated different study procedures at each study site to meet practice requirements, increasing innovation complexity. Similarly, institutional policies led to varying levels of compatibility with existing triage, rooming, and documentation workflows. These workflow conflicts were compounded by limited available resources, as well as an implementation climate of optional participation, few participation incentives, and thus low relative priority compared to other clinical duties.
CONCLUSIONS: Both between and within health care systems, significant variability existed in workflows for patient intake and triage. Even in a relatively straightforward clinical workflow, workflow and cultural differences appreciably impacted intervention adoption. Takeaways from this study can be applied to other RN delegation protocol implementations of new and innovative CDS tools within existing workflows to support integration and improve uptake. When implementing a system-wide clinical care intervention, considerations must be made for variability in culture and workflows at the state, health system, practice, and individual levels.
BACKGROUND: ClinicalTrials.gov NCT04255303; https://clinicaltrials.gov/ct2/show/NCT04255303.

BACKGROUND: Gastrointestinal (GI) bleeding events (BEs) in von Willebrand disease (VWD) are difficult to diagnose and often recurrent. Limited data from clinical trials has led to lack of consensus on treatment options.
OBJECTIVE: Describe current treatments and outcomes for GI BEs in people with VWD.
METHODS: This retrospective, observational, multicentre chart review study was conducted from January 2018 through December 2019 and included patients with inherited VWD with ≥1 GI BE in the preceding 5 years. Baseline characteristics, number and aetiology of BEs, associated GI-specific morbidities/lesions, treatment and outcomes were analysed descriptively.
RESULTS: Sixty bleeds were reported in 20 patients with type 1 (20%), type 2 (50%) and type 3 (30%) VWD. During the 5-year study period, 31 (52%) BEs had one identified or suspected cause; multiple causes were reported in 11 (18%). Most GI BEs (72%) were treated with a combination of von Willebrand factor (VWF), antifibrinolytics and/or other haemostatic or non-haemostatic treatments. Time to resolution did not differ by VWF treatment use; however, BEs treated with non-VWF treatments tended to resolve later. In patients with GI-specific morbidities/lesions, 84% resolved with first-line treatment; time to resolution tended to be longer than in patients without such morbidities/lesions. Thirteen BEs occurred in patients receiving prophylaxis and 47 in patients receiving on-demand treatment; 18 BEs resulted in a switch to prophylaxis after bleed resolution.
CONCLUSIONS: This study confirms the unmet need for the management of recurrent GI BEs in people with VWD and the need for prospective data, especially on prophylaxis.

UNASSIGNED: Claims data can be leveraged to study rare diseases such as Guillain-Barré Syndrome (GBS), a neurological autoimmune condition. It is difficult to accurately measure and distinguish true cases of disease with claims without a validated algorithm. Our objective was to identify the best-performing algorithm for identifying incident GBS cases in Medicare fee-for-service claims data using chart reviews as the gold standard.
UNASSIGNED: This was a multi-center, single institution cohort study from 2015 to 2019 that used Medicare-linked electronic health record (EHR) data. We identified 211 patients with a GBS diagnosis code in any position of an inpatient or outpatient claim in Medicare that also had a record of GBS in their electronic medical record. We reported the positive predictive value (PPV = number of true GBS cases/total number of GBS cases identified by the algorithm) for each algorithm tested. We also tested algorithms using several prevalence assumptions for false negative GBS cases and calculated a ranked sum for each algorithm\'s performance.
UNASSIGNED: We found that 40 patients out of 211 had a true case of GBS. Algorithm 17, a GBS diagnosis in the primary position of an inpatient claim and a diagnostic procedure within 45 days of the inpatient admission date, had the highest PPV (PPV = 81.6%, 95% CI (69.3, 93.9). Across three prevalence assumptions, Algorithm 15, a GBS diagnosis in the primary position of an inpatient claim, was favored (PPV = 79.5%, 95% CI (67.6, 91.5).
UNASSIGNED: Our findings demonstrate that patients with incident GBS can be accurately identified in Medicare claims with a chart-validated algorithm. Using large-scale administrative data to study GBS offers significant advantages over case reports and patient repositories with self-reported data, and may be a potential strategy for the study of other rare diseases.

BACKGROUND: Post-COVID-19 condition (colloquially known as \"long COVID-19\") characterized as postacute sequelae of SARS-CoV-2 has no universal clinical case definition. Recent efforts have focused on understanding long COVID-19 symptoms, and electronic health record (EHR) data provide a unique resource for understanding this condition. The introduction of the International Classification of Diseases, Tenth Revision (ICD-10) code U09.9 for \"Post COVID-19 condition, unspecified\" to identify patients with long COVID-19 has provided a method of evaluating this condition in EHRs; however, the accuracy of this code is unclear.
OBJECTIVE: This study aimed to characterize the utility and accuracy of the U09.9 code across 3 health care systems-the Veterans Health Administration, the Beth Israel Deaconess Medical Center, and the University of Pittsburgh Medical Center-against patients identified with long COVID-19 via a chart review by operationalizing the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) definitions.
METHODS: Patients who were COVID-19 positive with either a U07.1 ICD-10 code or positive polymerase chain reaction test within these health care systems were identified for chart review. Among this cohort, we sampled patients based on two approaches: (1) with a U09.9 code and (2) without a U09.9 code but with a new onset long COVID-19-related ICD-10 code, which allows us to assess the sensitivity of the U09.9 code. To operationalize the long COVID-19 definition based on health agency guidelines, symptoms were grouped into a \"core\" cluster of 11 commonly reported symptoms among patients with long COVID-19 and an extended cluster that captured all other symptoms by disease domain. Patients having ≥2 symptoms persisting for ≥60 days that were new onset after their COVID-19 infection, with ≥1 symptom in the core cluster, were labeled as having long COVID-19 per chart review. The code\'s performance was compared across 3 health care systems and across different time periods of the pandemic.
RESULTS: Overall, 900 patient charts were reviewed across 3 health care systems. The prevalence of long COVID-19 among the cohort with the U09.9 ICD-10 code based on the operationalized WHO definition was between 23.2% and 62.4% across these health care systems. We also evaluated a less stringent version of the WHO definition and the CDC definition and observed an increase in the prevalence of long COVID-19 at all 3 health care systems.
CONCLUSIONS: This is one of the first studies to evaluate the U09.9 code against a clinical case definition for long COVID-19, as well as the first to apply this definition to EHR data using a chart review approach on a nationwide cohort across multiple health care systems. This chart review approach can be implemented at other EHR systems to further evaluate the utility and performance of the U09.9 code.

UNASSIGNED: Evidence on co-occurring mental health problems in youth with physical disabilities is growing, however how services are provided remains unclear. This study examined current interprofessional rehabilitation practices for physical and mental health services.
UNASSIGNED: Youth (aged 15-24) followed for a physical disability that had mental health problems were identified. Chart reviews were used to identify practices. Mental health-related diagnoses/symptoms, assessments, goals, interventions, and referrals were extracted for inductive content analysis.
UNASSIGNED: Sixty charts were reviewed. Mental health problems included anxiety (n = 53), depression (n = 25), neurodevelopmental (n = 19) and personality disorders (n = 8), often (n = 36) citing more than one. No mental health assessments were found, and in 43%, no goals or interventions were evident. Relevant goals (n = 98) targeted emotional management, autonomy/communication of needs, acceptance of physical condition, socialization, routines/energy levels, school/work supports, and leisure/calming environments. Interventions (n = 104) included emotional management, formal individual/group therapy, links with external supports, routines/activities, reflection/acceptance, and school/work support. Mental health services were received in-house (n = 24) and/or externally (n = 30), plus 18 referrals pending and 14 not referred.
UNASSIGNED: Many had more than one mental health problem, suggesting the complexity of their condition. While some mental health goals/interventions are documented, problems may often not be reported or addressed in this context.
Further attention can be directed to the needs of youth with physical disabilities and co-occurring mental health problems as they are not fully addressed by current interdisciplinary rehabilitation practices.Follow-up (services and referrals) should be adapted to the holistic needs of youth and their goals within the rehabilitation context.Rehabilitation professionals can be provided with training to build workforce capacity in mental health screening and have access to guidance when addressing situations related to mental health or referring to external services.

UNASSIGNED: : This study tried to observe clinical benefit of aripiprazole augmentation (ARPA) treatment for major depressive disorder with anxious distress (MDDA) in routine practice.
UNASSIGNED: : Retrospective chart review (n = 41) was conducted for clinical benefit of ARPA in patients with MDDA in routine practice. The primary endpoint was the mean change of Hamilton Anxiety Rating scale (HAMA) total scores from baseline to the endpoint. Additional secondary endpoints were also retrieved.
UNASSIGNED: : The changes of primary endpoint HAMA (t = 5.731, -4.6, p = 0.001), and secondary endpoints including Hamilton Depression Rating scale (HAMD, t = 4.284, -3.4, p ＜ 0.001), Clinical Global Impression-Clinical Benefit (CGI-CB, -0.9, t = 1.821, p = 0.026), and Clinical Global Impression Score-Severity (CGI-S, t = 3.556, -0.4, p ＜ 0.001) scores were also significantly improved during the study. No significant adverse events were observed.
UNASSIGNED: : This study has shown additional benefit of ARPA treatment for MDDA patients in routine practice. However, adequately-powered and well-controlled studies are necessary for generalization of the present findings.