Citations

Abstract AIMS Methods for disease monitoring in glioma are currently limited. Liquid biopsies are of increasing interest within the field but have been challenging due to the blood-brain barrier. To bypass this challenge, we aimed to assess the technical and clinical feasibility of obtaining intracranial cerebrospinal fluid (CSF) for disease monitoring via cell-free DNA (cfDNA). METHOD Adults with gliomas were recruited for longitudinal intracranial CSF collection via CSF access devices, including Ommaya reservoirs in four patients and an existing VP shunt in one patient. cfDNA was then extracted and analyzed using two sequencing platforms, PredicineCARE for cancer variant profiling and PredicineSCORE for low-pass whole genome sequencing (LP-WGS). This analysis generated genomic aberration profiles and genome wide copy number burden (CNB) score. RESULTS Across five patients, thirty-five CSF samples were obtained (median volume: 3.80 mL; 0.5-5 mL), with 30 samples (85.7%) yielding sufficient cfDNA. Tumor fraction increased by 6.28x and 2.87x in two patients with radiographic disease progression and decreased by 0.08x and 0.04x in another two after chemoradiation. In another patient with pseudoprogression, tumor fraction decreased from 0.26 after resection to unmeasurable levels. Patient specific tumor-associated variant allelic frequencies (VAFs), including TP53, PTEN, and TERT, decreased within individual patients after resection and chemoradiation. In two patients with IDH-mutant gliomas, IDH1 VAF after resection correlated with decreased CSF D-2-hydroxyglutarate (D-2-HG) levels (0.64x and 0.62x, respectively, for the first patient, and 0.01x and 0.07x for the other patient). Both IDH1 VAF and D-2-HG increased in a patient with radiographic progression (2.56x and 9.21x, respectively). CNB decreased below the limit of quantification during treatment and increased above the limit at progression. CONCLUSION Longitudinal CSF cfDNA can feasibly be obtained via CSF access devices in patients with gliomas during their disease course. Further sample collection and analysis are ongoing to determine the thresholds of change indicative of treatment response and progression.

Abstract Pharmacogenomic (PGx) biomarkers integrated using machine learning can be embedded within the electronic health record (EHR) to provide clinicians with individualized predictions of drug treatment outcomes. Currently, however, drug alerts in the EHR are largely generic (not patient‐specific) and contribute to increased clinician stress and burnout. Improving the usability of PGx alerts is an urgent need. Therefore, this work aimed to identify principles for optimal PGx alert design through a health‐system‐wide, mixed‐methods study. Clinicians representing multiple practices and care settings ( N = 1062) in urban, rural, and underserved regions were invited to complete an electronic survey comparing the usability of three drug alerts for citalopram, as a case study. Alert 1 contained a generic warning of pharmacogenomic effects on citalopram metabolism. Alerts 2 and 3 provided patient‐specific predictions of citalopram efficacy with varying depth of information. Primary outcomes included the System's Usability Scale score (0–100 points) of each alert, the perceived impact of each alert on stress and decision‐making, and clinicians' suggestions for alert improvement. Secondary outcomes included the assessment of alert preference by clinician age, practice type, and geographic setting. Qualitative information was captured to provide context to quantitative information. The final cohort comprised 305 geographically and clinically diverse clinicians. A simplified, individualized alert (Alert 2) was perceived as beneficial for decision‐making and stress compared with a more detailed version (Alert 3) and the generic alert (Alert 1) regardless of age, practice type, or geographic setting. Findings emphasize the need for clinician‐guided design of PGx alerts in the era of digital medicine.

Abstract Objective SNOMED CT provides a standardized terminology for clinical concepts, allowing cohort queries over heterogeneous clinical data including Electronic Health Records (EHRs). While it is intuitive that missing and inaccurate subtype (or is-a) relations in SNOMED CT reduce the recall and precision of cohort queries, the extent of these impacts has not been formally assessed. This study fills this gap by developing quantitative metrics to measure these impacts and performing statistical analysis on their significance. Material and Methods We used the Optum de-identified COVID-19 Electronic Health Record dataset. We defined micro-averaged and macro-averaged recall and precision metrics to assess the impact of missing and inaccurate is-a relations on cohort queries. Both practical and simulated analyses were performed. Practical analyses involved 407 missing and 48 inaccurate is-a relations confirmed by domain experts, with statistical testing using Wilcoxon signed-rank tests. Simulated analyses used two random sets of 400 is-a relations to simulate missing and inaccurate is-a relations. Results Wilcoxon signed-rank tests from both practical and simulated analyses (P-values < .001) showed that missing is-a relations significantly reduced the micro- and macro-averaged recall, and inaccurate is-a relations significantly reduced the micro- and macro-averaged precision. Discussion The introduced impact metrics can assist SNOMED CT maintainers in prioritizing critical hierarchical defects for quality enhancement. These metrics are generally applicable for assessing the quality impact of a terminology’s subtype hierarchy on its cohort query applications. Conclusion Our results indicate a significant impact of missing and inaccurate is-a relations in SNOMED CT on the recall and precision of cohort queries. Our work highlights the importance of high-quality terminology hierarchy for cohort queries over EHR data and provides valuable insights for prioritizing quality improvements of SNOMED CT's hierarchy.

Objective To explore associations between general health-related problems and subclinical coronary artery disease (CAD), determined by CT coronary calcium score (CT-CCS), in a general population. Design A cross-sectional design. Setting This study was performed in a prospective population-based cohort, examining the health and health-related behaviour of individuals living in the Northern Netherlands. Participants The initial cohort comprised 6763 participants ≥45 years of age who underwent CT-scanning. Participants were included for the current analysis if they filled in three validated questionnaires (Symptomatic Checklist-90, Research and Development Survey-36 and Reviving the Early Diagnosis of CardioVascular Diseases questionnaire (RED-CVD)) and did not have a history of cardiovascular disease. The final analysis included 6530 participants. Primary outcome measure Backward-stepwise and forward-stepwise logistic regression analyses were performed to determine associations between general health-related problems and subclinical CAD (CCS≥100 and ≥300). Results The median age was 53 years (25th, 75th percentile: 48, 58); 57% were women. CRCS≥100 was found in 1236 (19%) participants, 437 (12%) in women and 799 (29%) men and CCS≥300 in 643 (9.9%) participants of which 180 (4.8%) were women and 463 (16.6%) men. In univariate analysis, in women the expectation of health to worsen (OR=1.13, 95% CI: 1.05 to 1.21), and in men reduced exercise intolerance (OR=1.14, 95% CI: 1.06 to 1.23) were associated with CCS≥100. The total RED-CVD score in women (OR=1.06, (95% CI: 1.05 to 1.08) and men (OR=1.07, 95% CI: 1.06 to 1.09), and in men also reduced exercise intolerance (OR=1.15, 95% CI: 1.06 to 1.25) and headache (OR=0.55, 95% CI: 0.38 to 0.79) were associated with CCS≥300. In multivariate analyses, only general health expectation in women was still significantly associated with subclinical CAD (CCS≥300) (OR=1.92, 95% CI: 1.56 to 2.37). Conclusion Only a few general health-related problems were associated with the presence of subclinical CAD in the general population, however, these problems showed no strong association. Therefore, using health-related symptoms does not seem useful to pre-select for CT-CCS. Trial registration number CCMO Register, NL17981.042.07 and NL58592.042.16.

AbstractQuantitative susceptibility mapping (QSM) is a tool for mapping tissue susceptibility. Using QSM for functional brain mapping, it is possible to directly quantify blood‐oxygen‐level‐dependent (BOLD) susceptibility changes. This study presents a submillimeter functional QSM (fQSM) approach compared to BOLD fMRI from data acquired with 3D gradient‐echo echo planar imaging (EPI) at ultra‐high field. Complex EPI data were acquired in nine healthy subjects with varying temporal and spatial resolutions and used for BOLD fMRI and for fQSM. Right‐hand finger tapping experiments were performed as well as one measurement with intentional subject movement. Susceptibility maps were computed using 3D path‐based unwrapping, the variable‐kernel sophisticated harmonic artifact reduction for phase data, and the streaking artifact reduction for QSM algorithm. Functional data analysis included general linear modeling and computation of z‐scores. Submillimeter data were denoised using NOise reduction with DIstribution Corrected (NORDIC), which improved z‐scores in the motor cortex for fQSM and fMRI. An expected increase in BOLD fMRI signal and corresponding decrease in magnetic susceptibility was observed in sensorimotor areas during active periods. For all experiments, fQSM showed smaller activation regions compared with fMRI. The percentage of high negative t‐values localized in the cortex was higher for fQSM (52%) than for positive or negative t‐values for fMRI (45%). For the scans with intentional motion, movement exceeded the size of a voxel, but paradigm dependent signal evolution could be recovered using motion correction. In conclusion, this study demonstrates the feasibility of submillimeter whole‐brain fQSM with voxel volume of 0.53 μL. In comparison to traditional BOLD fMRI, fQSM provided improved localization of brain activation within the cortex, especially in submillimeter 3D EPI sequences.

Purpose: We describe a case of nontraumatic macular hole in a pediatric patient associated with numerous epiretinal lesions throughout the macula. Methods: A healthy 9-year-old girl presented to retina clinic with several months of blurry vision in the right eye. Clinically, there was a full-thickness macular hole with serous detachment and white epiretinal tufts. Spectral-domain optical coherence tomography confirmed the presence of the full-thickness macular hole with hyperreflective epiretinal proliferations in the right eye and an unremarkable left eye. Systemic workup was negative. After a short period of observation, the patient underwent vitrectomy with internal limiting membrane peel and 14% C3F8 gas tamponade in the right eye. Multiple intraoperative samples were sent for further testing, which were also negative. Results: At 1- and 12 months/1 year postoperative visits, examination showed successful closure of the full-thickness macular hole with resolution of the subretinal fluid and improved VA. Conclusion: Nontraumatic macular holes in pediatric patients warrant systemic and ocular workup, including fluorescein angiography and laboratory testing. Good anatomic and visual outcomes are generally seen with spontaneous and surgical closures of macular holes in this age group. Early vitrectomy with histologic analysis of ocular samples should be considered in pediatric macular hole cases associated with vitreoretinal traction, especially those with epiretinal abnormalities.