Proportional Hazards Regression Models Research Articles

Nonlinear relationship between hepatic steatosis index and reversion to normal glucose regulation in Chinese adults with prediabetes.

The hepatic steatosis index (HSI) has been demonstrated to have a significant correlation with prediabetes and diabetes; however, its potential association with reversion to normal glucose regulation (NGR) from prediabetes remains insufficiently investigated. The primary objective of this study was to elucidate the relationship between HSI levels and the probability of reversion to NGR among Chinese adults with prediabetes. This retrospective cohort study utilized health examination data from 11,241 Chinese adults with prediabetes. Cox proportional hazard models were employed to calculate hazard ratios (HR) and 95% confidence intervals (CI) to assess the association between HSI levels and reversion to NGR. Additionally, a Cox proportional hazards regression model incorporating cubic spline functions and smooth curve fitting was utilized to determine any nonlinear relationships between HSI levels and reversion to NGR. The results of the multivariate analyses demonstrated a significant association between reduced HSI levels and an increased likelihood of reversion to NGR (HR = 0.92, 95%CI: 0.89-0.95, P < 0.0001). Furthermore, a nonlinear relationship was identified between HSI levels and the reversion to NGR, with a critical threshold at an HSI value of 43.08. Below this threshold, a strong negative association was observed, markedly enhancing the probability of returning to normoglycemic status (HR = 0.91, 95% CI: 0.88-0.94, P < 0.0001). This study reveals a negative, nonlinear correlation between HSI levels and the reversion to NGR in individuals with prediabetes. These findings highlight the essential role of effectively managing HSI as part of comprehensive prediabetes treatment strategies, which may significantly enhance the likelihood of achieving normoglycemic status.

Hospitalization for cardiovascular disease in the year after delivery of twin pregnancies.

Increased cardiovascular demand in twin pregnancies, even those without hypertensive disease of pregnancy (HDP), may pose a greater risk for cardiovascular complications compared with singletons. In this study, the risk of cardiovascular disease (CVD)-related hospitalizations and mortality within the year following delivery in relation to HDP was compared between twin and singleton pregnancies. Using the Nationwide Readmissions Database of US hospitals from 2010 to 2020, the rates of CVD readmission in four exposure groups (twin deliveries with and without HDP and singleton deliveries with and without HDP) were estimated. Cox proportional hazard regression models were used to determine associations with singletons without HDP as the reference. Of 36 million delivery hospitalizations, the rates of CVD readmission in twin and singleton pregnancies were 1105.4 and 734.1 per 100 000 delivery admissions, respectively. Compared with singletons without HDP, the adjusted hazard ratio (HR) of CVD readmission was highest for twins with HDP [HR 8.21, 95% confidence interval (CI) 7.48-9.01], followed by singletons with HDP (HR 5.89, 95% CI 5.70-6.08) and then twins without HDP (HR 1.95, 95% CI 1.75, 2.17). Compared with singletons without HDP, twin pregnancies, even in the absence of HDP, are associated with increased risks for CVD complications in the first year post-partum. These findings highlight the increased strain twin pregnancies place on the maternal cardiovascular system. These findings advocate the need for appropriate pre-conception counselling for those with cardiovascular risk factors undergoing infertility treatment, which increase the risks of multi-foetal gestation, and increased post-partum surveillance in twin pregnancies.

Analysis Method of Real-World Digital Biomarkers for Clinical Impact in Cancer Patients

Introduction: Wearable technologies can enhance measurements completed from home by participants in decentralized clinical trials. These measurements have shown promise in monitoring patient wellness outside the clinical setting. However, there are challenges in handling data and its interpretation when using consumer wearables, requiring input from statisticians and data scientists. This paper describes three methods to estimate daily steps to address gaps in data from the Apple Watch in cancer patients and uses one of these methods in an analysis of the association between daily step count estimates and clinical events for these patients. Methods: A cohort of 50 cancer patients used the DigiBioMarC app integrated with an Apple Watch for 28 days. We identified different gap types in watch data based on their length and context to estimate daily steps. Cox proportional hazards regression models were used to determine the association between step count and time to death or time to first clinical event. Decision tree modeling and participant clustering were also employed to identify digital biomarkers of physical activity that were predictive of clinical event occurrence and hazard ratio to clinical events, respectively. Results: Among the three methods explored to address missing steps, the method that identified different step data gap types according to their duration and context provided the most reasonable estimate of daily steps. Ten hours of waking time was used to differentiate between sufficient and insufficient measurement days. Daily step count on sufficient days was the most promising predictor of time to first clinical event (p = 0.068). This finding was consistent in participant cluster and decision tree analyses where the participant cluster that emerged naturally from the different levels of daily steps was the group with the highest steps on sufficient days and lowest hazard probability of mortality and clinical events. Additionally, daily steps on sufficient days can also be used as a predictor of whether a participant will have clinical events with an accuracy of 83.3%. Conclusion: We have developed an effective way to estimate daily steps from consumer wearable data containing unknown data gaps. Daily step counts on days with sufficient sampling is a strong predictor of the timing and occurrence of clinical events, with individuals exhibiting higher daily step counts having reduced hazard of death or clinical events.

Cognitive function differs across healthy lifestyle behavior profiles: a 10-year population-based prospective cohort study.

Modifiable lifestyle behaviors significantly influence the risk of cognitive impairment. However, the cumulative effects of multidimensional lifestyle profiles on cognitive function remain poorly understood, as most studies examine individual lifestyle behaviors in isolation. This study aimed to identify distinct profiles of individuals based on healthy lifestyle behaviors and to examine associations between these profiles and cognitive function in older Chinese adults. We used a prospective cohort, including 5381 participants of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) between 2008 and 2018, aged 65 years and older with normal cognition at baseline. Questionnaires were used to collect self-reported data on healthy diet, sleep quality, physical activities, cognitive activities, and social activities. Repeated measures of the Mini-Mental State Examination (MMSE) were utilized to assess cognitive function. Latent Profile Analysis (LPA) was conducted to identify profiles characterized by similar characteristics of lifestyle behaviors. The resultant profiles, were then used to further explore associations with cognitive function using cox proportional hazard regression and linear mixed models. During a 10-year follow-up period, 2017 (37.5%) out of 5381 participants developed cognitive impairment. Three latent profiles were identified: (1) "active engagement" (n = 347, 6.4%); (2) "moderate engagement" (n = 627, 11.7%); and (3) "negative engagement" (n = 4407, 81.9%). Compared to negative engagement, the active profile had the lower risk of cognitive impairment (HR = 0.693, 95% CI: 0.553-0.868), longer years to develop cognitive impairment (mean = 7.818, range: 6.701, 8.935) and slower rate of annual cognitive decline (0.407 points per year). Similarly, the moderate engagement profile had the lower risk of cognitive impairment (HR = 0.781, 95% CI: 0.664-0.919), longer years to develop cognitive impairment (mean = 7.541, 95%CI: 6.464, 8.619) and slower rate of annual cognitive decline (0.297 points per year) compared to negative profile. Subgroup analysis revealed that there were no significant differences observed across any of the subgroups, including age, gender, year of schooling, marital status, residence, live alone, family economic status. These findings imply the likelihood of an inverse correlation between the levels of engagement in healthy lifestyle behavior and the risk of cognitive impairment. Even adopting a few healthy lifestyle habits is superior to none at all, underscoring the value of lifestyle modifications for cognitive health.

Do Existing Magnetic Resonance Imaging Definitions of Knee Osteoarthritis Identify Knees That Will Develop Clinically Significant Disease Over Up To 11 Years of Follow-Up?

In individuals without radiographic knee osteoarthritis (OA), we investigated whether magnetic resonance imaging (MRI)-defined knee OA at baseline was associated with incident radiographic and symptomatic disease during up to 11 years of follow-up. Osteoarthritis Initiative participants without tibiofemoral radiographic knee OA at baseline were assessed for MRI-based tibiofemoral cartilage damage, osteophyte presence, bone marrow lesions, and meniscal damage/extrusion. We defined MRI knee OA using alternative, reported definitions (Def A and Def B). Kellgren-Lawrence (KL) grade, joint space narrowing (JSN), and frequent knee symptoms (Sx) were assessed at baseline, 1-, 2-, 3-, 4-, 6-, 8-, and 10/11-year follow-up visits. Incident tibiofemoral radiographic knee OA (outcome) was defined as (1) KL ≥2, (2) KL ≥2 and JSN, or (3) KL ≥2 and Sx. Adjusted Cox proportional hazards regression models examined associations of baseline MRI-defined knee OA (Def A and Def B) with incident outcomes during up to 11 years of follow-up. Among 1,621 participants (mean ± SD age 58.8 ± 9.0 years, mean ± SD body mass index 27.2 ± 4.5 kg/m2, 59.5% women), 17% had MRI-defined knee OA by Def A and 24% by Def B. Baseline MRI-defined knee OA was associated with incident KL ≥2 (odds ratio 2.94 [95% confidence interval (95% CI) 2.34-3.68] for Def A and 2.44 [95% CI 1.97-3.03] for Def B). However, a substantial proportion of individuals with baseline MRI-defined knee OA did not develop incident KL ≥2 during follow-up (59% for Def A and 64% for Def B). Findings were similar for the other two outcomes. Current MRI definitions of knee OA do not adequately identify knees that will develop radiographic and symptomatic disease.

Association between adjuvant component of perioperative chemotherapy and survival outcomes in resected gastric cancer (GC).

378 Background: Perioperative chemotherapy is the standard of care for resectable GC but many patients do not proceed to or complete adjuvant chemotherapy (AC). It remains unclear whether AC following neoadjuvant chemotherapy (NAC) improves survival. Methods: Patients with GC who received NAC and underwent curative-intent gastrectomy from 2006-2022 were identified from an institutional database. Patients with mismatch repair-deficient/microsatellite instability-high tumors, GEJ tumors, M1 disease, neoadjuvant radiotherapy, total neoadjuvant intent treatment, incomplete NAC (&lt;66% of planned cycles), and incomplete data were excluded. A lymph node ratio (LNR) risk cutoff was determined using maximally selected rank statistics. Kaplan-Meier analysis with log-rank tests were used to compare overall survival (OS) and disease-free survival (DFS). Cox proportional hazards regression models were used to identify independent predictors of OS and DFS. All analyses were performed in R statistical software. Results: Of 340 patients included, 264 (78%) received AC. Most common reasons for incomplete AC were postoperative complications (20%), poor performance status (16%), minimal pathologic response to NAC (14%), patient choice (14%), and NAC toxicity (9%). Median follow-up was 6.4 years. In the overall cohort, there was no significant difference in OS (median 10 vs. 8.3 years; p=0.14) or DFS (7.0 vs. 7.5 years; p=0.12) between AC and non-AC groups. In node-negative (ypN-) patients (n=170), there was no association between receipt of AC and OS (12 vs. 10 years; p=0.6) or DFS (12 vs. 10 years; p=0.8). On univariable analysis, lack of AC receipt was not associated with shorter OS (p=0.3) or DFS (p=0.4). In the node-positive (ypN+) cohort (n=170), AC receipt was associated with significantly longer DFS (4.8 vs. 2.7 years; p=0.031) but not OS (5.5 vs. 2.8 years; p=0.071). However, on multivariate analysis, AC only showed a non-significant trend towards longer DFS (HR 0.77 [95% CI 0.49-1.19]; p=0.20). High-risk patients based on LNR (LNR&gt;0.0684; n=112) who received AC (n=87; 78%) had longer OS (p=0.033) and DFS (p=0.014). No such differences were observed in the low risk LNR subgroup (LNR&lt;0.0684; n=227). Conclusions: Following NAC, AC was not associated with improved survival in patients with ypN- GC. The association between AC and survival in ypN+ GC remains unclear but LNR may be used to identify patients with ypN+ disease who may benefit from AC. These observations require prospective validation but may have implications for clinical care and future trial design.

Outcomes of surveillance in patients with intraductal papillary mucinous neoplasms (IPMNs) who tested negative for high-risk mutations (HRMs) in next-generation sequencing (NGS).

704 Background: HRMs in NGS have demonstrated high sensitivity and specificity for predicting advanced neoplasia in patients with IPMNs. However, the outcomes of surveillance in patients who tested negative for these HRMs have not been investigated in prior studies. This study aimed to identify the predictors of progression in patients with negative NGS results for HRMs. Methods: We conducted a retrospective review of prospectively collected data from patients who underwent NGS testing between 2016 and 2023 in our pancreatic cancer prevention program. Patients without IPMNs (i.e., negative for KRAS/GNAS), with HRMs, and those without at least one follow-up imaging post-NGS were excluded from the study. Progression was defined as the development of new or additional worrisome features or high-risk stigmata (per Kyoto guidelines), or advanced neoplasia (HGD/PDAC) following NGS testing. A Cox proportional hazards regression model was used to identify predictors of progression. Results: A total of 543 patients underwent NGS testing during the study period, of which 210 patients met the inclusion criteria. The median follow-up duration was 22 months (IQR = 12-36). Of these, 72 patients developed progression following NGS testing. A total of 11 patients underwent surgical resection, and 5 of them had HGD. Factors predictive of progression included a history of smoking (HR = 1.74; 95% CI = 1.06 - 2.86), larger cyst size (HR = 1.09; 95% CI = 1.03 - 1.16), and the presence of a dilated main pancreatic duct (MPD) (HR = 2.56; 95% CI = 1.5 - 4.4) prior to NGS testing. The median time to progression for patients with worrisome features was 33 months, compared to 59 months for those without worrisome features at baseline. Similarly, the median time to progression for patients with cysts ≥ 2 cm was 38 months, compared to 57 months for those with cysts &lt; 2 cm. Conclusions: Patients who test negative for high-risk mutations in NGS are not exempt from the risk of progression. Any smoking history and presence of any worrisome features before NGS testing showed to be independent predictors of disease progression. For patients with smoking history, worrisome features or cysts ≥ 2 cm, frequent surveillance should be recommended following NGS testing. Results of Cox proportional hazards regression model for identifying the predictors of progression. Variables Hazards ratio (HR) 95% Confidence Interval P-value Age 0.99 0.96 – 1.01 0.257 Male sex 1.02 0.62 – 1.7 0.93 White race 1.07 0.63 – 0.83 0.8 Family history of pancreatic cancer 0.6 0.26 – 1.36 0.22 Personal history of other cancers 0.95 0.56 – 1.62 0.86 Diabetes 1.22 0.72 – 2.05 0.46 Any history of smoking 1.74 1.06 – 2.86 0.03* Pre-NGS cyst size (cm) 1.09 1.03 – 1.16 0.006* Pre-NGS dilated main pancreatic duct (≥5mm) 2.56 1.5 – 4.4 0.001* Pre-NGS presence of mural nodules 0.32 0.04 – 2.37 0.26 *Significant p-value.

Impact of sirtuin genes expression on first-line treatment outcomes in patients (pts) with metastatic colorectal cancer (mCRC) enrolled in CALGB/SWOG 80405 (Alliance).

269 Background: Sirtuins (SIRT1-7) are class III histone deacetylases with different roles in CRC as tumor suppressive and oncogenic, mainly influencing proliferation, migration, invasion, DNA damage and chemoresistance. In the present study, we explored the association between tumor gene expression of sirtuins and first-line treatment outcomes in mCRC pts. Methods: We evaluated the impact of the tumor gene expression of sirtuin genes ( SIRT1 -7) on treatment outcomes (overall survival: OS; progression free survival: PFS) in 433 pts enrolled in the randomized, phase III CALGB/SWOG 80405 (NCT00265850) trial. RNA extracted from FFPE tumor samples was sequenced using the HiSeq 2500 (Illumina). Subgroup analyses were based on treatment (bevacizumab [bev] (N = 226) vs. cetuximab [cet] (N = 207)). For each gene, expression was divided into tertiles of high, medium and low. The associations between tumor gene expression and outcomes (PFS and OS) were assessed using log-rank test in univariate analysis. Multivariable Cox proportional hazards regression model was used to compute hazard ratios (HR) and 95% confidence intervals while adjusting for baseline characteristics. Treatment-gene interactions were analyzed using the likelihood ratio test. Results: Of the seven genes analyzed, SIRT3 high was associated with both longer PFS (HR: 0.59 [95% CI: 0.46-0.74], P &lt; 0.001) and OS (HR:0.64 [95% CI: 0.50-0.83], P = 0.002) overall. Treatment-gene interaction testing found significant interactions for SIRT1 and SIRT5 with PFS ( P values: 0.021 and 0.016, respectively) and OS ( P values: 0.038 and 0.014, respectively) with targeted therapies (bev vs. cet). Multivariate analysis showed SIRT1 high associated with longer PFS (HR: 0.62 [95% CI: 0.42-0.89], P = 0.014) and OS (HR: 0.59 [95% CI: 0.40-0.89], P = 0.036) in cet-treated pts; in contrast with shorter observed PFS (HR: 1.38 [95% CI: 0.96-1.99], P = 0.22) and OS (HR: 1.31 [95% CI: 0.90-1.93], P = 0.23) in bev-treated pts. SIRT5 high showed similar results and associated with longer PFS (HR: 0.64 [95% CI: 0.45-0.91], P = 0.039) and OS (HR: 0.57 [95% CI: 0.39-0.83], P = 0.013) in cet-treated pts, with no similar associations in bev-treated pts. Conclusions: Our results highlight a potential role for SIRT3 as prognostic and, SIRT1 and SIRT5 as predictive biomarkers for first-line treatment in mCRC, with differential effects based on targeted agents. Significant interaction favored cet treatment in SIRT1 high and SIRT5 high tumors. However, previous reports suggest an opposite role of SIRT5 that has been linked to chemotherapy and/or cet resistance in CRC via the inactivation of succinate dehydrogenase complex subunit A. Therefore, further studies are warranted to dissect the mechanism behind the interaction of SIRT5 with cetuximab activity and establish the potential of targeting SIRT1/5 in CRC.

Association between the triglyceride glucose-body mass index and memory-related diseases: A nationwide cohort study.

This study aimed to examine the longitudinal association between the triglyceride glucose-body mass index (TyG-BMI) index and memory-related diseases (MDs) among Chinese adults. Nationwide cohort study. Data were obtained from the China Health and Retirement Longitudinal Study (CHARLS), which is an ongoing nationally representative prospective cohort study. The exposure was the participants' TyG-BMI index at baseline from 2011 to 2012. MDs were acquired by self-reporting questions in 2018. Cox proportional hazards regression models were conducted to assess the relationship between the TyG-BMI index and MDs. During a median follow-up of 7.0 years, a total of 197 incident MDs events occurred. After multivariate adjustments for established MD-related risk factors, participants with the highest tertile of the TyG-BMI index had a higher risk of MDs (HR: 1.65; 95% CI: 1.02-2.09; P-trend <0.001) relative to individuals with the lowest tertile. Furthermore, the subgroup analyses of the association remained consistent. A high TyG-BMI index was associated with an increased risk of MDs. Our study suggests that monitoring long-term changes in the TyG-BMI index could assist with the early identification and prevention of MDs among individuals at high risk.

Association of statins use and genetic susceptibility with incidence of Alzheimer's disease.

The effect of statins use on the incidence of Alzheimer's disease (AD) is still under debate, and it could be modified by a series of factors. We aimed to examine the association of statins use with the risk of cognitive impairment and AD, and assess the moderating roles of genetic susceptibility and other individual-related factors. A longitudinal study was conducted from the UK Biobank where individuals completed baseline surveys (2006-2010) and were followed (mean follow-up period: 9 years). A population-based study. A total of 371,019 dementia-free participants (mean age 56.4 years; 53.6% female). The effects of statins use on cognitive performance and incident AD were examined by using linear regression model and Cox proportional hazards regression model, respectively. We further evaluated the moderating roles of genetic risks and individual-related factors on both multiplicative and additive scales. The findings showed statins use was associated with an increased risk of AD development [hazard ratio (HR) 1.19 (95% CI: 1.08, 1.30)] compared with no use of statins. We further found significant negative additive interactions of statins use with APOE ε4 allele. Besides, the effects of statins use would be modified by age, sex and cardiovascular diseases (CVDs). A protective effect of statins use was observed in those who carried two APOE ε4 alleles. Also, sex, age and CVDs could modify the effects of statins use, which would provide insights for the guideline of the statins therapy.

Association of early tumor shrinkage with survival in patients with HER2-positive advanced gastric cancer treated with trastuzumab deruxtecan.

360 Background: Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate composed of an anti-human epidermal growth factor receptor 2 (HER2) antibody and a cytotoxic topoisomerase I inhibitor, has been approved as third or later-line treatment for unresectable HER2-positive advanced gastric cancer (AGC) based on the results of phase II DESTINY-Gastric 01 trial. However, there are few studies on real-world clinical outcomes and clinicopathological factors associated with efficacy of T-DXd in patients with HER2-positive AGC. Methods: This single-center retrospective study enrolled patients with AGC treated with T-DXd as third- or later-line chemotherapy between March 2018 and December 2023. Early tumor shrinkage (ETS) was defined as the relative change in the sum of longest diameters of RECIST target lesions at 8 ± 2 weeks compared with baseline. Prognostic outcomes were assessed using the log-rank test and Cox proportional hazards regression model. Results: A total of 57 patients were enrolled. The median age was 66 years (range, 31–82); 68% were male; 79% had HER2 3+; 23% had pulmonary metastasis; 67% were treated with T-DXd in the third-line setting. At a median follow-up of 27.6 months, the median progression-free survival (PFS) was 4.5 months (95% confidence interval [CI], 3.8–5.5), and the median overall survival (OS) was 7.3 months (95% CI, 4.9–9.4). Among 40 patients with target lesions, the overall response rate was 35.0% and the disease control rate was 90.0%. Patients with ETS had notably longer PFS (median PFS (months) 8.6 vs 4.1, P &lt; 0.01) and OS (median OS (months) 9.1 vs 6.1, P &lt; 0.01) than those without ETS. In multivariate analysis, ETS was associated with significantly longer PFS (hazard ratio [HR], 0.23; 95% CI, 0.08–0.63; P = 0.004) and OS (HR, 0.27; 95% CI, 0.12–0.65; P = 0.004), whereas pulmonary metastasis was associated with significantly shorter OS (HR 2.46, 95% CI, 1.07–5.65; P = 0.03). Conclusions: This study showed that achieving an ETS was significantly associated with a favorable prognosis in patients with HER2-positive AGC treated with T-DXd.

Association between chemotherapy and the risk of developing breast cancer-related lymphedema: a nationwide retrospective cohort study.

Breast cancer-related lymphedema (BCRL) is a well-known complication of breast cancer treatment, which often includes chemotherapy. This study aimed to investigate the association between chemotherapy and the risk of developing BCRL in patients with new-onset breast cancer. This nationwide retrospective cohort study utilized data from the Korean National Health Insurance database and the Korea National Cancer Incidence Database (2006-2017). Using 1:1 propensity score matching, 37,202 participants who received chemotherapy and 37,202 who did not receive chemotherapy were included in the analysis. Cox proportional hazard regression models were employed to examine the association between chemotherapy and the risk of developing BCRL. Among the 74,404 participants, 11,508 (15.5%) were diagnosed with BCRL during the follow-up period. Compared with patients who did not receive chemotherapy, the risk of BCRL was higher in patients undergoing chemotherapy (hazard ratio [95% confidence interval]: 1.95 [1.87-2.04]). Furthermore, compared to patients who did not receive chemotherapy, the risk of BCRL was confirmed in the taxane (3.38 [3.19-3.58]), antimetabolite (1.79 [1.67-1.91]), and anthracycline (1.49 [1.41-1.56]) chemotherapy groups. Chemotherapy administration following a diagnosis of breast cancer increases the risk of BCRL. Therefore, vigilant monitoring for BCRL, particularly in patients undergoing chemotherapy with taxanes, antimetabolites, or anthracyclines, is warranted during follow-up.

Identifying proteomic prognostic markers for Alzheimer's disease with survival machine learning: The Framingham Heart Study.

Protein abundance levels, sensitive to both physiological changes and external interventions, are useful for assessing the Alzheimer's disease (AD) risk and treatment efficacy. However, identifying proteomic prognostic markers for AD is challenging by their high dimensionality and inherent correlations. Our study analyzed 1128 plasma proteins, measured by the SOMAscan platform, from 858 participants 55 years and older (mean age 63 years, 52.9 % women) of the Framingham Heart Study (FHS) Offspring cohort. We conducted regression analysis and machine learning models, including LASSO-based Cox proportional hazard regression model (LASSO) and generalized boosted regression model (GBM), to identify protein prognostic markers. These markers were used to construct a weighted proteomic composite score, the AD prediction performance of which was assessed using time-dependent area under the curve (AUC). The association between the composite score and memory domain was examined in 339 (of the 858) participants with available memory scores, and in a separate group of 430 participants younger than 55 years (mean age 46, 56.7 % women). Over a mean follow-up of 20 years, 132 (15.4 %) participants developed AD. After adjusting for baseline age, sex, education, and APOE ε4 + status, regression models identified 309 proteins (P ≤ 0.2). After applying machine learning methods, nine of these proteins were selected to develop a composite score. This score improved AD prediction beyond the factors of age, sex, education, and APOE ε4 + status across 15-25 years of follow-up, achieving its peak AUC of 0.84 in the LASSO model at the 22-year follow-up. It also showed a consistent negative association with memory scores in the 339 participants (beta = -0.061, P = 0.046), 430 participants (beta = -0.060, P = 0.018), and the pooled 769 samples (beta = -0.058, P = 0.003). These findings highlight the utility of machine learning method in identifying proteomic markers in improving AD prediction and emphasize the complex pathology of AD. The composite score may aid early AD detection and efficacy monitoring, warranting further validation in diverse populations.

Comparison between neoadjuvant chemotherapy followed by surgery and definitive chemoradiotherapy for survival in patients with resectable esophageal squamous cell carcinoma (JCOG2305A).

417 Background: Neoadjuvant triplet chemotherapy followed by surgery (Neo-S) has become the standard treatment for resectable esophageal squamous cell carcinoma (ESCC) based on the results of JCOG1109. However, definitive chemoradiotherapy (CRT) remains an option for organ preservation with curative intent. This analysis aimed to explore subgroups of patients undergoing CRT, including salvage treatment, to identify those with survival outcomes potentially equivalent to Neo-S. Methods: Pooled data from two clinical trials of patients with resectable (T1N1-3M0 and T2-3NanyM0) ESCC. JCOG0909 was a single-arm trial that evaluated upfront CRT consisting of 5-FU (1000 mg/m 2 on day1-4, 29-32) and cisplatin (80 mg/m 2 on day1, 29) combined with radiotherapy at a dose of 50.4 Gy, including salvage treatment. If there was no progression at the time of salvage treatment, it was not regarded as an event for progression-free survival (PFS) in JCOG0909. JCOG1109 compared neoadjuvant treatment with doublet chemotherapy, triplet chemotherapy, and doublet chemotherapy with radiotherapy followed by surgery. The patients were enrolled in JCOG0909 between 2010 and 2014 and in JCOG1109 between 2012 and 2018. Subgroup analyses of clinical data, including tumor location, cT, cN, and clinical stage, were conducted on overall survival (OS) and PFS using Cox proportional hazards regression models for patients with JCOG0909 and JCOG1109. When a subgroup with a multivariable hazard ratio (HR) of more than 0.91 was detected, CRT including salvage treatment was considered not to be inferior to Neo-S in that subgroup. Results: Ninety-three patients in the CRT group from JCOG0909 and 196 patients in the Neo-S group from the triplet chemotherapy arm of JCOG1109 were included in this analysis. Although there were no significant differences, PFS and OS tend to be better in the Neo-S group than in the CRT group (PFS, HR 0.72, 95% confidence interval [CI] 0.50-1.03; OS, HR 0.89, 95% CI 0.59-1.36). For patients with Ut/Mt or cT1-2 disease, OS in the Neo-S group had a HR of 0.91 or more compared with those in the CRT group (Table). Conclusions: Subgroups in which OS after CRT including salvage treatment was not inferior to that of Neo-S were identified. Hazard ratios of Neo-S to CRT by subgroups in multivariable Cox regression. Progression-free survival Overall survival Subgroups Hazard ratio 95% confidence interval Hazard ratio 95% confidence interval Ut/Mt 0.85 0.56-1.28 1.13 0.70-1.83 Lt 0.45 0.21-0.97 0.44 0.19-1.00 cT1-2 0.88 0.46-1.68 1.45 0.65-3.24 cT3 0.66 0.42-1.02 0.72 0.44-1.16 cStage IB+II 0.79 0.45-1.36 1.06 0.56-2.00 cStage III 0.75 0.45-1.23 0.92 0.52-1.62 Overall 0.72 0.50-1.03 0.89 0.59-1.36 Ut upper thoracic esophagus, Mt middle thoracic esophagus, Lt lower thoracic esophagus.

Comprehensive analysis of socioeconomic and clinical factors contributing to treatment delay in early-onset colorectal cancer.

32 Background: The prevalence of early-onset colorectal cancers (EOCRC) is rising globally. Disparities in social determinants of health can delay access to treatment and impacting outcomes. This study aims to analyze factors influencing time from diagnosis to treatment among EOCRC patients in a racially diverse population, considering tumor factors and sociodemographics. Methods: We analyzed EOCRC data from patients diagnosed between 2000 and 2022 at Queen’s Medical Center in Honolulu, Hawaii. Time from diagnosis to treatment for Asians, Whites, and Native Hawaiian or Other Pacific Islanders (NHOPI) was assessed using the Kaplan-Meier Method. Cox proportional hazards regression models were used to identify predictors, adjusting for clinical and pathological factors. Results: A total of 379 patients were analyzed. NHOPI were more like to be underinsured compared to Whites and Asians. In the unadjusted Cox model, underinsured/uninsured status, older age, unknown stage, left sided, and rectal locations were associated with delayed treatment. After adjustment, underinsured/uninsured status, older age, and rectal location remained significant predictors of delayed treatment. Conclusions: EOCRC patients with underinsured/uninsured status, age, and rectal tumor location are significantly associated with delayed in cancer treatment. While age was statistically significant, its clinical impact appears minimal. The need for a multidisplinary approach and additional preoperative staging in rectal cancer may explain treatment delays even after adjustment. Improving treatment accessibility and reducing delays, especially for underinsured EOCRC patients, is important. Univariate and multivariate analysis of time from diagnosis to treatment. Univariate Multivariate HR (95% CI) p-value HR (95% CI) p-value Insurance - - - - Private insurance - - - - Underinsured/Uninsured 0.692 (0.545-0.878) 0.003 0.706 (0.55-0.906) 0.006 Race White - - - - Asian 0.912 (0.696-1.195) 0.503 0.817 (0.619-1.077) 0.151 NHOPI 0.749 (0.548-1.025) 0.071 0.779 (0.562-1.08) 0.134 Age 0.978 (0.96-0.997) 0.021 0.968 (0.949-0.987) 0.001 Histopathology grade Grade 1&amp;2 - - - - Grade 3&amp;4 1.046 (0.798-1.371) 0.746 1.083 (0.813-1.441) 0.587 Stage 1 - - - - 2 1.022 (0.718-1.456) 0.902 1.071 (0.744-1.539) 0.713 3 1.227 (0.896-1.682) 0.203 1.387 (0.997-1.931) 0.052 4 0.964 (0.673-1.381) 0.842 1.039 (0.716-1.507) 0.842 Unknown 0.631 (0.406-0.981) 0.041 0.748 (0.473-1.182) 0.213 Sex Male - - - - Female 1.029 (0.836-1.267) 0.785 1.072 (0.868-1.325) 0.518 Microsatellite status Stable - - Unstable 1.074 (0.616-1.875) 0.8 Not done/Unknown 1.259 (1.004-1.577) 0.046 Location of Tumors Right - - - - Left 0.631 (0.468-0.851) 0.003 0.735 (0.535-1.011) 0.058 Rectal 0.43 (0.317-0.582) &lt;0.001 0.448 (0.327-0.613) &lt;0.001 NHOPI: Native Hawaiians and Other Pacific Islanders. HR: Hazard Ratio CI: Confidence Interval.

Comprehensive analysis of Native Hawaiians and other Pacific Islanders with early-onset colorectal cancer.

31 Background: Rates of early-onset colorectal cancers (EOCRC) are increasing in Hawaii across all racial groups. Although previous studies have shown that Native Hawaiians have a higher mortality rate compared to other racial groups, the adjustment for sociodemographic factors have been limited. Our objective is to perform a comprehensive analysis of outcomes among patients with EOCRC in a racially diverse population accounting for tumor factors and patient sociodemographics. Methods: Patients diagnosed with EOCRC between 2000 and 2022 in Hawaii. Overall survival of Asians, Whites, and Native Hawaiian or Other Pacific Islanders (NHOPI) were calculated using the Kaplan-Meier method. Cox proportional hazard regression models assessed survival predictors adjusting for clinical and sociodemographic factors. Results: We included 379 patients in the final analysis. NHOPI had higher prevalence of underinsured status and higher histopathology grade compared to Whites and Asians. In unadjusted Cox regression, NHOPI race, underinsured status, grade, and stage were prognostic for survival. After adjusting for confounders, underinsured status, grade, and stage remained prognostic, but race was not significantly associated with survival. Conclusions: This study concludes that while NHOPI patients with EOCRC demonstrated poorer survival outcomes compared to other racial groups, this disparity was largely explained by the large percentage of underinsured NHOPI patients. Addressing treatment disparities in underinsured or uninsured is essential to improve survival outcomes. Univariate and multivariate analysis of survival. Univariate Multivariate HR (95% CI) p-value HR (95% CI) p-value Insurance Private Insurance - - - - Underinsured &amp; Uninsured 1.865 (1.331-2.612) &lt;0.001 1.843 (1.285-2.643) &lt;0.001 Race White - - - - Asian 1.179 (0.746-1.865) 0.48 0.936 (0.585-1.496) 0.781 NHOPI 2.005 (1.231-3.265) 0.005 1.051 (0.714-1.547) 0.8 Age at diagnosis 0.996 (0.967-1.025) 0.771 1.002 (0.971-1.034) 0.901 Histopathology grade Grade 1&amp;2 - - - - Grade 3&amp;4 2.785 (1.958-3.963) &lt;0.001 2.278 (1.571-3.303) &lt;0.001 Stage Stage 1 - - - - Stage 2 1.104 (0.49-2.487) 0.81 1.028 (0.451-2.342) 0.948 Stage 3 3.255 (1.666-6.359) &lt;0.001 2.873 (1.447-5.706) 0.003 Stage 4 14.851 (7.499-29.41) &lt;0.001 12.778 (6.283-25.987) &lt;0.001 Unknown 3.738 (1.506-9.275) 0.004 3.008 (1.189-7.608) 0.02 Sex Male - - - - Female 0.812 (0.587-1.123) 0.22 0.852 (0.609-1.194) 0.352 Microsatellite status Stable - - Unstable 0.481 (0.148-1.562) 0.204 Not done/Unknown 1.08 (0.737-1.582) 0.739 Time to Treatment Less than 1 month - - - - More than 1 month 1.221 (0.863-1.727) 0.26 1.123 (0.784-1.609) 0.527 Location of Tumors Right - - - - Left 1.239 (0.76-2.02) 0.391 1.466 (0.886-2.425) 0.137 Rectal 1.391 (0.86-2.249) 0.178 1.211 (0.738-1.986) 0.449 NHOPI: Native Hawaiians and Other Pacific Islanders; HR: Hazard Ratio; CI: Confidence Interval.

The prognostic value of HER2 gene dosage and heterogeneity at a single-cell resolution in gastroesophageal adenocarcinoma.

473 Background: HER2 gene dosage (i.e. level of amplification) and heterogeneity are key prognostic variables for HER2+ gastroesophageal adenocarcinoma (GEA), yet no standardized approach to test these in routine clinical use exists. Here we modify the analytical pipeline for HER2 FISH to quantitatively estimate these prognostic variables and correlate them with clinical outcomes. Methods: Patients with metastatic HER2+ GEA who received trastuzumab-based therapy between 2011-2024 at Dana-Farber Cancer Institute and had available pre-treatment tissue for FISH analysis were included. HER2 FISH was conducted in a CLIA approved clinical pathology laboratory. Standard HER2/CEP17 ratio (an average of 50 cells) and individual cell HER2/CEP17 ratio were calculated. Kaplan-Meier method was used to estimate progression free (PFS) on trastuzumab-based therapy and overall survival (OS). Survival outcomes were adjusted for age, gender, tumor site, grade, prior resection, number of metastatic sites, and HER2 IHC using cox proportional hazard regression models. Results: A total of 77 patients were included. Median age was 60 years, 88% were male, and 92% had HER2 3+ tumors. Individual cells with HER2/CEP17 ratio ≥ 2.0 were defined as amplified (same cutoff as current bulk standard) and those with HER2/CEP17 ratio ≥ 4.95 (population median) were labeled highly HER2 amplified providing objective metrics to assess heterogeneity and gene dosage. Using these metrics we defined three subgroups: 1. Heterogenous (Het, n = 15): &lt;75% cells HER2+; 2. Homogenous, low gene dosage (HL, n = 30): &gt;75% cells HER2+, &lt;50% cells with high HER2 amplification; 3. Homogenous, high gene dosage (HH, n = 32): &gt;75% cells HER2+, &gt;50% cells with high HER2 amplification. Cutoffs for both metrics were determined using data distribution patterns. The subgroups were prognostically relevant and PFS and OS were significantly lower for heterogenous tumors and numerically lower for homogenous tumors with low gene dosage after multivariable adjustment (Table). Conclusions: HER2 gene dosage and heterogeneity significantly impact outcomes in HER2+ GEA. More importantly by deconvoluting clinical HER2 FISH data at single cell level, we demonstrate an objective metric with prognostic value that could be adopted for routine clinical use and for patient stratification. Further insights into differing biology of these molecular subtypes are needed. Outcomes of patients by HER2 heterogeneity and gene dosage. Hazards ratio (HR) and p values are adjusted using multivariable cox proportional hazard regression model. PFS OS Patients, No. Median, mo HR (95%CI) P Value Median, mo HR (95%CI) P Value HH 32 16.2 1 16.4 1 HL 30 12.1 1.70 (0.79-3.66) 0.173 15.7 1.71 (0.93-3.14) 0.085 Het 15 6.7 3.12 (1.35-7.2) 0.008 12.4 2.72 (1.28-5.75) 0.009

Association of active commuting with incidence of depression and anxiety: prospective cohort study.

Evidence is limited on the incidence of depression and anxiety in relation to active commuting. Our study aimed to explore their association and examine the mediating role of inflammatory. This study included 240,547 workers in the UK Biobank. The exposure variable was the mode of transport used to get to and from work including active (walking, cycling, mixed mode) and non-active commuting (car or public transport). The incidence of depression and anxiety was defined using ICD-10 codes. Cox proportional hazard regression models were used to explore the hazard ratios (HRs) of active commuting with depression and anxiety, and mediation analyses were used to test the mediating role of inflammatory in this association. There were 10,862 depression and 9407 anxiety events. Active commuting was associated with lower risk of depression [cycling: HR 0.775, 95% confidence interval (0.674-0.890); mixed mode walking: 0.858 (0.800-0.919); mixed mode cycling: 0.821 (0.744-0.907)] and anxiety [cycling: 0.781 (0.675-0.904); mixed mode walking: 0.867 (0.805-0.934); mixed mode cycling 0.810 (0.728-0.902)], and there were distinct dose-response trends between commuting distance and incidence of depression or anxiety. Inflammatory explained 19.75% of the association between cycling with depression, and 18.05% with anxiety. There were interactions between commuting and occupation type. Cycle and mix mode commuting were associated with lower risk of depression and anxiety, and inflammation partially mediated these association. Implementing initiatives that facilitate active commuting may help alleviate the poor mental health.

Familial confounding in the associations between maternal health and autism.

Evidence suggests that maternal health in pregnancy is associated with autism in the offspring. However, most diagnoses in pregnant women have not been examined, and the role of familial confounding remains unknown. Our cohort included all children born in Denmark between 1998 and 2015 (n = 1,131,899) and their parents. We fitted Cox proportional hazard regression models to estimate the likelihood of autism associated with each maternal prenatal ICD-10 diagnosis, accounting for disease chronicity and comorbidity, familial correlations and sociodemographic factors. We examined the evidence for familial confounding using discordant sibling and paternal negative control designs. Among the 1,131,899 individuals in our sample, 18,374 (1.6%) were diagnosed with autism by the end of follow-up. Across 236 maternal diagnoses we tested (prevalence ≥0.1%), 30 were significantly associated with autism after accounting for sociodemographic factors, disorder chronicity and comorbidity, and correction for multiple testing. This included obstetric, cardiometabolic and psychiatric disorders (for example, diabetes in pregnancy (hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.08-1.31) and depression (HR 1.49, 95% CI 1.27-1.75)), previously shown to be associated with autism. Family-based analyses provided strong evidence for familial confounding in most of the observed associations. Our findings indicate pervasive associations between maternal health in pregnancy and offspring autism and underscore that these associations are largely attributable to familial confounding.

Associations between neutrophil-percentage-to-albumin ratio level and all-cause mortality and cardiovascular disease-cause mortality in diabetes population

BackgroundThe prevalence of type 2 diabetes mellitus (T2DM) remains high and biomarkers related to T2DM are needed to be investigated. This study aimed to investigate the association between neutrophil percentage-to-albumin ratio (NPAR) with all-cause mortality and the risk of cardiovascular disease (CVD) mortality in community-dwelling individuals with T2DM.MethodsThis prospective cohort study included 3602 adults aged 20 or above who were diagnosed with diabetes by the American Diabetes Association criteria in the US National Health and Nutrition Examination Survey (NHANES) database from 1999 to 2016, and followed up until 2019. Multivariable Cox proportional hazards regression models were utilized to determine the relationship between NPAR with all-cause mortality and cardiovascular disease (CVD) mortality. Restricted cubic spline regression analyses were employed to explore the nonlinear relationship between NPAR and cardiovascular disease (CVD) mortality. The assessment of nonlinearity was conducted using the likelihood ratio test.ResultsAfter adjustment, the risk ratio for all-cause mortality in the highest NPAR group (≥ 15.40) compared to the lowest serum NPAR reference group (< 13.30) was 1.62 (95% CI, 1.36, 1.94) with P values < 0.001. Nevertheless, the risk ratio for cardiovascular disease (CVD) mortality in the highest NPAR group (≥ 15.40) versus the lowest serum NPAR reference group (< 13.30) was 1.41 (95% CI, 0.99, 2.00) with a P value of 0.06. Among patients with T2DM, serum NPAR levels exhibited a nonlinear correlation with both CVD mortality risk and all-cause mortality risk, with P values < 0.001 for both.ConclusionsThis study identified a significant association between elevated levels of the neutrophil percentage-to-albumin ratio (NPAR) and an increased risk of all-cause mortality among individuals with type 2 diabetes mellitus (T2DM). Conversely, no correlation was found between NPAR levels and CVD mortality.