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01.

medRxiv (Medicine) 2026-06-22 DOI: HASH:ee67e3574abe8fab2aca00d8333370bb

Assessment of adaptive functioning in Angelman syndrome using the Vineland Adaptive Behavior Scales, Third Edition

作者:

Potter↗S. N↗Zhang↗Friedman↗Gable↗Ali↗Barbieri-Welge↗R. L↗Ben-Tall↗Caravella↗K. E↗DeRamus↗…

Purpose: This study examined longitudinal trajectories of adaptive functioning in 331 individuals with Angelman syndrome (AS) using the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) and examined differences by molecular subtype. Methods: A total of 331 individuals (156 females, 47%) with genetically confirmed AS (ages 6 months to 52 years) were assessed between 2018 and 2025, including 207 with a deletion subtype, 63 with uniparental disomy or imprinting defect, and 61 with a UBE3A point mutation. Growth scale values were analyzed using linear mixed-effects models with log2-transformed age. Results: Individuals with deletion subtypes demonstrated significantly lower adaptive functioning across domains compared to those with non-deletion subtypes. Adaptive skills across all Vineland-3 subdomains increased nonlinearly with age, showing faster growth early in life that slowed over time, with largely parallel trajectories across subtypes. Conclusion: Individuals with AS demonstrate slow but steady growth in adaptive functioning that continues into adulthood, with progress varying by molecular subtype. These findings provide updated natural history benchmarks and demonstrate the utility of the Vineland-3 for clinical trials.

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02.

arXiv (CS.LG) 2026-06-25 DOI: arXiv:2508.07952

Shapley-Inspired Feature Weighting in $k$-means with No Additional Hyperparameters

作者:

Richard J. Fawley↗Renato Cordeiro de Amorim↗

arXiv:2508.07952v2 Announce Type: replace Abstract: Clustering algorithms often assume all features contribute equally to the data structure, an assumption that usually fails in high-dimensional or noisy settings. Feature weighting methods can address this, but most require additional parameter tuning. We propose SHARK (Shapley Reweighted $k$-means), a feature-weighted clustering algorithm motivated by the use of Shapley values from cooperative game theory to quantify feature relevance, which requires no additional parameters beyond those in $k$-means. We prove that the $k$-means objective can be decomposed into a sum of per-feature Shapley values, providing an axiomatic foundation for unsupervised feature relevance and reducing Shapley computation from exponential to polynomial time. SHARK iteratively re-weights features by the inverse of their Shapley contribution, emphasising informative dimensions and down-weighting irrelevant ones, and is equivalent to replacing the arithmetic mean of feature dispersions with their harmonic mean. Experiments on synthetic and real-world data sets show that SHARK consistently matches or outperforms existing methods, achieving superior robustness and accuracy, particularly in scenarios where noise may be present. Software: https://github.com/rickfawley/SHARK.

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03.

medRxiv (Medicine) 2026-06-24 DOI: HASH:66fc319886384051d442694593651c99

Clinical care site data integration reveals heterogeneity in EHR phenotyping and healthcare utilization patterns

作者:

Shelley↗J. P↗Lake↗A. M↗Sealock↗J. M↗Ueland↗T. E↗Peterson↗J. F↗Davis↗L. K↗…

Objective: Genomic research using electronic health record (EHR)-linked biobanks is influenced by heterogeneity in the clinical settings (care sites) where encounters occur. We developed two methods leveraging care site data: ClinicScan identifies where phenotype documentation occurs, and ClinicWAS identifies specialty utilization patterns associated with a risk factor. Materials and Methods: We extracted care sites for each clinical encounter at an academic medical center and mapped each to a clinical specialty. ClinicScan summarizes the specialty distribution of a user-specified diagnosis; ClinicWAS fits a logistic regression for each care site to identify specialty encounters associated with a user-specified risk factor. We applied ClinicScan to depression to test whether requiring a psychiatry encounter strengthened the association between a polygenic risk score (PRS) and a depression phenotype, and ClinicWAS to a coronary heart disease (CHD) PRS to identify sites enriched for high-risk patients. Results: Across 64,983,257 encounters, 2,544 care sites mapped to 57 specialties. Most depression diagnoses occurred in primary care (30.3%) and psychiatry (19.8%). Requiring a psychiatry encounter strengthened the PRS-phenotype association (OR=1.30, 95% CI 1.26-1.35) versus two or more diagnosis codes alone (OR=1.21, 95% CI 1.19-1.24). CHD ClinicWAS identified 19 associated care sites, including 5 catheterization labs. Men and women with high genetic risk (PRS[≥]95th percentile) underwent catheterization for CHD 3.1 (1.5-4.6) and 4.6 (2.5-6.7) years earlier than normal-risk participants, respectively. Discussion: Care site data capture phenotype heterogeneity that otherwise distorts EHR-based phenotypes and obscures high-risk subpopulations. Conclusion: Clinical care site data are an under-utilized resource in EHR-linked biobanks.

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04.

arXiv (CS.AI) 2026-06-24 DOI: arXiv:2606.24752

Can Scale Save Us From Plasticity Loss in Large Language Models?

作者:

J. Fernando Hernandez-Garcia↗Tom\'as Figliolia↗Beren Millidge↗

arXiv:2606.24752v1 Announce Type: new Abstract: The loss of plasticity - the ability of a network to learn new information after having already learned older information - is a fundamental challenge in creating artificial neural networks capable of continual learning. Although this phenomenon has been known for decades, it has mostly been studied in older, relatively small architectures and rarely in natural-language domains. To determine whether loss of plasticity remains a problem in the modern transformer-based LLM paradigm, we study plasticity loss in GPT-style Transformer models trained on a multilingual continual learning problem. Consistent with prior work, we find evidence of plasticity loss across models ranging from 5M to 314M non-embedding parameters, as measured by deterioration on a held-out Vietnamese probing task. We further find that the onset of plasticity loss follows a predictable scaling law, growing sublinearly with model size. These results suggest that larger models may delay the measurable effects of plasticity loss, but that increasing parameter count alone is likely to be insufficient to completely prevent it. We also find evidence of plasticity loss under stationary multilingual training, challenging the view that the phenomenon is exclusive to continual learning with abrupt task changes. Overall, our results suggest that even large Transformer language models trained on natural-language will eventually lose the ability to efficiently adapt to new data after sufficiently long training, in both continual and stationary settings.

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05.

arXiv (quant-ph) 2026-06-25 DOI: arXiv:2512.03853

Modelling the Impact of Device Imperfections on Electron Shuttling in SiMOS devices

作者:

Jack J. Turner↗Christian W. Binder↗Guido Burkard↗Andrew J. Fisher↗

arXiv:2512.03853v3 Announce Type: replace Abstract: Extensive theoretical and experimental work has established high-fidelity electron shuttling in Si/SiGe systems, whereas demonstrations in Si/SiO2 (SiMOS) remain at an early stage. To help address this, we perform full 3D simulations of conveyor-belt charge shuttling in a realistic SiMOS device, building on earlier 2D modelling. We solve the Poisson and time-dependent Schrodinger equations for varying shuttling speeds and gate voltages, focusing on potential pitfalls of typical SiMOS devices such as oxide-interface roughness, gate fabrication imperfections, and charge defects along the transport path. The simulations reveal that for low clavier-gate voltages, the additional oxide screening in multi-layer gate architectures causes conveyor-belt shuttling to collapse to the bucket-brigade mode, inducing considerable orbital excitation in the process. Increasing the confinement restores conveyor-belt operation, which we find to be robust against interface roughness, gate misalignment, and charge defects buried in the oxide. However, our results indicate that defects located at the Si/SiO2-interface can induce considerable orbital excitation. For lower conveyor gate biases, positive defects in the transport channel can even capture passing electrons. Hence we identify key challenges and find operating regimes for reliable charge transport in SiMOS architectures.

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06.

medRxiv (Medicine) 2026-06-15 DOI: HASH:1f74d46aefdb8263985160a270383b1f

Association of Genetic Liability to Psychiatric Disorders with Peripheral Metabolic Dysregulation

作者:

De la Hoz↗J. F↗Lee↗Y. H↗Tubbs↗J. D↗Meyerson↗Cudic↗Watts↗Feng↗Y.-C. A↗Chen↗…

Importance: Individuals with psychiatric disorders face elevated cardiometabolic risk which is linked to increased mortality. The extent to which this reflects shared pathogenesis or the downstream effects of illness and treatment remains poorly understood. Objective: To characterize the direct pleiotropic effects of psychiatric genetic liability on circulating metabolites and aggregate cardiometabolic risk, independent of psychiatric diagnosis and psychotropic medication use. Design: Cohort study. Setting: Mass General Brigham Biobank (MGBB). Participants: MGBB participants with metabolomic profiling, genomic data, and linked electronic health records. Exposures: Genetic liability to nine psychiatric disorders quantified using polygenic risk scores (PRS): attention deficit/hyperactivity disorder (ADHD), anorexia nervosa (ANO), anxiety disorder (ANX), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), PTSD, schizophrenia (SCZ), and substance use disorder (SUD). Main Outcomes and Measures: 249 circulating metabolites and four metabolomic risk scores (MRS) for type 2 diabetes, myocardial infarction, ischemic stroke, and vascular dementia. PRS-metabolite associations were estimated using nested models adjusting for lifetime psychiatric diagnosis and psychotropic medication use. Results: Across 25,290 participants, we identified 604 significant PRS-metabolite associations (Bonferroni p< 1.36 x 10-4), of which 89% persisted after adjustment for lifetime diagnosis and medication use, suggesting that the direct genetic effects on metabolism are largely independent of illness or treatment. PRS for MDD, PTSD, and ADHD showed the most extensive dysregulation, with a transdiagnostic pattern of elevated lipids and systemic inflammation, specifically triglycerides ({beta} = 0.04 to 0.05, all p< 4.4 x10-13) and glycoprotein acetyls ({beta} = 0.05, all p< 2.2 x10-16). Notably, PRS for SCZ and BD showed minimal metabolite dysregulation despite having the strongest association with their target diagnoses. PRS for MDD, PTSD, ADHD, and SUD were associated with increased MRS across cardiometabolic conditions ({beta} = 0.03 to 0.08, all p< 2.1 x10-4). Sensitivity analyses controlling for BMI or excluding participants without any psychiatric history (N: 21,305 and 11,150, respectively) showed a similar pattern. Conclusions and Relevance: Psychiatric genetic liability is associated with systemic metabolic dysregulation independent of illness onset or treatment, supporting a partially pleiotropic basis for psychiatric-cardiometabolic comorbidity.

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07.

medRxiv (Medicine) 2026-06-18 DOI: HASH:714fa8811b28f86b97ee80e37f04643e

Development and Initial Validation of the Quality of life Evaluation in NF2-related Schwannomatosis Trials (QUEST) Assessment

作者:

Merker↗V. L↗Carias↗S. C↗Ferner↗R. E↗Golding↗J. F↗Plotkin↗S. R↗Buono↗F. D↗…

Individuals with NF2-related schwannomatosis (NF2-SWN) experience a complex constellation of physical, emotional, and social symptoms that substantially impact quality of life (QoL). Although disease-specific patient-reported outcome measures are increasingly important for evaluating treatment benefit in clinical trials, existing NF2-SWN QoL measures have limitations in content coverage and sensitivity to change. This study describes the development and initial validation a new disease-specific QoL assessment – the Quality of Life Evaluation in NF2-related Schwannomatosis Trials (QUEST). Using a three-phase, mixed-methods approach, items were generated through concept elicitation interviews with individuals with NF2-SWN and clinicians, prioritized via patient survey data, and refined through iterative cognitive debriefing procedures. The resulting 21-item QUEST assesses the extent to which NF2-SWN has negatively impacted a persons daily life over the past seven days. Initial psychometric evaluation was conducted in an international sample of 174 individuals with NF2-SWN aged 15 years and older (117 women (67%), 158 White individuals (89%)). Exploratory factor analysis supported a four-factor structure, and the total score demonstrated excellent internal consistency and strong test-retest reliability. Evidence of construct validity was demonstrated through hypothesized associations with disease-specific, generic, and domain-specific QoL measures, as well as known-groups validity based on self-reported disease severity and number of prior surgeries. Incremental validity analyses indicated that QUEST explained unique variance beyond existing measures. Together, findings support the QUEST as a reliable and valid disease-specific QoL measure with strong content validity and feasibility for use as a clinical trial endpoint in NF2-SWN.

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