Category: Statistics

J Asthma. 2026 Jul 30:1-18. doi: 10.1080/02770903.2026.2712839. Online ahead of print.

ABSTRACT

BACKGROUND: Smoking relapse is prevalent, yet its long-term association with incident asthma remains underexplored. Repeated quit-relapse cycles may exacerbate airway inflammation more acutely than steady-state smoking. We investigated the association between smoking-relapse trajectories and incident asthma risk using a nationally representative longitudinal dataset.

METHODS: We analyzed 10-year data (2009-2018) from the Korea Health Panel Survey for 16,240 adults without baseline asthma. Participants were classified into five trajectories: non-smokers (NS), successful quitters without relapse (SQ-), successful quitters with relapse (SQ+), unsuccessful quitters with relapse (UQ+, chronic relapsers), and always smokers (AS). Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) for incident asthma (ICD-10 J45-J46).

RESULTS: During the 10-year follow-up, 159 incident asthma cases were identified. Compared to NS, chronic relapsers (UQ+) exhibited the highest risk (aHR 3.81; 95% CI 1.84-7.91), followed by SQ- (aHR 2.54; 95% CI 1.30-4.96) and AS (aHR 2.25; 1.08-4.71). While UQ + showed a higher point estimate than AS, the difference was not statistically significant. Other significant risk factors included age ≤65 years, Medical Aid enrollment, and higher comorbidity scores.

CONCLUSIONS: Smoking-relapse trajectories, particularly chronic relapse, are associated with an elevated risk of incident asthma. These findings should be interpreted as hypothesis-generating and require confirmation in independent cohorts.

PMID:42530977 | DOI:10.1080/02770903.2026.2712839

J Int Med Res. 2026 Jul;54(7):3000605261469014. doi: 10.1177/03000605261469014. Epub 2026 Jul 30.

ABSTRACT

ObjectiveThe potential causal role of molecular biomarkers of biological aging in osteoporosis remains uncertain. This study aimed to evaluate whether genetically predicted levels of aging-related traits are causally associated with the risk of osteoporosis.MethodsIn this study, we selected eight exposures: telomere length, mitochondrial DNA copy number, insulin-like growth factor 1 levels, DNA methylation PhenoAge acceleration, leucine, isoleucine, valine, and Dickkopf-related protein 1. A bidirectional two-sample Mendelian randomization analysis was conducted among the European population. The inverse-variance weighted method served as the primary analysis, complemented by Mendelian randomization-Egger, weighted median, mode-based methods, Cochran’s Q test, the Mendelian randomization-Egger intercept, and leave-one-out analysis to assess robustness, heterogeneity, and pleiotropy.ResultsThe inverse-variance weighted analysis showed nominal associations (p < 0.05) between genetically predicted higher insulin-like growth factor 1 (odds ratio = 0.910, 95% confidence interval: 0.840 to 0.985, p = 0.019) and isoleucine (odds ratio = 0.780, 95% confidence interval: 0.618 to 0.984, p = 0.036) with a lower risk of osteoporosis and elevated Dickkopf-related protein 1 (odds ratio = 1.195, 95% confidence interval: 1.043 to 1.368, p = 0.010) with a higher risk of osteoporosis; however, none remained significant after Bonferroni correction (p > 0.00625). Sensitivity analyses suggested a statistically significant association for Dickkopf-related protein 1 (weighted median and mode, p < 0.00625), whereas no significant causal effects were observed for any of the other biomarkers. Reverse Mendelian randomization revealed no evidence that osteoporosis influenced any of the biomarkers.ConclusionsIn this study, no robust causal effects were identified between the eight aging biomarkers and osteoporosis in the European population. However, the nominal associations observed for insulin-like growth factor 1, isoleucine, and Dickkopf-related protein 1 warrant further investigation into the aging-skeleton axis.

PMID:42530965 | DOI:10.1177/03000605261469014

Stat Methods Med Res. 2026 Jul 30:9622802261468019. doi: 10.1177/09622802261468019. Online ahead of print.

ABSTRACT

In lifetime studies, a proportion of subjects may never experience the event of interest, giving rise to the notion of cure rate. While traditional cure models address this in univariate set-up, many applications involve paired lifetimes, such as twin survival studies, paired organs, or dependent components in a system. In such cases, both the possibility of cure in one or both marginals and the dependence between lifetimes need to be modeled simultaneously, motivating bivariate cure models. We propose here a flexible framework for analyzing bivariate cure data by combining parametric modeling of each marginal survival distribution with a shared frailty term for capturing dependence. The shared frailty is assumed to follow a generalized gamma distribution, providing substantial flexibility in representing diverse dependence structures induced by unobserved frailty. This formulation accommodates cured individuals in one or both marginals and captures the joint survival dynamics of susceptible pairs. Likelihood-based inference for the proposed model is then developed, with estimation carried out using the expectation-maximization algorithm. The performance of the model and the associated inferential method are then evaluated through extensive simulation studies, demonstrating the efficiency and accuracy in estimating model parameters. A real data application, concerning diabetic retinopathy, further illustrates how the model provides insights into cure dynamics and associations that will not be evident in univariate analyses. The proposed bivariate cure model offers a comprehensive statistical tool for jointly studying cure fractions and survival dependence in paired lifetime settings, broadening the applicability of cure rate methodology in biomedical research.

PMID:42530958 | DOI:10.1177/09622802261468019

JAMA Ophthalmol. 2026 Jul 30. doi: 10.1001/jamaophthalmol.2026.2767. Online ahead of print.

ABSTRACT

IMPORTANCE: Whether prior pars plana vitrectomy (PPV) independently increases the risk of cystoid macular edema (CME) following cataract surgery remains unknown.

OBJECTIVE: To evaluate associations between prior PPV and incidence of CME after cataract surgery.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was conducted using the TriNetX US Network, a multicenter federated electronic health record network from December 2005 to December 2025 including academic and community hospitals in the US. Adults aged 18 years or older who underwent cataract surgery were categorized into those with vs those without a history of PPV (≥6 months prior to cataract surgery), excluding those with preexisting CME or risk factors for CME. Data were analyzed from December 2025 through January 2026.

EXPOSURE: History of PPV performed more than 6 months prior to cataract surgery.

MAIN OUTCOMES AND MEASURES: The primary outcome was the incidence of CME within 30 to 90 days postoperatively, identified by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes. Risk ratios (RR) were used to compare outcomes. Propensity score matching was performed for demographic and clinical covariates (age, sex, race, hypertension, hyperlipidemia, diabetes, myopia, retinal detachment [RD] history).

RESULTS: After propensity score matching with 615 983 patients undergoing cataract surgery, 7422 patients had a prior PPV. After propensity score matching, among patients with prior PPV, mean (SD) age was 62.0 (11.6) years, and 3623 patients (49.5%) were female; among the non-PPV group, mean (SD) age was 61.9 (12.2) years, and 3625 patients (49.5%) were female. Among 14 636 patients representing 7318 propensity score-matched pairs, CME occurred in 336 of 7318 patients with prior PPV (4.59%) compared with 90 of 7318 non-PPV controls (1.23%) (difference, 3.36%; 95% CI, 2.82%-3.90%; RR, 3.73; 95% CI, 2.97-4.70; P < .001). Elevated CME risk persisted in subgroup analyses evaluating prior PPV for RD (5.65% vs 1.22%; absolute difference, 4.43%; 95% CI, 3.48%-5.38%; RR, 4.62; 95% CI, 3.20-6.67; P < .001), as well as those for non-RD indications (3.99% vs 1.23%; absolute difference, 2.76%; 95% CI, 2.06%-3.48%; RR, 3.26; 95% CI, 2.36-4.50; P < .001). Furthermore, after excluding patients with intraoperative and postoperative complications of cataract surgery, the prior PPV group was still found to have a higher risk of CME (4.59% vs 1.26%; absolute difference, 3.32%; 95% CI, 2.77%-3.88%; RR, 3.63; 95% CI, 2.88-4.58; P < .001).

CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that eyes with vs without prior PPV have higher incidences of postoperative CME. However, numerous limitations, including dependence on coding-based diagnoses and lack of visual acuity outcomes, preclude determining the role of prophylaxis or monitoring for CME in vitrectomized eyes undergoing cataract extraction.

PMID:42530955 | DOI:10.1001/jamaophthalmol.2026.2767

JAMA Oncol. 2026 Jul 30. doi: 10.1001/jamaoncol.2026.2366. Online ahead of print.

ABSTRACT

IMPORTANCE: Transarterial chemoembolization (TACE) is the standard of care for liver-confined hepatocellular carcinoma (HCC) that is not amenable to curative treatment; however, TACE has demonstrated unsatisfactory survival benefits.

OBJECTIVE: To evaluate whether combining TACE with subsequent thermal ablation improves clinical outcomes compared with TACE alone in patients with liver-confined unresectable HCC.

DESIGN, SETTING, AND PARTICIPANTS: The open-label, phase 3 TORCH randomized clinical trial was conducted from May 2015 to August 2024 at 2 tertiary medical centers in China. Patients with Barcelona Clinic Liver Cancer stage B HCC were enrolled. The data cutoff was October 31, 2025.

INTERVENTIONS: Patients were randomly assigned (1:1) to receive either TACE combined with subsequent selective radiofrequency ablation (TACE-ablation) or TACE alone.

MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS), assessed per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Secondary end points included overall survival (OS), treatment response and PFS per modified RECIST, untreatable PFS, and safety.

RESULTS: Among 241 patients included in the intention-to-treat population, 121 received TACE-ablation (median [IQR] age, 59.0 [51.0-66.0] years; 108 [89.3%] male), and 120 received TACE alone (mean [IQR] age, 58.0 [50.0-64.0]; 106 [88.3] male). The number of patients with 6-and-12 tumor burden scores of lower than 6, 6 to 12, and more than 12 points were 34 (28.1%), 79 (65.3%), and 8 (6.6%) in the TACE-ablation group and 31 (25.8%), 76 (63.3%), and 13 (10.8%) in the TACE alone group, respectively. At the data cutoff, the median PFS per RECIST, version 1.1, was 17.7 months (95% CI, 11.4-23.1 months) in the TACE-ablation group vs 7.3 months (95% CI, 6.4-10.4 months) in the TACE alone group (hazard ratio [HR], 0.47; 95% CI, 0.34-0.65; P < .001). TACE-ablation also resulted in statistically significant prolonged untreatable PFS compared with TACE (35.1 months vs 12.3 months; HR, 0.40; 95% CI, 0.27-0.58; P < .001). Median OS was 88.6 months (95% CI, 43.1 months to not estimable) with TACE-ablation and 35.1 months (95% CI, 25.4-45.5 months) with TACE alone (HR, 0.50; 95% CI, 0.34-0.73; P < .001). Clinically meaningful improvements in both PFS and OS were observed in patients with low to moderate tumor burden scores (≤6 and 6-12 points). Grade 3 and 4 treatment-related adverse events occurred in 23 patients (23.2%) in the TACE-ablation group and 24 (18.3%) in the TACE alone group.

CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, TACE combined with subsequent thermal ablation demonstrated superior survival outcomes than TACE alone in patients with liver-confined unresectable HCC. Sequential TACE-ablation could serve as a feasible treatment option for such patients.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02435953.

PMID:42530948 | DOI:10.1001/jamaoncol.2026.2366

J Alzheimers Dis. 2026 Jul 30:13872877261471048. doi: 10.1177/13872877261471048. Online ahead of print.

ABSTRACT

BackgroundEye movement dysfunction plays an important role in understanding the pathology of neurodegenerative disorders. Fine particulate matter (PM_2.5) exposures are associated with hallmark proteins diagnostic of Alzheimer’s and Parkinson’s diseases in Metropolitan Mexico City (MMC) ≤ 40-year-old residents.ObjectiveTo assess oculomotor function with neuroanatomical correlates using magnetic resonance imaging (MRI) region of interest analysis in young urbanites.MethodsVideo-based eye-tracking was used to explore oculomotor dysfunction and structural brain MRI changes in two highly exposed PM_2.5 cohorts. We assessed fixation stability, smooth pursuit, pro-saccades, and anti-saccades using the Eyelink 1000-plus eye-tracker, in 80 volunteers’ age 33 ± 11 years from MMC and Cuernavaca. Forty-five MMC subjects age 31.2 ± 14.7 years with oculomotor assessment had brain MRIs. Measurements of saccadic accuracy, latency, and smooth pursuit gain and square wave jerk frequency were collected.ResultsOculomotor variables did not reach statistically significant differences in MMC versusCuernavaca. Abnormal antisaccades, low gain pursuit, and square wave jerks were documented more often in MMC residents. Correlational analysis between oculomotor function and structural MRI data revealed statistical cortical and subcortical changes at frontal-temporal-parietal regions, hippocampus, thalamus, caudate, amygdala, habenula, nucleus accumbens, and cerebellum. Involved regions potentially reveal the location and severity of neurodegeneration processes via altered saccade parameters.ConclusionsOur findings suggest that simple oculomotor test batteries may provide a useful tool to monitor and/or measure the impact of pollution on neurodevelopment and early neurodegeneration. The integration of ocular movement parameters into the Continuum model of neurodegeneration offers a promising approach for neuroprotection decision-making and rigorous emissions control in polluted settings.

PMID:42530934 | DOI:10.1177/13872877261471048

JAMA Netw Open. 2026 Jul 1;9(7):e2626334. doi: 10.1001/jamanetworkopen.2026.26334.

ABSTRACT

IMPORTANCE: Pathogenic variants in BRCA1 and BRCA2 confer substantial risks of breast and ovarian cancer; however, risk for female individuals undergoing testing, particularly those with variants of uncertain significance (VUS) or negative results, remain poorly defined.

OBJECTIVE: To estimate lifetime incidence of breast and ovarian cancer among female individuals undergoing BRCA1 or BRCA2 testing across all result categories and evaluate the modifying association of family history.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was conducted as part of the What Comes Next Cohort Study, a near-population-based cohort in Ontario, Canada, established through linkage with administrative databases. Female participants who underwent BRCA1 or BRCA2 testing from 2007 to 2016 were matched 1:5 to females from the general population. Participants were followed up to September 2024. Data were analyzed from May to December 2025.

MAIN OUTCOMES AND MEASURES: The outcome of interest was the cumulative incidence of breast and ovarian cancer to age 80 years, stratified by genetic test result and family history.

RESULTS: Of 15 986 individuals in the What Comes Next Cohort Study cohort, 6966 individuals eligible for breast cancer analyses (median [IQR] age, 49 [38-60] years) were matched to 34 830 individuals from the general population and 13 276 individuals eligible for ovarian cancer analyses (median [IQR] age, 51 [41-61] years) were matched to 66 380 individuals from the general population. Cumulative breast cancer incidence to age 80 years was 62.1% (95% CI, 52.2%-69.9%) for BRCA1 pathogenic variant carriers and 66.1% (95% CI, 57.5%-72.9%) for BRCA2 pathogenic variant carriers, compared with 12.0% (95% CI, 11.2%-12.8%) in the general population; corresponding ovarian cancer incidence was 56.0% (95% CI, 40.0%-67.7%) for BRCA1 pathogenic variant carriers and 29.3% (95% CI, 14.2%-41.7%) for BRCA2 pathogenic variant carriers, compared with 1.5% (95% CI, 1.3%-1.7%) in the general population. Family history modified breast cancer risk, reaching a cumulative incidence of 86.3% (95% CI, 70.9%-93.5%) in carriers with at least 2 affected first-degree relatives vs 55.8% (95% CI, 45.4%-64.2%) in carriers without a family history of breast cancer. Among individuals with test results positive for pathogenic variants, lifetime risk of ovarian cancer was similarly modified by family history, reaching 64.2% (95% CI, 37.0%-79.7%) in those with vs 38.2% (95% CI, 25.8%-48.4%) in those without a family history of ovarian cancer. Individuals with VUS and negative test results also had increased lifetime breast cancer risks (31.2% [95% CI, 19.2%-41.4%] and 26.3% [95% CI, 23.0%-29.4%], respectively) but no increase in ovarian cancer risk. Individuals with test results negative for a known familial variant had risks similar to the general population.

CONCLUSIONS AND RELEVANCE: In this cohort study of females who underwent BRCA1 or BRCA2 testing, the lifetime cancer risk varied substantially across BRCA test result groups and was further modified by family history. Elevated breast cancer risk among individuals with VUS or negative results highlights the need for individualized risk assessment and management beyond genetic test results alone.

PMID:42530926 | DOI:10.1001/jamanetworkopen.2026.26334

Toxicol Sci. 2026 Jul 30:kfag094. doi: 10.1093/toxsci/kfag094. Online ahead of print.

ABSTRACT

We previously described an integrated in vitro liability assay for seizure, a new approach methodology (NAM) to reduce toxicity due to central nervous system (CNS) liability in drug discovery and development. Here we report the development of SAR (structure activity relationships) to guide drug design away from this liability. SAR test compounds were selected from the Enamine REadily AccesibLe (REAL) database using pharmacophore features and similarity to previous test compounds (amoxapine, diphenhydramine, quetiapine, 4-AP, linopirdine) or to ion channel positive reference compounds (bepridil, NS1619, quinidine, verapamil, XE991). These 88 compounds (10 parent compounds and 78 structurally related derivatives) were screened by automated electrophysiology in cell lines expressing human KV2.1, NaV1.2, the α1β2γ2 GABAA or α4β2 nicotinic receptors to generate IC50 values. Across all four ion channels, the derivative compounds exhibited increased, equivalent or reduced potency compared with the parent compounds, providing a complex and rich dataset for SAR. Regarding individual pharmacophoric features, statistical analysis identified 12 features significantly associated with activity at the α4β2 nicotinic receptor; 4 of these were also significantly associated with activity at KV2.1. Selected parent compounds (amoxapine, diphenhydramine, quetiapine) and structural analogues were screened for seizure-like activity in human induced pluripotent stem cell neurons using microelectrode array. The seizure-like phenotype was altered with the derivatives, as expected from the respective ion channel IC50 values. These data provide insight into specific substructures associated with seizure-like drug toxicity, offering the opportunity to avoid CNS liability in the development of novel compounds, saving time, money and resources.

PMID:42530889 | DOI:10.1093/toxsci/kfag094

Prim Care Companion CNS Disord. 2026 Jul 23;28(4):26m04192. doi: 10.4088/PCC.26m04192.

ABSTRACT

Objective: Internet gaming disorder (IGD) has gained increasing global recognition, yet little is known about how health care providers perceive and manage this condition in clinical practice. The objective of this study was to assess health care providers’ IGD-related beliefs, familiarity with diagnostic criteria, confidence in diagnosis and management, and perceived training needs.

Methods:A cross-sectional online survey of internal medicine and psychiatry health care providers was conducted between September and October 2025 at a large academic medical center, assessing IGD-related beliefs, familiarity with diagnostic criteria, confidence in diagnosis and management, and perceived training needs.

Results: Among 67 respondents, most participants endorsed IGD as a clinically significant condition (84%) that contributes to psychiatric comorbidities (87%). However, fewer than half of providers reported confidence diagnosing (44%) or managing IGD (29%), and only 37% were familiar with currently proposed Diagnostic and Statistical Manual of Mental Disorders criteria. Psychiatric health care providers reported greater confidence and familiarity with IGD than their internal medicine counterparts, particularly in diagnosis, management, and identification of diagnostic criteria during clinical encounters. Overall, 81% of participants indicated that they would benefit from additional IGD-related education.

Conclusion: Despite broad recognition of IGD’s clinical significance, substantial gaps remain in provider confidence and familiarity with diagnostic and management approaches, particularly outside of psychiatry. These findings identify actionable gaps in provider preparedness and highlight the need for targeted educational efforts to support effective clinical management of IGD across medical specialties.

Prim Care Companion CNS Disord 2026;28(4):26m04192.

Author affiliations are listed at the end of this article.

PMID:42530875 | DOI:10.4088/PCC.26m04192

Prim Care Companion CNS Disord. 2026 Jul 21;28(4):26m04184. doi: 10.4088/PCC.26m04184.

ABSTRACT

Objective: To adapt the Borderline Symptom List 23 (BSL-23) to Brazilian Portuguese and evaluate its psychometric properties in a large nonclinical sample.

Methods: A total of 2,682 participants completed an online questionnaire between December 2021 and January 2022. Participants had a mean age of 26.64 years; most were female (78.2%) and had completed higher education. The adaptation process followed established guidelines, including translation, back-translation, expert evaluation, and target-population review. In addition to the BSL-23, participants completed the Depression, Anxiety and Stress Scale-21 Items (DASS-21), Difficulties in Emotion Regulation Scale (DERS), Barratt Impulsiveness Scale, and Childhood Trauma Questionnaire. Statistical analyses included exploratory and confirmatory factor analyses, internal consistency assessment, and tests of concurrent validity and measurement invariance.

Results: The BSL-23 maintained a unidimensional structure and demonstrated excellent internal consistency (Cronbach α=0.95). Exploratory factor analysis indicated high factor loadings for most items, while confirmatory factor analysis required minor adjustments due to collinearity between certain item pairs. Measurement invariance analyses showed small but statistically significant gender differences with minimal practical impact. Concurrent validity was supported by strong correlations with DASS-21 stress and depression subscales and moderate correlations with DERS dimensions.

Conclusion: The Brazilian Portuguese version of the BSL-23 demonstrated robust psychometric properties, confirming its validity for use in Brazilian samples. Future studies should include clinical populations and assess test-retest reliability to strengthen evidence of temporal stability.

Prim Care Companion CNS Disord 2026;28(4):26m04184.

Author affiliations are listed at the end of this article.

PMID:42530867 | DOI:10.4088/PCC.26m04184