Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

The Use of the Lateral Tibial Line to Assess Ankle Alignment: A Preliminary Investigation

BACKGROUND: Although the medial clear space (MCS) is commonly used to assess talar alignment and ankle stability, its measurement is variable with multiple reported normal values. We have observed that the lateral tibial shaft is a reliable landmark to assess talar alignment. The objective of the current investigation was to determine the normal relationship of the lateral tibia to the superolateral talus using a tangent drawn inferiorly from the lateral tibial shaft, which we refer to as the lateral tibial line (LTL). METHODS: The relationship of the LTL to the superolateral talus was assessed by three reviewers on 99 standing ankle mortise radiographs in uninjured patients. This relationship was quantified by measuring the distance (in millimeters) between the LTL and the superolateral talus. In addition, the interobserver reliability of the LTL measurement was recorded and compared with that of the MCS. RESULTS: The median value for the distance between the superolateral talus and LTL was -0.50 mm with an interquartile range of -1.4 to 0.0 mm. The LTL was within 1 mm of the lateral talus in 176 of 297 reviewer measurements (59.3%). Moreover, it was either lateral to or at most 1 mm medial to the lateral talus in 90.9% of cases. The LTL measurement also demonstrated good interobserver reliability (0.764, 95% confidence interval, 0.670 to 0.834), similar to the measurement of MCS (0.742, 95% confidence interval, 0.539 to 0.846). CONCLUSIONS: The relationship between the LTL and superolateral talus is easily measured with good reliability for assessing the anatomic relationship of the tibia and talus. The LTL uncommonly fell more than 1 mm medial to the superolateral talus, as might be seen with displaced ankle fractures. These findings will hopefully serve as a basis for future studies evaluating its role in assessing lateral displacement and stability of isolated fibula fractures. LEVEL OF EVIDENCE: Level III, retrospective review

The Use of the Lateral Tibial Line to Assess Ankle Alignment: A Preliminary Investigation

Category: Ankle; Trauma Introduction/Purpose: Although the medial clear space (MCS) is commonly used to assess talar alignment and ankle stability, its measurement is variable with multiple reported “normal” values. We have observed that the lateral tibial shaft is a reliable landmark to assess talar alignment. The objective of the current investigation was to determine the normal relationship of the lateral tibia to the superolateral talus using a tangent drawn inferiorly from the lateral tibial shaft, which we refer to as the “lateral tibial line” (LTL). Methods: The relationship of the LTL to the superolateral talus was assessed and characterized on ninety-nine standing ankle mortise radiographs in uninjured patients. This relationship was quantified by measuring the distance (in millimeters) between the LTL and the superolateral talus. Additionally, the inter-observer reliability of the LTL measurement, determined by three reviewers, was recorded and compared to medial clear space measurements. Results: The median value for the lateral tibial line was -0.50 mm with an interquartile range of -1.4mm - 0.0mm. The LTL was within 1mm of the lateral talus in 176 of 297 reviewer measurements (59.3%). Moreover, it was either lateral to or was at most 1mm medial to the lateral talus in 90.9% of cases. The LTL measurement also demonstrated good inter-observer reliability (0.764, 95% CI: 0.670-0.834), similar to the measurement of MCS (0.742, 95% CI: 0.539-0.846). Conclusion: The LTL is easily measured with good reliability for assessing the anatomic relationship of the tibia and talus. It uncommonly fell more than 1 mm medial to the superolateral talus. In other words, it was uncommon for the talus to shift lateral to this line, as might be seen with displaced ankle fractures. These findings will hopefully serve as a standard for future studies evaluating the role of the LTL in assessing lateral displacement and stability of isolated fibula fractures

Primary Care Physicians’ Preferences Regarding Communication from Orthopaedic Providers

Category: Other Introduction/Purpose: Musculoskeletal consultations constitute a growing portion of primary care physician (PCP) referrals. Optimization of communication between PCPs and orthopaedists can potentially reduce the time PCPs spend in the electronic medical record (EMR). This, in turn, may help reduce burnout. However, little is known about the preferences of PCPs regarding communication from orthopaedic specialists. The current study therefore investigated the preferences of PCPs across a large health network regarding communication from orthopaedists. Methods: One hundred and seventy-five PCPs across 15 practices within our health network were surveyed. These providers universally used the Epic Systems EMR. PCPs were asked to report their years in practice, panel size, typical number of electronic clinical messages received each day, time spent in the EMR after normal clinical hours, and burnout level. Likert scales and top-box scores were used to assess the PCPs’ perceived importance of communication from orthopedists in specific clinical scenarios. PCPs were further asked to report their preferred method of communication in each scenario and overall interest in communication from orthopaedists. Regression analyses were performed to determine if any PCP characteristics are associated with communication preferences and overall PCP interest in communication from orthopaedists. Results: A total of 107 (61%) PCPs completed the survey. PCPs most commonly rated communication from orthopaedists as highly important when the orthopaedist needed information from the PCP. In this scenario, PCPs preferred to receive an Epic Staff Message. Other scenarios rated as important included: the decision for surgery, hospitalization, and a major clinical change. In these scenarios, a CC’d Chart rather than Staff Message was preferred. Increased EMR use after-hours was associated with diminished odds of having high interest in communication from orthopaedists (odds ratio=0.65, 95% confidence interval: 0.48-0.88, P=0.005). Ninety-three PCPs (86.9%) reported spending at least 1 hour a day in Epic after normal clinical hours. Twenty-seven (25.2%) spent more than 3 hours. Forty-six PCPs (42.9%) reported experiencing at least one symptom of burnout. Conclusion: In the current study, there were distinct preferences among PCPs regarding clinical communication from orthopaedic surgeons. In addition, there was evidence of substantial burnout and after-hours work effort by PCPs. Our results may be helpful in optimizing communication between PCPs and orthopaedists, while also reducing time spent in the EMR by PCPs

The utility of vertebral Hounsfield units as a prognostic indicator of adverse events following treatment of spinal epidural abscess

ABSTRACT: Background: Spinal epidural abscesses (SEAs) are a devastating condition with high levels of associated morbidity and mortality. Hounsfield units (HUs), a marker of radiodensity on CT scans, have previously been correlated with adverse events following spinal interventions. We evaluated whether HUs might also be associated with all-cause complications and/or mortality in this high-risk population. Methods: This retrospective cohort study was carried out within an academic health system in the United States. Adults diagnosed with a SEA between 2006 and 2021 and who also had a CT scan characterizing their SEA within 6 months of diagnosis were considered. HUs were abstracted from the 4 vertebral bodies nearest to, but not including, the infected levels. Our primary outcome was the presence of composite 90-day complications and HUs represented the primary predictor. A multivariable logistic regression analysis was conducted adjusting for demographic and disease-specific confounders. In sensitivity testing, separate logistic regression analyses were conducted (1) in patients aged 65 and older and (2) with mortality as the primary outcome. Results: Our cohort consisted of 399 patients. The overall incidence of 90-day complications was 61.2% (n=244), with a 7.8% (n=31) 90-day mortality rate. Those experiencing complications were more likely to have undergone surgery to treat their SEA (58.6% vs. 46.5%; p=.018) but otherwise the cohorts were similar. HUs were not associated with composite 90-day complications (Odds ratio [OR] 1.00 [95% CI 1.00—1.00]; p=.842). Similar findings were noted in sensitivity testing. Conclusions: While HUs have previously been correlated with adverse events in certain clinical contexts, we found no evidence to suggest that HUs are associated with all-cause complications or mortality in patients with SEAs. Future research hoping to leverage 3-dimensional imaging as a prognostic measure in this patient population should focus on alternative targets. Level of Evidence: Level III; Observational Cohort study

Supplemental Material - Neurological Outcomes and the Need for Retreatments Among Multiple Myeloma Patients With High-Grade Spinal Cord Compression: Radiotherapy vs Surgery

Supplemental Material for Neurological Outcomes and the Need for Retreatments Among Multiple Myeloma Patients With High-Grade Spinal Cord Compression: Radiotherapy vs Surgery by Hester Zijlstra, MD, Alexander M. Crawford, MD, Brendan M. Striano, MD, Robert-Jan Pierik, BSc, Daniel G. Tobert, MD, Nienke Wolterbeek, PhD, Diyar Delawi, MD, PhD, Wim E. Terpstra, MD, PhD, Diederik H. R. Kempen, MD, PhD, Jorrit-Jan Verlaan, MD, PhD, and Joseph H. Schwab, MD, MS in Global Spine Journal</p