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PubMed1984

On the lod score method in linkage analysis.

Genetic epidemiology deals with the interaction of environmental and genetic determinants in common diseases. Linkage analysis is an important branch of this field. The current practice of claiming linkage between two genetic loci when the maximum lod score z(theta) exceeds 3 has not received theoretical justification, whether considered as a sequential or as a fixed sample size test. Within the framework of significance testing, Wald's (1947) formulae are not applicable to allow this procedure a sequential interpretation. Considered as a fixed sample size test, we find that a chi 2 approximation would instead be very adequate. Since repeated significance testing is performed on linkage data, the nominal significance level should be more stringent for each test than the overall level. Some recent developments in group sequential trials by Pocock (1977) and in repeated significance testing by Woodroofe (1979) seem to indicate that the critical value of the maximum lod score should lie roughly between 0.9 and 3.3, depending on the maximum number of repetitions anticipated, on whether the significance level is desired to be 0.05, 0.01 or 0.001, and on whether the test is derived from a one-sided or a two-sided consideration. In terms of the group sequential approach, if a maximum of twenty repetitions is allowed, if z(theta) greater than log10 A is considered as a one-sided test and assumed to be symmetric when linkage is absent, then the type I error is approximately given by 1/A. We also treat the confidence interval approach for exclusion of unlikely recombination values.

Genetic Linkage↗

PubMed2026

Nondominant Hand Training in Laparoscopy for Surgical Interns: Feasibility and Impact.

OBJECTIVE: Laparoscopy requires bimanual proficiency, yet early trainees demonstrate underdeveloped nondominant hand (NDH) performance. Although deliberate practice of NDH skill contributes to overall performance, NDH training is rarely incorporated into residency simulation curricula and has not been formally evaluated in surgical trainees. We assessed feasibility and impact of integrating structured NDH training with established laparoscopic curriculum for surgery interns. DESIGN: Prospective, single-institution randomized pilot study. Interns were assigned the standard 4-week curriculum of laparoscopic dominant hand and bimanual tasks (Control) or completed assigned NDH tasks in addition to the standard curriculum (Intervention). Feasibility was determined by assigned task completion, daily standard and NDH-specific self-reported practice time, and improvement in bimanual task performance. Performance was video recorded weekly and assessed by blinded evaluators using MISTELS and GOALS scoring. Cognitive workload during laparoscopic tasks was measured via NASA-TLX. Exploratory analyses were conducted within a Bayesian framework. SETTING: A single academic institution with a surgical simulation training program. PARTICIPANTS: General surgery interns on their 4-week simulation rotation. RESULTS: Eleven general surgery interns (6 intervention, 5 controls; all right-hand dominant) completed the study with 100% task completion and practice log compliance. Both groups improved in bimanual performance and perceived cognitive load. Reduction in cognitive workload during bimanual task performance was greater in the NDH group. Time spent on NDH practice over 4 weeks was associated with improved bimanual performance, independent of time spent on standard curriculum tasks. CONCLUSIONS: Structured NDH training is feasible to implement within an existing curriculum and reduces perceived cognitive workload during bimanual laparoscopic tasks. NDH practice demonstrates a beneficial dose-response relationship with performance, supporting its integration into early laparoscopic training.

Laparoscopy↗

PubMed2026

From complexity to clarity: Building dashboards for hit selection in high throughput screens.

High throughput screening produces large, complex datasets that are difficult to interrogate without programming expertise, making hit selection time-consuming and inflexible. While instrument software and commercial tools offer partial solutions, they often lack adaptability or require costly infrastructure. Interactive dashboards provide an effective alternative by enabling dynamic filtering and integrated visualization within a single interface. Here, we present simple R Markdown-based templates for creating customizable, modular dashboards for screen data analysis. Built using the flexdashboard and crosstalk R packages, and HTML widgets, these lightweight, easy-to-build HTML dashboards require no complex installation process or installation of licensed software. They support linked visualizations, threshold-based filtering (e.g., Z-score, p-value, fold change), and interactive data exploration and are shared as a standalone HTML file. This framework enables rapid, flexible hit selection across diverse high throughput screening applications and is designed for users with basic R experience.

High-Throughput Screening Assays↗

PubMed2026

Recommendations for return of secondary genomic findings in observational cohort studies.

The return of secondary genomic findings (ROSF) to participants in observational cohort studies has evolved from a topic of debate to an accepted standard. This Perspective synthesizes the proceedings of a 2024 National Heart, Lung and Blood Institute-sponsored workshop and the broader literature to provide updated guidance for ROSF. Building on the 2010 National Heart, Lung and Blood Institute Working Group recommendations and the 2014 Clinical Sequencing Exploratory Research/Electronic Medical Records and Genomics 'floor and ceiling' framework, we address four areas: an integrated ethical framework for observational cohort settings; the emerging challenge of returning novel result types beyond monogenic variants, including polygenic risk scores, somatic mosaicism and pharmacogenomic findings; health equity and community engagement as structural prerequisites for ethical ROSF; and scalability challenges, including technology-assisted disclosure. Drawing on implementation experience from large-scale sequencing programs, we offer recommendations that balance researcher obligations with participant autonomy and equitable access to the benefits of genomic research.

Journal Article↗

PubMed2025

SpaceBar enables clone tracing in spatial transcriptomic data.

We report a cellular barcoding strategy, SpaceBar, that enables simultaneous clone tracing and spatial transcriptomics profiling. Our approach uses a library of 96 synthetic barcode sequences that can be robustly detected by imaging based spatial transcriptomics (seqFISH), delivered such that each cell is labeled with a combination of barcodes. We used these barcodes to label melanoma cells in a tumor xenograft model and profiled both clone identity and spatial gene expression in situ. We developed a gene scoring metric that quantifies how strongly gene expression is driven by intrinsic cellular cues or extrinsic environmental signals. Our framework distinguishes between clonal dynamics and environmentally-driven transcriptional regulation in complex tissue contexts.

Journal Article↗

PubMed1979

Attitudes of health workers toward old people.

The Tuckman-Lorge Questionnaire was used to study the attitudes of three groups of health workers toward old people and to test their acceptance of geriatric stereotypes. The health workers tested were medical students, housestaff members, and members of a mobile psychogeriatric screening team. Many significant differences were found between and within the groups tested, as well as between male and female subjects. The female housestaff had extremely high and significantly different scores from all other groups. The geriatric staff adhered least to the stereotypes. The results are discussed in the framework that the attitudes of care givers are directly related to the quality of the care provided. It is hypothesized that female housestaff members have special difficulties with role conflicts that cause them to adhere to stereotypes of the aged. The milieu of geriatric treatment, rather than knowledge of statistics about old people, is the most effective background for positive changes in attitudes toward the elderly.

Aged↗

PubMed2026

LDLR Variant Classification Through Activity-Normalized Prime Editing Screening.

BACKGROUND: Inherited variants in the LDL (low-density lipoprotein) receptor (LDLR) gene are the most common cause of familial hypercholesterolemia, significantly increasing coronary artery disease risk. Early identification of pathogenic LDLR variants enables prompt lipid-lowering therapy and cascade testing of at-risk relatives; however, most LDLR variants observed in the population have uncertain or absent clinical classifications, leaving many patients without actionable information. METHODS: We developed the first activity-normalized prime editing screening pipeline to measure the impact of 5184 LDLR coding variants on LDL-cholesterol (LDL-C) uptake. Each prime editing guide RNA is paired with a genotypic outcome reporter to correct for variable editing efficiency, overcoming a key limitation of previous pooled genome editing screens. A statistical framework further improves variant effect estimates by jointly analyzing all missense variants at each amino acid position. RESULTS: We show that prime editing of the reporter construct correlates with endogenous variant installation frequency, validating the activity normalization approach. The resulting scores capture a continuous spectrum of functional effects, robustly separate pathogenic versus benign ClinVar variants, and show concordance with LDL-C levels in UK Biobank participants. We calibrate functional evidence strengths to the ACMG/AMP variant interpretation framework, enabling integration into a clinical variant classification workflow. By combining functional, computational, population, and contextual evidence, 322 of 434 LDLR variants currently classified as variants of uncertain significance, conflicting, or absent from ClinVar appear to meet evidence thresholds for reclassification and can be prioritized for expert review, substantially expanding the pool of actionable variant classifications. The screen also reveals a cluster of gain-of-function variants in LDLR class A repeat 5, at least some of which enhance LDL-C uptake through increased apolipoprotein B interaction, with implications for therapeutic genome editing. Last, prime editing uniquely detects splice-altering coding variants missed by cDNA-based screens and pathogenicity predictors, revealing an advantage of endogenous variant installation. CONCLUSIONS: Altogether, activity-normalized prime editing provides a scalable framework for LDLR variant classification that substantially expands the proportion of variants with evidence for genetic diagnosis and reveals novel biology with therapeutic relevance.

CRISPR screening↗

PubMed2026

Large-scale simulation of coverage and error rate tradeoffs for cancer detection in cell-free DNA whole-genome sequencing.

MOTIVATION: Cell-free DNA (cfDNA) whole-genome sequencing (WGS) is a promising approach for detecting cancer recurrence. It enables cancer detection by identifying all tumor-derived cfDNA (ctDNA) molecules carrying somatic single nucleotide variants (sSNVs). While ideally, a sequencing platform should be highly accurate for reliable ctDNA detection, in reality, all sequencing platforms introduce sequencing errors that generate false positives indistinguishable from true SNVs. Understanding how sequencing parameters influence ctDNA detection sensitivity at low tumor fractions (TFs) in cfDNA samples is essential for guiding sequencing strategies in clinical contexts. To model cfDNA sequencing for tumor detection, which contains asymmetric noise and multiple interacting parameters, analytical modeling is intractable, motivating large-scale parallelized simulation. RESULTS: We developed a simulation framework to generate in silico cfDNA data across 10 cancer types. In total, 480 million cfDNA samples were simulated from tumor WGS profiles. Overall, the lowest detectable TF differs substantially between cancer types under identical sequencing conditions due to variations in mutational load. For cancers with high mutational load, 3× coverage with low-error techniques reliably detects TFs below 0.1%. In contrast, cancers with low mutational load require at least six-fold higher coverage to achieve comparable detection thresholds. Increasing sequencing quality scores from Q30 to Q55 at 30× coverage further enhances sensitivity, enabling detection of TFs as low as 1 × 10-5. This study provides a comprehensive framework for optimizing sequencing parameters, offering valuable guidance for tailoring future technology development for specific cancer types and clinical applications. AVAILABILITY AND IMPLEMENTATION: The code is publicly available at https://github.com/UMCUGenetics/cfdetect/tree/main.

Whole Genome Sequencing↗

PubMed1993

Age differences in memory-span errors: speed or inhibitory mechanisms?

This study investigated age differences in errors on the digit-span task. Protocols of 119 men and women, aged 18-99 years, were scored for the occurrence of three types of errors derived from the speed-of-processing and inhibition-deficit frameworks: omission errors, intrusion errors, and transposition errors. The types of errors made on the digit-span task varied with span size. At larger span sizes, participants were more likely to omit digits or introduce nonstimulus digits than to transpose those in storage. No age differences in intrusion errors were found, however, old-old women (75+ years) were significantly more likely than young (18-25 years) and old (60-70 years) adults of either sex to exhibit transposition errors. Consequently, old-old women were significantly less likely to exhibit omission errors. The results indicate that the digit-span task may involve two parallel processes: digit storage/recall and serial/position storage-recall. Age differences in the serial-processing component, rather than in the digit storage/recall component, may be age sensitive. These results are discussed within an inhibition-deficit framework of cognitive aging.

Adolescent↗

PubMed1984

The permanence of otoplasty in the rabbit ear: a comparison of techniques.

Otoplasty should restructure the cartilage framework of the ear with permanent results. Major techniques include the placement of permanent sutures, with or without concomitant cartilage scoring, and cartilage abrasion alone. Our study evaluates the durability of the results of each method. Fifteen New Zealand white rabbits were divided into two groups. In 10 rabbits, the posterior surface of the right ear cartilage was abraded, and the ear was folded forward and secured with nylon stitches. A similar procedure was performed on the left ear, omitting the cartilage abrasion. In 4 rabbits, both ears were abraded transversely on the posterior cartilaginous surface and no sutures were placed. In 1 rabbit only the posterior skin was undermined on both ears. For one week dressings maintained a right-angle fold at the operative site. Rabbit ears reshaped with abrasion only failed to maintain the desired conformation. Ears with suture and abrasion did not maintain the full 90-degree angle created at surgery, although they did not fully straighten. Ears reshaped with suture alone maintained a folded angle close to the original right angle. Three months after operation the sutures within the cartilage were removed to approximate the clinical situation of late suture disruption from trauma to the operated ear and the shape was assessed.

Animals↗

PubMed1993

[The relation of ideal self to perception of self and others].

One hundred and twelve (112) junior high school students made ratings of their ideal and actual selves, and of other persons of same sex whom they liked or disliked, using uni-polar scales of 42 positive and 42 negative traits words. Positive and negative ideal-self rating scores correlated with those for actual-self and others. At the same time, rating scores on important traits for each subject which gained the highest score in ideal-self rating differed among the actual self and the liked other and disliked other--the liked other was rated more positively than the disliked other, though self-esteem affected relative positiveness of actual self to liked or disliked others. However, no such differences were found on unimportant traits which gained lower scores in ideal-self rating. These results seem to indicate that both positive and negative ideal selves provide cognitive framework for perception of self and others.

Adolescent↗

PubMed1992

Preoperative cardiac risk assessment for patients having peripheral vascular surgery.

PURPOSE: To review the methods used for preoperative cardiac risk stratification of patients having peripheral vascular surgery. DATA SOURCES: Relevant studies published before August 1991 were identified using a MEDLINE search of the English-language literature, followed by a manual search of the references of all identified articles. STUDY SELECTION: All clinical studies evaluating methods used for preoperative cardiac risk stratification of patients having peripheral vascular surgery. DATA EXTRACTION: The key data extracted from each article included the inclusion and exclusion criteria of the study patients, the techniques used for testing and the corresponding definitions of positive test results, and the clinical outcomes of the tested patients. Data were analyzed using a Bayesian conceptual framework, and pretest probabilities were converted to post-test probabilities using calculation of likelihood ratios. RESULTS: Patients with high scores on clinical cardiac risk indexes (Goldman index greater than 12 or Detsky index greater than 15), or more than three of the criteria identified by Eagle (age greater than 70 years, diabetes, angina, Q waves on electrocardiogram, or ventricular arrhythmias) are likely to be at higher risk for cardiac death and myocardial infarction after vascular surgery. Those with both low scores and none of Eagle's criteria may be at lower risk, but this result has not been reproduced by independent studies. Neither group of patients would benefit from further investigation for cardiac risk stratification. Patients with one or two of these criteria may be at intermediate risk and would benefit most from further testing for the purposes of risk stratification. Most of the published evidence shows that the absence of redistribution on dipyridamole-thallium scanning identifies a low risk for postoperative cardiac complications, whereas the presence of redistribution predicts a high risk. Preliminary reports suggest that preoperative monitoring for silent myocardial ischemia may also be useful in identifying a high-risk subset of patients. CONCLUSIONS: Patients identified clinically to be at either very low or high risk for cardiac complications after peripheral vascular surgery are unlikely to benefit from further risk stratification. Dipyridamole-thallium scanning is the test of choice for further evaluation of patients at intermediate clinical risk because studies have shown that it is sensitive enough to rule out a high-risk status for patients who do not have redistribution.

Bayes Theorem↗

PubMed2025

Unicorn: enhancing single-cell Hi-C data with blind super-resolution for 3D genome structure reconstruction.

MOTIVATION: Single-cell Hi-C (scHi-C) data provide critical insights into chromatin interactions at individual cell levels, uncovering unique genomic 3D structures. However, scHi-C datasets are characterized by sparsity and noise, complicating efforts to accurately reconstruct high-resolution chromosomal structures. In this study, we present ScUnicorn, a novel blind super-resolution framework for scHi-C data enhancement. ScUnicorn uses an iterative degradation kernel optimization process, unlike traditional super-resolution approaches, which rely on downsampling, predefined degradation ratios, or constant assumptions about the input data to reconstruct high-resolution interaction matrices. Hence, our approach more reliably preserves critical biological patterns and minimizes noise. Additionally, we propose 3DUnicorn, a maximum likelihood algorithm that leverages the enhanced scHi-C data to infer precise 3D chromosomal structures. RESULTS: Our evaluation demonstrates that ScUnicorn achieves superior performance over the state-of-the-art methods in terms of Peak Signal-to-Noise Ratio, Structural Similarity Index Measure, and GenomeDisco scores. Moreover, 3DUnicorn's reconstructed structures align closely with experimental 3D-FISH data, underscoring its biological relevance. Together, ScUnicorn and 3DUnicorn provide a robust framework for advancing genomic research by enhancing scHi-C data fidelity and enabling accurate 3D genome structure reconstruction. AVAILABILITY AND IMPLEMENTATION: Unicorn implementation is publicly accessible at https://github.com/OluwadareLab/Unicorn.

Single-Cell Analysis↗

PubMed2026

Symptom assessment and health-related quality of life in children with lower urinary tract dysfunction: A retrospective cross-sectional study.

INTRODUCTION: Lower urinary tract dysfunction (LUTD) significantly impacts children's health-related quality of life (HRQoL), but key determinants of this impairment remain incompletely understood within a patient-centered framework. METHODS: This retrospective cross-sectional study enrolled 272 children with LUTD. Clinical symptoms were assessed using the Dysfunctional Voiding Scoring System (DVSS) and the Overactive Bladder Symptom Score (OABSS), and HRQoL via the Pediatric Quality of Life Inventory (PedsQL™) 4.0 Generic Core Scales. RESULTS: The mean total PedsQL score was 83.66 ± 16.07, with the School Functioning domain being the most impaired (73.75 ± 20.94). Univariate analysis identified older age (≥11 years), daytime urinary leakage, overactive bladder (OAB) symptoms, and abnormal DVSS scores as factors associated with reduced HRQoL (all P < 0.05); multivariate regression further confirmed only older age and abnormal DVSS were independent influencing factors (both P < 0.001). A significant negative correlation existed between the total DVSS score and the total PedsQL score (r = -0.390, P < 0.01), indicating that greater symptom severity predicts poorer overall HRQoL. CONCLUSION: This study indicates that in children with LUTD, the severity of voiding dysfunction (quantified by DVSS) is inversely correlated with HRQoL. Voiding dysfunction impairs multiple domains of daily functioning, including physical well-being, emotional adjustment, social interaction, and school performance. Shifting from a symptom-focused to a patient-centered care model and integrating routine HRQoL assessment into standard clinical management can optimize clinical practice for pediatric LUTD.

Humans↗

PubMed2026

Beyond Exons: Linking Noncoding Heritability and Polygenicity across Complex Human Traits and Disorders.

The genetic architecture of complex traits spans a continuum of polygenicity, yet it remains unclear how differences in polygenicity relate to the functional localization of SNP heritability across the genome. We use a MiXeR-based framework to partition heritability across exonic, intronic, and intergenic regions for 34 traits and introduce a likelihood-based annotation contribution score that quantifies annotation-specific impact on heritability. Exons explain a minority of heritability, and their contribution decreases with increasing polygenicity, from an average of 22% in less polygenic somatic diseases and biomarkers to 13% in highly polygenic psychiatric and cognitive phenotypes. Intergenic fractions show the opposite trend, whereas intronic fractions remain relatively stable. Analysis of a broader set of functional annotations reveals systematic differences along the polygenicity axis: highly polygenic traits show stronger contributions from comparative genomics and variant-effect scores, whereas less polygenic traits show stronger contributions in promoter, transcription, and chromatin annotations. Together, these results indicate that the functional partitioning of heritability systematically varies with polygenicity, pointing to a shift from gene-proximal regulatory architectures to architectures shaped by numerous dispersed regulatory effects as a key determinant of differences in polygenicity across traits.

Journal Article↗

PubMed1991

Nonparametric tests of association between survival time and continuously measured covariates: the logit-rank and associated procedures.

O'Brien's logit-rank procedure (1978, Biometrics 34, 243-250) is shown to arise as a score test based on the partial likelihood for a proportional hazards model provided the covariate structure is suitably defined. Within this framework the asymptotic properties claimed by O'Brien can be readily deduced and can be seen to be valid under a more general model of censoring than that considered in his paper. More important, perhaps, it is now possible to make a more natural and interpretable generalization to the multiple regression problem than that suggested by O'Brien as a means of accounting for the effects of nuisance covariates. This can be achieved either by modelling or stratification. The proportional hazards framework is also helpful in that it enables us to recognize the logit-rank procedure as being one member of a class of contending procedures. One consequence of this is that the relative efficiencies of any two procedures can be readily evaluated using the results of Lagakos (1988, Biometrika 75, 156-160). Our own evaluations suggest that, for non-time-dependent covariates, a simplification of the logit-rank procedure, leading to considerable reduction in computational complexity, is to be preferred to the procedure originally outlined by O'Brien.

Biometry↗

PubMed1986

Recognition and frequency judgments in young and elderly adults.

Three experiments examined frequency judgments and recognition memory in young and elderly adults. Subjects were presented a long list of words at either a 5-s rate (Experiments 1 & 3) or a 1-s rate (Experiment 2), after which frequency-judgment and recognition memory tasks were administered. Either an absolute (Experiments 1 & 2) or a relative (Experiment 3) frequency-judgment task was used. The recognition test, which involved repeated tests of some items, involved either one incorrect item paired with each correct item (Experiments 1 & 2), or four incorrect items (Experiment 3). Age-related differences in frequency judgments, for the more frequently presented items, were found in all three experiments. For the recognition scores, the predicted interaction between age and successive tests was found only in Experiment 3. The results were interpreted within the framework of age-related differences in elaborative encoding and in distractibility to irrelevant stimuli.

Adolescent↗

PubMed2026

Evolving Role of Immunotherapy in Advanced Esophageal Squamous Cell Carcinoma: Are Programmed Death-Ligand 1 (PD-L1) Cutoffs Still Relevant?

Immune checkpoint inhibitors have transformed the management of advanced esophageal squamous cell carcinoma (ESCC) across first-line, second-line, and perioperative settings. Programmed death-ligand 1 (PD-L1) expression has served as the principal biomarker guiding patient selection for these agents, yet it is measured inconsistently across trials and antibody platforms, and its predictive value has come under renewed scrutiny as follow-up data have matured. This review synthesizes the pivotal randomized trials that established anti-programmed cell death protein-1 therapy in ESCC, critically appraises the pooled and patient-level meta-analyses that have re-examined outcomes across biomarker subgroups, and situates recent regulatory reassessment of PD-L1 thresholds within this broader evidence base. Assay heterogeneity between scoring systems, discordance across antibody clones, and the biological distinction between PD-L1 as a prognostic versus a predictive marker are examined as sources of continued uncertainty. The review concludes by considering emerging genomic and microenvironmental biomarkers that may eventually complement or refine PD-L1-based patient selection, and offers a framework for interpreting a single expression threshold as an approximate, assay-dependent stratifier rather than a precise biological boundary.

combined positive score↗