Category: Statistics

Microsc Microanal. 2026 Jul 1;32(4):ozag046. doi: 10.1093/mam/ozag046.

ABSTRACT

In-situ, large-area, and high-quality surface preparation is essential for statistically representative microstructure characterization. Focused ion beam (FIB) systems are typically confined to scales below a hundred microns, while standalone broad ion beam (BIB) polishing systems often suffer from surface contamination and repositioning errors during sample transfer. Herein, we report an integrated argon broad ion beam scanning electron microscope (BIB-SEM) system achieved by mounting an electron cyclotron resonance (ECR) ion source directly into the SEM chamber. Three key engineering challenges were addressed through dual-layer magnetic shielding to suppress stray fields from the ECR ion source, a sputter-shielding assembly to mitigate debris contamination, and a wide-range tilt stage enabling flexible polishing angles and EBSD analysis. The integration establishes an iterative polishing-and-characterization workflow, allowing for in-situ assessment and parameter optimization without breaking vacuum. This capability enabled feedback-driven optimization on aluminum alloy to reach 99.98% EBSD indexing rates, uniform surfaces on molybdenum with >98% EBSD indexing rates across multiple regions on a ∼21 mm2 area, statistical analysis of estimated over 8 × 105 NCM811 particle cross-sections, and rapid cleaning of contaminated surface within 5 min. This integrated BIB-SEM system enables in-situ, millimeter-scale surface preparation with SEM/EBSD validation, advancing representative microstructural characterization in materials science.

PMID:42390897 | DOI:10.1093/mam/ozag046

Cancer. 2026 Jul 15;132(14):e70504. doi: 10.1002/cncr.70504.

ABSTRACT

BACKGROUND: Survivors of Ewing sarcoma (EWS) are at significant long-term risk of treatment- and disease-related complications. The purpose of this study was to characterize long-term outcomes in EWS survivors according to treatment regimen.

METHODS: Five-year survivors of EWS diagnosed between 1970 and 1999 from the Childhood Cancer Survivor Study were included. Late mortality (>5 years from diagnosis), subsequent malignant neoplasms (SMNs), and severe to fatal chronic health conditions (CHCs) by chemotherapy regimen were compared. Patients were compared to siblings via cumulative incidence and proportional hazards models. Standardized mortality ratios (SMRs) compared late mortality between survivors and the general population.

RESULTS: Survivors (N = 739) had higher all-cause (SMR, 6.16; 95% CI, 5.36-7.05), SMN-related (SMR, 9.24; 95% CI, 6.92-12.08), cardiac-related (SMR, 4.53; 95% CI, 2.81-6.93), and noncardiopulmonary health-related (SMR, 2.04; 95% CI, 1.25-3.15) mortality compared with the general population. Compared with siblings (N = 5040), survivors had an increased risk of developing CHCs (any: hazard ratio [HR], 5.49; 95% CI, 4.58-6.59; cardiovascular: HR, 4.59; 95% CI, 3.67-5.74; neurological: HR, 2.82; 95% CI, 1.72-4.63; respiratory: HR, 5.37; 95% CI, 2.76-10.5; renal: HR, 4.61; 95% CI, 2.26-9.40). Between chemotherapy groups within EWS, there were no statistically significant differences in all-cause, SMN-caused, or health-related late mortality and the risk of developing SMNs or CHCs (any, cardiovascular, neurological, or respiratory), except that the vincristine, doxorubicin, and cyclophosphamide (VDC) plus ifosfamide and etoposide (IE) group had a higher risk of renal complications (HR, 2.55; 95% CI, 1.07-11.7; 30-year incidence was 0.56% for VDC and 3.2% for VDC/IE).

CONCLUSIONS: No differences in late mortality, SMNs, and most CHCs were observed between patients who received VDC versus VDC/IE. Aging EWS survivors’ elevated risk of morbidity and mortality underscores the need for lifelong survivorship care and therapies that reduce the risk for late effects.

PMID:42390889 | DOI:10.1002/cncr.70504

JAMA Netw Open. 2026 Jul 1;9(7):e2621153. doi: 10.1001/jamanetworkopen.2026.21153.

ABSTRACT

IMPORTANCE: As populations age and cities become more densely populated, urbanicity is transforming neighborhood environments that influence healthy aging. However, how dementia mortality varies across the urbanicity gradient and how neighborhood conditions contribute to this pattern remain unknown.

OBJECTIVE: To examine dose-response associations of urbanicity with dementia mortality, quantify the extent to which neighborhood socioeconomic and environmental factors attenuate this pattern, and estimate potential deaths averted under feasible improvements in modifiable conditions.

DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study used person-level mortality data linked to the national census across 32 844 lower super output areas (ie, small census-based geographic areas) in England from March 2011 to February 2023. Individuals aged 16 years and older with National Health Service general practice registration in England were included. Data were analyzed from July 2025 to January 2026.

EXPOSURE: Participants’ residential addresses were linked to UK Census-based social and environmental data. Urbanicity was defined as neighborhood population density (persons per hectare), and neighborhood conditions included income, employment, education, crime, living environment, housing, and service accessibility.

MAIN OUTCOMES AND MEASURES: The primary outcome was mortality with dementia as the underlying cause, and the secondary outcome was mortality with dementia mentioned anywhere on the death certificate. Dose-response associations were examined using Cox proportional hazards models with hazard ratios and 95% CIs. Contribution of neighborhood conditions to these associations was assessed using the percentage of excess risk attenuated. Potential death averted under feasible improvements were estimated using parametric g-computation.

RESULTS: A total of 40 948 445 individuals (mean [SD] age, 46.9 [19.3] years, 21 263 986 females [51.9%]; 1 190 069 Black [2.9%]; 1 091 312 Indian [2.7%]; 35 973 092 White [87.9%]) were followed up for a median (IQR) of 8.68 (4.47-11.90) years. There were 5 309 719 deaths, including 621 756 underlying-cause and 926 502 any-mention dementia deaths. Dementia mortality showed a curvilinear inverted U-shaped association with urbanicity, peaking at mid-urbanicity (around 20 to 40 persons per hectare) and declining at both extremes. This pattern was consistent across subgroups, dementia subtypes, and all-cause mortality. For mortality with dementia as the underlying cause, adjustment for all factors largely eliminated the gradient (≥71% attenuated), with accessibility and living environment contributing the most. Scenario analyses shifting both service accessibility and outdoor living environment from the lowest to the second quintile estimated 65 572 (95% CI, 42 036-88 783) dementia deaths averted (10.5% reduction), compared with 43 452 (95% CI, 24 214-62 775) deaths averted (7.0% reduction) for accessibility-only, and 22 700 (95% CI, 11 086-34 201) deaths averted (3.7% reduction) for living environment-only improvements. Estimated gains were larger in males, adults aged 45 to 54 years, residents of private households (vs residents of care homes), and Black residents living under a scenario of improvement to both accessibility and environment.

CONCLUSIONS AND RELEVANCE: In this cohort study, dementia mortality risk was greatest in mid-urbanicity and lower in dense urban cores and rural areas, and this gradient was largely attenuated by neighborhood conditions. These findings suggest that targeted improvements in modifiable neighborhood conditions may substantially reduce dementia mortality and advance equity, particularly in vulnerable communities.

PMID:42390865 | DOI:10.1001/jamanetworkopen.2026.21153

JAMA Netw Open. 2026 Jul 1;9(7):e2621585. doi: 10.1001/jamanetworkopen.2026.21585.

ABSTRACT

IMPORTANCE: In the US, Black patients with cancer consistently experience worse survival compared to White patients, even after adjusting for age, sex, and disease stage. Whether these disparities exist among patients receiving care in the Veterans Health Administration (VHA), an integrated health system designed to provide near-equal access to care, remains uncertain.

OBJECTIVE: To evaluate whether overall survival (OS) and cancer-specific survival (CSS) differ between Black veterans and those with other race receiving cancer care through VHA.

DATA SOURCES: PubMed was searched from January 2015 through April 2022. Reference lists from identified studies were also reviewed.

STUDY SELECTION: Studies of US veterans receiving cancer care through the VHA were included if they reported OS or CSS by race and provided hazard ratios (HRs). Dual independent rating of titles and abstracts was conducted for inclusion.

DATA EXTRACTION AND SYNTHESIS: A random-effects model was used to pool effect sizes, the Paule-Mandel estimator was used to calculate the heterogeneity variance τ2, and Knapp-Hartung adjustments were used to calculate the confidence interval of the pooled effect. Review and meta-analysis was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline.

MAIN OUTCOMES AND MEASURES: OS and CSS were compared between Black veterans and those who were not Black using pooled HRs.

RESULTS: Of 101 studies identified, 39 met inclusion criteria and 29 provided sufficient data for meta-analysis. The reported outcomes represented 603 256 veterans with cancer treated between 1983 and 2017, with a mean 29.0% (range, 8.9%-55.0%) of patients categorized as Black. All studies compared race by Black compared with White, except for 7 of 20 prostate cancer studies, which compared race by Black compared with non-Black. Black veterans were found to have better OS (HR, 0.93; 95% CI, 0.89-0.97) and CSS (HR, 0.94; 95% CI, 0.90-0.98). Survival advantages for Black veterans were observed across several cancer types, including bladder, laryngeal, lung, oropharyngeal, prostate, and plasma cell cancers. Between-study heterogeneity was low to moderate.

CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis of peer-reviewed publications reporting the outcomes of veterans receiving cancer care through VHA, survival outcomes were generally similar or better for Black compared with White or non-Black veterans. These findings suggest that integrated health care systems providing near-equitable access to comprehensive cancer care can substantially reduce or eliminate disparities in cancer outcomes.

PMID:42390864 | DOI:10.1001/jamanetworkopen.2026.21585

JAMA Netw Open. 2026 Jul 1;9(7):e2621622. doi: 10.1001/jamanetworkopen.2026.21622.

ABSTRACT

IMPORTANCE: Risk and protective factors for suicide mortality in youths remain poorly synthesized, as prior reviews have focused on all ages or nonfatal outcomes.

OBJECTIVE: To systematically assess factors associated with risk of suicide mortality in youths.

DATA SOURCES: MEDLINE, PsycINFO, Embase, and CINAHL from inception to March 7, 2025.

STUDY SELECTION: Case-control and cohort studies of youths (aged ≤24 years) examining risk and/or protective factors associated with suicide mortality vs living general-population controls were included. Two independent reviewers screened 9497 records.

DATA EXTRACTION AND SYNTHESIS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, 2 reviewers independently screened reports; 1 extracted data, verified by a second. Evidence was synthesized using vote counting and random-effects meta-analysis in April 2026.

MAIN OUTCOMES AND MEASURES: The primary outcome was suicide mortality at age 24 years or younger.

RESULTS: Ninety reports from 68 studies, mostly from high-income countries, identified distinct risk and/or protective factors; 54 reports contributed to 30 meta-analyses. The factors associated with the highest odds of suicide risk included schizophrenia (odds ratio [OR], 22.23; 95% CI, 12.05-41.03; I2 = 85.4%; 7 reports), mood disorders (OR, 11.32; 95% CI, 6.11-20.97; I2 = 64.6%; 7 reports), and self-harm (OR, 14.06; 95% CI, 5.58-35.39; I2 = 90.1%; 10 reports). Clinical indicators of health care use were also associated with higher risk, including mental health services use in preceding year (OR, 7.39; 95% CI, 6.45-8.47; I2 = 0.0%; 5 reports) and psychiatric admission (OR, 31.96; 95% CI, 13.83-73.86; I2 = 94.8%; 6 reports). At the socioecological level, several indicators were associated with higher risk, including maltreatment (OR, 4.03; 95% CI, 1.41-11.50; I2 = 67.1%; 5 reports), out-of-home placement (OR, 4.47; 95% CI, 2.15-9.28; I2 = 42.1%; 5 reports), youth justice system involvement (OR, 2.70; 95% CI, 1.94-3.75; I2 = 64.2%; 7 reports), and low educational attainment (OR, 2.95; 95% CI, 1.66-5.24; I2 = 76.0%; 5 reports). In contrast, indicators of family stability were associated with lower risk, including living with both parents (OR, 0.55; 95% CI, 0.48-0.62; I2 = 12.1%; 11 reports). Heterogeneity was substantial across analyses, while Newcastle-Ottawa ratings indicated moderate-to-high study quality.

CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis, suicide mortality in youths was associated with mental disorders, health care contact, and adversity, supporting both clinical care and population-level prevention, with future research needed in underrepresented populations.

PMID:42390862 | DOI:10.1001/jamanetworkopen.2026.21622

JAMA Netw Open. 2026 Jul 1;9(7):e2621697. doi: 10.1001/jamanetworkopen.2026.21697.

ABSTRACT

IMPORTANCE: Changes in family structure in the US may be a driving force behind the growing need for friend caregivers. Yet, this segment of caregivers is often overlooked in health care settings and related research.

OBJECTIVE: To provide national estimates of friend caregivers, compare the characteristics of care provided by friend vs family caregivers, and identify characteristics of older adults associated with receiving care from friends.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional analysis of the 2023 National Health and Aging Trends Study included data on older adults (aged ≥65 years).

EXPOSURE: Sociodemographic and health-related characteristics of care recipients.

MAIN OUTCOMES AND MEASURES: The primary outcome was having a friend who provided assistance in the past month due to health or functional limitations. Adjusted Wald tests were used for continuous variables and Rao-Scott χ2 tests for categorical variables to compare characteristics of care provided by friend versus family caregivers and of care recipients receiving friend-involved versus family-only care. Multivariable logistic regression was used to identify older adult characteristics independently associated with friend involvement in care networks.

RESULTS: This study included 451 friend and 4985 family caregivers identified by 2619 older adults with activity limitations (weighted mean [SE] age, 78.7 [0.25] years; 63.2% [95% CI, 60.5%-65.9%] female) representing 2.4 million friend caregivers and 21.4 million family caregivers providing care to approximately 12.2 million recipients. Compared with family caregivers, friend caregivers were less likely to coreside with the care recipient (3.3% [95% CI, 1.6%-6.7%] vs 46.4% [95% CI, 44.2%-48.6%]; P < .001) or serve as the sole caregiver (11.1% [95% CI, 7.7%-15.9%] vs 21.2% [95% CI, 19.4%-23.3%]; P < .001). Although they provided fewer care hours per month than family caregivers (mean [SE], 18.1 [3.8] vs 66.6 [2.7] hours; P < .001), friends were more likely to help with transportation (65.7% [95% CI, 59.8%-71.2%] vs 52.7% [95% CI, 50.6%-54.8%]; P < .001), specialize in a single domain of care (66.4% [95% CI, 60.6%-71.9%] vs 33.6% [95% CI, 31.7%-35.5%]; P < .001), and share care with others. In multivariable models, being older (odds ratio [OR], 0.97; 95% CI, 0.95-0.99; P = .002) and married (OR, 0.52; 95% CI, 0.31-0.97; P = .01) were associated with a lower likelihood of having friends involved in the care network, whereas having a college degree (OR, 1.66; 95% CI, 1.14-2.43; P = .01) and living alone (OR, 2.29; 95% CI, 1.50-3.50; P < .001) were associated with a greater likelihood of having friends involved in the care network.

CONCLUSIONS AND RELEVANCE: In this cross-sectional study of Medicare beneficiaries aged 65 years and older, friend caregivers represented a specialized segment of the unpaid caregiving workforce, particularly for older adults lacking family resources. Understanding how friends provide care can help health care professionals better recognize them as an integral part of the caregiving network.

PMID:42390861 | DOI:10.1001/jamanetworkopen.2026.21697

JAMA Netw Open. 2026 Jul 1;9(7):e2622131. doi: 10.1001/jamanetworkopen.2026.22131.

ABSTRACT

IMPORTANCE: In February 2024, the South Korean government announced plans to increase medical school enrollment by 2000 students to address physician shortages, prompting opposition from the medical community. More than 90% of trainee physicians joined a nationwide walkout that continued through August 2025, but its systemwide implications remain unclear.

OBJECTIVES: To examine the association of the trainee physicians’ walkout with mortality, health care use, and spending patterns in South Korea.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used nationwide health insurance claims data and a historical-control event-study design. Data from 200 teaching hospitals before and after the walkout in week 8 of 2024 were compared, using October 2023 to September 2024 as the exposed year and October 2022 to September 2023 as the historical control.

MAIN OUTCOMES AND MEASURES: The primary outcomes were mortality, health care use, and spending per encounter measured weekly at the hospital level. The association between the trainee physicians’ walkout and hospital-level outcomes was assessed using a group-time average treatment effect framework.

RESULTS: The analysis included 7 719 828 patients with inpatient admissions (3 520 242 [45.6%] aged ≥65 years; 3 883 073 [50.3%] female) and 41 891 392 with outpatient visits (17 552 493 [41.9%] aged ≥65 years; 21 992 981 [52.5%] female). The walkout was associated with a 0.008-percentage point increase in weekly mortality among hospital users (95% CI, 0.000 to 0.015 percentage points) and a 0.39-percentage point increase in 30-day mortality after hospitalization (95% CI, 0.24 to 0.54 percentage points), concentrated among admissions for general conditions. These associations were largest early in the walkout and attenuated over time. The walkout was associated with reductions in both inpatient and outpatient use, with a larger relative decline for inpatient care (decrease of 19.2 hospitalizations per 10 million people; 95% CI, -24.1 to -14.3 per 10 million people [-17.3%] vs decrease of 158 outpatient visits per 10 million people; 95% CI, -198 to -118 visits [-8.6%]), and with higher mean spending per hospitalization (US $301; 95% CI, $202-$399). Hospitalizations for general conditions showed the largest relative decline in service volume (-23.5%) and the greatest increase in mean spending per hospitalization (US $242; 95% CI, $108 to $375), whereas mortality, use, and spending for complex conditions remained stable. Little evidence of care shifting to nonteaching hospitals was found.

CONCLUSIONS AND RELEVANCE: In this retrospective cohort study of teaching hospitals in South Korea, the trainee physicians’ walkout was associated with small, short-term increases in mortality, reductions in hospital use, and higher spending per encounter, concentrated among admissions for general conditions. Outcomes for complex conditions were largely unchanged, suggesting that teaching hospitals prioritized high-acuity care. Rapid hospital and governmental responses may have helped limit harm and support resource allocation.

PMID:42390860 | DOI:10.1001/jamanetworkopen.2026.22131

JAMA Netw Open. 2026 Jul 1;9(7):e2622603. doi: 10.1001/jamanetworkopen.2026.22603.

ABSTRACT

IMPORTANCE: Meningioma is a known adverse reaction of high-dose progestogens, but evidence regarding the risk associated with progestogens used as contraception is limited.

OBJECTIVE: To examine whether different progestogens used as hormonal contraception are associated with increased risk of meningiomas.

DESIGN, SETTING, AND PARTICIPANTS: This nested case-control study conducted over a 25-year study period from January 1, 2000, to December 31, 2024, is a Danish nationwide population-based register study, which included 3 million females aged 15 to 59 years with residence in Denmark. Meningioma cases were dentified, and for each case, 10 controls were matched on age, birthplace, and marital status and randomly selected from the cohort if considered eligible on the day of the case’s meningioma diagnosis. Data were analyzed from July 10, 2025, to May 12, 2026.

EXPOSURE: Use of progestogens was identified in the registers by date of dispensing or procedural records and grouped by route of administration and active substance. Exposure time was determined by redeemed daily doses or product duration. If a female switched to a different product or became pregnant, her exposure time was changed to the new exposure. The females included were allocated to their most recent use, defined as the exposure closest to the matching date.

MAIN OUTCOMES AND MEASURES: The main outcome was incident meningioma and was identified in the Danish National Cancer Register using validated International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses and International Classification of Diseases for Oncology, Third Edition codes.

RESULTS: A total of 1473 cases and 14 717 controls with a median age of 48 years (IQR, 42-53 years) were included in the nested cohort. For combined oral contraceptives, the estimated odds ratios (ORs) for the association between use of progestogens and meningioma were 1.61 (95% CI, 1.00-2.59) with cyproterone, 1.66 (95% CI, 1.31-2.10) with desogestrel, 1.58 (95% CI, 1.05-2.37) with drospirenone, 1.44 (95% CI, 1.17-1.77) with gestodene, 1.40 (95% CI, 1.12-1.76) with levonorgestrel, 1.38 (95% CI, 0.77-2.47) with norethisterone, and 1.04 (95% CI, 0.70-1.54) with norgestimate. For oral progestogen-only contraceptives, the ORs were 1.73 (95% CI, 1.17-2.56) with desogestrel and 0.95 (95% CI, 0.57-1.57) with norethisterone. For injectable medroxyprogesterone, the OR was 4.55 (95% CI, 2.19-9.45). For intrauterine devices (IUDs) with high-dose levonorgestrel, the OR was 1.58 (95% CI, 1.28-1.94), and for IUDs with low-dose levonorgestrel, the OR was 1.14 (95% CI, 0.59-2.22). Exposure within the past year was associated with the highest risk.

CONCLUSIONS AND RELEVANCE: In this case-control study conducted using data from the entire Danish population, recent use of the contraceptive progestogens cyproterone, desogestrel, drospirenone, gestodene, levonorgestrel, injectable medroxyprogesterone, and high-dose IUD was associated with increased risk of meningioma. These findings are considered relevant information for the treated women and the prescribing physicians.

PMID:42390859 | DOI:10.1001/jamanetworkopen.2026.22603

JAMA Otolaryngol Head Neck Surg. 2026 Jul 2. doi: 10.1001/jamaoto.2026.1749. Online ahead of print.

ABSTRACT

IMPORTANCE: Squamous cell carcinomas of the oral cavity (OCSCC), oropharynx (OPSCC), hypopharynx (HPSCC), and larynx (LSCC) are the most common forms of head and neck cancer globally. Epidemiological studies have identified variations in blood trace metal concentrations as potential risk factors for the development of these cancers, but these studies are susceptible to multiple biases.

OBJECTIVE: To determine if variations in genetically predicted blood manganese are associated with risk of OCSCC, OPSCC, HPSCC, and LSCC.

DESIGN, SETTING, AND PARTICIPANTS: This population-based 2-sample cis-mendelian randomization study used a genetic instrument for blood manganese derived from a meta-analysis of 3 individual-level genome-wide association study datasets of 6564 Scandinavian participants. Genetic associations for the development of the specified cancers were obtained from a nonoverlapping, multi-ancestral meta-analysis that combined individual-level genome-wide association study datasets comprising 38 857 healthy controls, 5596 case patients with OCSCC, 2212 case patients with human papillomavirus (HPV)-positive OPSCC, 1473 case patients with HPV-negative OPSCC, 898 case patients with HPSCC, and 4409 case patients with LSCC.

EXPOSURES: Increases in genetically predicted whole blood manganese concentration proxied by a genetic instrument including 2 cis-variants (single-nucleotide variants) selected due to their known functions in regulating manganese metabolism.

MAIN OUTCOMES AND MEASURES: The primary outcomes were the risk of OCSCC, OPSCC (HPV positive and HPV negative), HPSCC, and LSCC, evaluated by estimating the odds ratio (OR) and 95% CI of each outcome per 1-SD increase in whole blood manganese concentration after rank-based inverse normalization transformation.

RESULTS: Genetically predicted higher blood manganese was found to have a statistically significant association with increased risk of OCSCC (OR, 1.25; 95% CI, 1.10-1.43; P < .001) and HPV-positive OPSCC (OR, 1.23; 95% CI, 1.04-1.45; P = .02). Associations between blood manganese and HPV-negative OPSCC (OR, 1.20; 95% CI, 0.95-1.50; P = .13), HPSCC (OR, 1.25; 95% CI, 0.75-2.07; P = .39), and LSCC (OR, 1.10; 95% CI, 0.92-1.32; P = .28) were directionally concordant but not statistically significant.

CONCLUSIONS AND RELEVANCE: This cis-mendelian randomization study demonstrates statistically significant associations between higher blood manganese concentrations and risk of OCSCC and HPV-positive OPSCC. Further work should aim to establish the pathophysiological mechanisms underlying this association to inform potential public health strategies for the prevention of these cancers.

PMID:42390852 | DOI:10.1001/jamaoto.2026.1749

JAMA Oncol. 2026 Jul 2. doi: 10.1001/jamaoncol.2026.2157. Online ahead of print.

ABSTRACT

IMPORTANCE: Hepatocellular carcinoma (HCC) surveillance in patients with cirrhosis remains suboptimal, with inadequate early-stage detection. α-Fetoprotein (AFP) demonstrates insufficient sensitivity. Circulating methylated septin 9 (SEPT9) has shown diagnostic promise.

OBJECTIVE: To determine whether methylated SEPT9 improves detection of HCC when combined with AFP in patients with cirrhosis undergoing surveillance.

DESIGN, SETTING, AND PARTICIPANTS: In this prospective, cross-sectional, diagnostic accuracy study, patients with cirrhosis undergoing routine HCC surveillance with ultrasonography and AFP were enrolled at 2 French academic centers from February 2018 through October 2024. HCC was diagnosed per international guidelines with centralized radiologic review, blinded to methylated SEPT9 results. Data were analyzed from October 2025 to January 2026.

EXPOSURES: Plasma methylated SEPT9 was analyzed from 3 independent plasma aliquots and classified by number of positive replicates (single-positive, double-positive, or triple-positive). Serum AFP was evaluated at a threshold of 20 ng/mL. Biomarkers were evaluated individually and in combination using disjunction logic (tier 1; maximizing sensitivity) or conjunction logic (tier 2; maximizing specificity).

MAIN OUTCOMES AND MEASURES: The primary outcome was the presence of HCC at enrollment. The primary end point was comparison of the area under the receiver operating characteristic curve (AUROC) between methylated SEPT9 and AFP. Secondary end points included diagnostic performance stratified by Barcelona Clinic Liver Cancer (BCLC) stage.

RESULTS: Among 574 participants, 414 (72.1%) were male, and the median (IQR) age was 63 (57-70) years. A total of 118 had HCC, including 51 (43.2%) with BCLC stage 0-A. Methylated SEPT9 outperformed AFP (AUROC: 0.79 [95% CI, 0.74-0.84] vs 0.71 [95% CI, 0.66-0.76], respectively; P = .002; posterior probability of superiority >99.8%). Tier 1a (at least single-positive methylated SEPT9 or AFP >20 ng/mL) achieved 87.8% (95% CI, 81.6-93.5) sensitivity and a negative likelihood ratio of 0.2 (95% CI, 0.1-0.3). Among 64 HCC cases missed by AFP, tier 1a recovered 50 (78%). For BCLC 0-A disease, tier 1a sensitivity was 74.5% (95% CI, 62.2-86.5) vs 23.5% (95% CI, 12.5-35.8) for AFP, 3.2-fold increase. Tier 2 (triple-positive methylated SEPT9 and AFP >20 ng/mL) achieved 99.6% (95% CI, 98.9-100) specificity, a positive likelihood ratio of 76.0 (95% CI, 26.9-181.0), and a diagnostic odds ratio of 112.1 (95% CI, 37.8-294.7).

CONCLUSIONS AND RELEVANCE: In this diagnostic study, combining methylated SEPT9 with AFP substantially improved HCC detection in patients with cirrhosis, particularly for early-stage disease amenable to curative treatment. Prospective studies are needed to determine whether improved detection translates into survival benefit.

PMID:42390849 | DOI:10.1001/jamaoncol.2026.2157