Use Of Cox Regression Research Articles

O-223 Can the theory of planned behavior predict parents’ disclosure of donor conception to their children within 5-9 years?

Abstract Study question Does application of the theory of planned behavior (TPB) help predict heterosexual-couple parents’ disclosure of donor conception (DC) to their children? Summary answer According to TPB, parents with a stronger will to act in accordance with social norms favoring disclosure were more likely to start the disclosure process. What is known already In contrast to same-sex couples and single mothers by choice, heterosexual couples need to make an active decision to disclose, or not disclose, their use of DC to their child. While disclosure at an early age is encouraged by international and national guidelines, many heterosexual-couple parents struggle with this. A previous study has found an association between parental scores of TPB factors and disclosure intention, but so far, no study has applied the TPB to predict parents’ de facto disclosure behavior. Study design, size, duration The present study is based on the fourth (2014-2017) and fifth (2022-2023) waves of data collection in the prospective, longitudinal Swedish Study on Gamete Donation (SSGD). The project collects survey data at five timepoints from acceptance to be donor-recipient, to the children were adolescents. Participating parents had conceived through identity-release oocyte donation (OD; n = 68, response rate 65%) and sperm donation (SD; n = 62, response rate 56%) as part of a heterosexual couple. Participants/materials, setting, methods The SSGD includes all parents seeking gamete donation treatment at Swedish university hospitals between 2005-2008, the present study including parents’ data when the children were 7-8 years (T4), and 13-17 years (T5). Parents completed the TPB Disclosure Questionnaire (TPB-DQ) at T4, and disclosure behavior was assessed at both T4 and T5. Data from the participants who had not yet disclosed at T4 were analyzed using survival analysis with Cox regressions. Main results and the role of chance Forty participants (31%) had not disclosed the DC to their children at T4 and out of these, 13 had still not disclosed at T5. The TPB-DQ consists of four factors affecting intent to disclose; Attitudes, Subjective norms, Perceived behavioral control and Behavioral intent. The use of Cox regression enabled us to estimate how the parents disclosing to their children related to TPB-DQ, as well as the effect of adjusting for possible confounders. We found a significant association between scores on the TPB-DQ factor Subjective norms at T4 and the subsequent disclosure behavior at T5 (HR = 2.019; 95% CI: 1.36 to 3.01). None of the other factors were significantly associated with disclosure behavior. Adjusting for potential confounders did not affect the outcomes. Our results show that parents with a stronger will to act in accordance with social norms favoring disclosure were more likely to start the disclosure process within the next 5-9 years. In particular, the co-parent’s opinion about disclosure was found to be an important motivating factor in disclosure behavior. Limitations, reasons for caution The present study concerns heterosexual-couple parents with children conceived following treatment with gametes from open-identity donors, which limits the generalizability of our findings to other groups and contexts. Other limitations include the risk of systematic attrition due to the longitudinal study design and decreased statistical power due to few participants. Wider implications of the findings Our findings highlight the importance of perceived subjective norms for parents’ disclosure behavior and indicate that the co-parent’s opinion about disclosure is particularly relevant. Counselors should focus on supporting prospective parents to initiate and maintain a healthy and open dialogue about concerns around family building with DC. Trial registration number Not applicable

Group sequential methods based on supremum logrank statistics underproportional and nonproportionalhazards.

Despite the widespread use of Cox regression for modeling treatment effects in clinical trials, in immunotherapy oncology trials and other settings therapeutic benefits are not immediately realized thereby violating the proportional hazards assumption. Weighted logrank tests and the so-called Maxcombo test involving the combination of multiple logrank test statistics have been advocated to increase power for detecting effects in these and other settings where hazards are nonproportional. We describe a testing framework based on supremum logrank statistics created by successively analyzing and excluding early events, or obtained using a moving time window. We then describe how such tests can be conducted in a group sequential trial with interim analyses conducted for potential early stopping of benefit. The crossing boundaries for the interim test statistics are determined using an easy-to-implement Monte Carlo algorithm. Numerical studies illustrate the good frequency properties of the proposed group sequential methods.

Aminoacyl-tRNA Synthetase-based Prognosis Model and Exploration of Potential Mechanisms in Hepatocellular Carcinoma.

Aminoacyl-tRNA synthetases (ARSs) participate in tumor initiation and progression but their involvement in hepatocellular carcinoma (HCC) is not clear. This study aimed to investigate the prognostic value and underlying mechanisms of ARS in HCC. Data were obtained from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium, Gene Expression Omnibus and Human Protein Atlas databases. The prognostic model was constructed with the use of Cox regression and least absolute shrinkage and selection operator regression. Kaplan-Meier survival analysis, enrichment analysis, single sample gene set enrichment analysis and tumor mutation burden calculation were performed with R to evaluate the model and explore the underlying mechanism. Wilcoxon tests were used for comparisons between groups. Aspartyl-tRNA synthetase 2 (DARS2), tyrosyl-tRNA synthetase 1 (YARS1) and cysteinyl-tRNA synthetase 2 (CARS2) were identified as prognostic biomarkers and enrolled in model construction. The area under receiver operating characteristic curve of the model was 0.775. The model was used to assign patients from TCGA into low- and high-risk groups. Those in the high-risk group had a worse prognosis (p<0.001). The clinical significance of the model was tested in different clinical subgroups. Genetic mutation analysis had a higher TP53 mutation frequency in high-risk group. Enrichment analysis and study of immune-related cells and molecules found that the high-risk group was characterized by immune-cell infiltration and immunosuppression states. A novel ARS family-based model of HCC prognosis was constructed. TP53 mutation frequency and immune-suppressive status accounted for a worse prognosis in patients included in the high-risk group.

Pediatric Acute Lymphoblastic Leukemia with Pdgfrb Fusions: A Multicenter Retrospective Study

Objective: PDGFRB fusions in acute lymphoblastic leukemia (ALL) is rare. PDGFRB fusions was mainly observed in B-ALL, but also in T-ALL. Previous studies were mostly limited to anecdotal cases, suggesting that this subtype of ALL had low rate of remission and poor prognosis. The addition of tyrosine kinase inhibitor (TKI) to intensive chemotherapy may improve the outcome, but lack of long-term survival data. Herein, we retrospectively analyzed the clinical characteristics, survival and prognostic factors for 28 pediatric patients with PDGFRB fusions ALL. Methods: This multicenter, retrospective study included pediatric patients with newly diagnosed PDGFRB fusion ALL after treatments according to the CCCG-ALL-2015 and CCCG-ALL-2020 protocols from April 2015 to April 2022 in 10 hospitals in China. All patients completed the followed up. The baseline characteristics and treatment outcomes of these patients, including complete remission, drug resistance, relapse, treatment-related mortality and minimal residual disease (MRD) at end of induction therapy, as well as hematopoietic stem cell transplantation (HSCT) were collected. The outcome was compared between patients treated with and without TKI. Fisher test and nonparametric rank sum test were used for comparative analysis. 4-year event-free survival (EFS) and 4-year overall survival (OS) were estimated by use of Kaplan-Meier methods, and the 4-year cumulative incidence of relapse was calculated by use of a competing risk model gray test. Univariate and multivariate analyses were performed by use of Cox regression. Results: We identified 28 pediatric patients with newly diagnosed PDGFRB fusion ALL, which accounted for approximately 0.5% of childhood ALL. In all 28 patients, 21 (75%) were male and 7 (25%) were female; the median age was 10 (1-16) years old; median white blood cell (WBC) was 29.8 (1.6-627.7) × 10^9/L; 24 (85.7%) were acute B-lymphoblastic leukemia and 4 (14.3%) were acute T-lymphoblastic leukemia; one case (3.5%) was observed accompanied by the CNS involvement at diagnosis. Twenty of the patients received TKI treatment. Only 6 patients underwent hematopoietic stem cell transplantation. For all 28 patients, the median follow-up was 25.5 (3-77) months, the 4-year EFS was 29.2% (95% CI, 13.6-36.4), the 4-year OS was 42.1% (95% CI, 30.6-61.4), and the 4-year cumulative incidence of relapse was 58% (95% CI, 45·6-70·1). Patients in TKI group had a high rate of complete remission after induction therapy compared with those in no-TKI group (90% vs 63.6%). However, no significant differences were observed in the 4-year EFS and 4-year OS between TKI group and no-TKI group (EFS, 21.1% vs 43.8%, P=0.925; OS, 50.1% vs 36.5%, P=0.807). The cumulative incidences of relapse between these two groups also have no remarkable differences (P >0.05). Among the 6 patients who underwent HSCT, 2 patients who achieved CR1 survived and 4 died. Univariate analysis showed that minimal residual disease (MRD) ≥10-4 after induction therapy for D46 and IKZF1 positive had a poor prognosis (all P <0.05). MRD≥10-4 at the end of induction therapy is an independent risk factor for poor prognosis (hazard ratio of event-free, 9.101 [95% CI 2.03-40.86], P =0·004, compared to those with a MRD of <10-4). Conclusion: Pediatric ALL patients with PDGFRB fusions have a poor outcome. This subtype of ALL is associated with high-risk clinical features such as older age, high WBC count at diagnosis, high MRD after induction therapy, and increased risk of leukemia relapse. The addition of TKI to chemotherapy can improve the early remission rate of treatment, but does not improve the long-term survival. Profitably, the TKI treatment can provide an opportunity for subsequent treatment, including HSCT. Additionally, HSCT has indeed potential to reduce the relapse rate for this subtype patients. HSCT is recommended for this subtype patients who achieve CR1. The MRD≥10-4 or more at the end of induction therapy was independently predictive factor for unfavorable outcome and stratified treatment based on MRD may improve survival of these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk factors for progression of appendiceal neuroendocrine tumours: low-stage tumours

Appendiceal well-differentiated neuroendocrine tumours (NETs) are usually incidental and clinically benign. Several studies have reported different risk factors for nodal metastasis. The aim of this study was to investigate our appendiceal NETs (App-NETs) to determine the factors associated with malignant behaviour. For 120 App-NETs, we reviewed the clinical presentation and follow-up, including serum chromogranin A (CgA) levels, and compiled several microscopic variables. Pathological factors were compared with nodal status and time to biochemical recurrence (elevated serum CgA level) by the use of Cox regression. We also reviewed similar App-NET data in the Surveillance, Epidemiology, and End Results (SEER) Programme. Among our 120 cases, seven patients had positive lymph nodes, and nine developed subsequent elevation of CgA levels; none developed distant metastases or died of disease. Only three patients had grade 2 NETs; none had nodal disease, and one developed an elevated CgA level. Increasing tumour size was associated with an increased risk of nodal disease [odds ratio (OR) 4.99, P=0.0055). All seven node-positive cases were ≥13mm. Factors associated with elevated CgA levels included age (OR 1.04, P=0.041), pT4 disease (OR 10.22, P=0.033), and nodal disease (OR 24.0, P=0.012), but not size (OR 2.13, P=0.072). Of the 1492 reported App-NETs in the SEER database with data on tumour size, 137 (9%) were pN1; only five of these (4%) were coded as being <5mm. Small (<5mm) App-NETs that do not invade the serosa or mesoappendix appear to be overwhelmingly benign and low-grade, requiring neither Ki67 staining nor synoptic reporting. Given their indolent behaviour, different nomenclature or staging may be more appropriate for these NETs.

Impact of polyvascular disease and renal dysfunction on cardiovascular outcomes in diabetes: post hoc analyses from EMPA-REG OUTCOME

Abstract Background Individuals with polyvascular disease and impaired renal function are at high risk of cardiovascular (CV) events, but this relationship is not well investigated in people with type 2 diabetes (T2D). Furthermore, the impact of polyvascular disease plus renal dysfunction on the risk for hospitalisation for heart failure (HHF) remains unclear. Purpose We investigated this in a post hoc analysis of the EMPA-REG OUTCOME trial in which empagliflozin reduced risk of CV death and HHF versus placebo in people with T2D and vascular disease. In addition, we explored the treatment effect of empagliflozin on CV, HF and mortality outcomes across the spectrum of baseline polyvascular disease and impaired renal function. Methods Patients with T2D, CV disease and estimated glomerular filtration rate (eGFR) of ≥30 ml/min/1.73 m2 received empagliflozin 10 mg, 25 mg, or placebo. Vascular beds (VBs) were defined as coronary artery disease, peripheral artery disease, and cerebrovascular disease (Fig). By use of Cox regression, we explored the association between baseline eGFR &amp;lt; or ≥60 ml/min/1.73 m2, with or without polyvascular disease (1 vs ≥2 VBs involved), and CV death, HHF, CV death (excl. fatal stroke)/HHF, and all-cause mortality (ACM), as well as the treatment effect of empagliflozin versus placebo on these outcomes. Results Patients with ≥2 VBs involved and eGFR &amp;lt;60 ml/min/1.73 m2 [n=463], were slightly older (mean age 68.2 vs. 64.3 or 62.6 years), had T2D duration &amp;gt;10 years more often (73.4% vs. 63.2% or 54.9%), and a higher HF prevalence at baseline (19.4% vs. 11.1% or 9.2%) versus those with ≥2 VBs involved and eGFR ≥60 ml/min/1.73 m2 [n=866], or those with only 1 VB involved regardless of eGFR [n=5630], respectively. However, characteristics were generally balanced between treatment groups. Notably, co-existing polyvascular disease and eGFR &amp;lt;60 ml/min/1.73 m2 was strongly associated with increased risk of all outcomes. The placebo incidence rates per 1000 patient-years for CV death were 14.4 (95% CI 10.9, 18.3) and 19.6 (12.8, 27.8) in those with 1 VB involved and eGFR ≥60 or eGFR &amp;lt;60, respectively, and 32.7 (21.7, 45.8), and 52.4 (32.9, 76.5) in those with 2 VBs and eGFR ≥60 or eGFR &amp;lt;60 ml/min/1.73 m2, respectively. Importantly, empagliflozin reduced the risk for all outcomes regardless of number of VBs affected and kidney function (Fig). Conclusions Co-existing polyvascular disease and eGFR &amp;lt;60 ml/min/1.73 m2 confer an extremely high risk of CV and all-cause mortality, and HHF. Empagliflozin lowered this risk consistently compared with placebo, regardless of polyvascular disease and impaired kidney function. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance

Prevalence and incidence of intra-ventricular conduction delays and outcomes in patients with heart failure and reduced ejection fraction: insights from PARADIGM-HF and ATMOSPHERE.

The importance of intra-ventricular conduction delay (IVCD), the incidence of new IVCD and its relationship to outcomes in heart failure and reduced ejection fraction (HFrEF) are not well studied. We addressed these questions in the PARADIGM-HF and ATMOSPHERE trials. The risk of the primary composite outcome of cardiovascular death or heart failure hospitalization and all-cause mortality were estimated by use of Cox regression according to baseline QRS duration and morphology in 11 861 patients without an intracardiac device. At baseline, 1789 (15.1%) patients had left bundle branch block (LBBB), 524 (4.4%) right bundle branch block (RBBB), 454 (3.8%) non-specific IVCD, 2588 (21.8%) 'mildly abnormal' QRS (110-129 ms) and 6506 (54.9%) QRS <110 ms. During a median follow-up of 2.5 years, the risk of the primary composite endpoint was higher among those with a wide QRS, irrespective of morphology: hazard ratios (95% confidence interval) LBBB 1.36 (1.23-1.50), RBBB 1.54 (1.31-1.79), non-specific IVCD 1.65 (1.40-1.94) and QRS 110-129 ms 1.35 (1.23-1.47), compared with QRS duration <110 ms. A total of 1234 (15.6%) patients developed new-onset QRS widening ≥130 ms (6.1 per 100 patient-years). Incident LBBB occurred in 495 (6.3%) patients (2.4 per 100 patient-years) and was associated with a higher risk of the primary composite outcome [hazard ratio 1.42 (1.12-1.82)]. In patients with HFrEF, a wide QRS was associated with worse clinical outcomes irrespective of morphology. The annual incidence of new-onset LBBB was around 2.5%, and associated with a higher risk of adverse outcomes, highlighting the importance of repeat electrocardiogram review. ClinicalTrials.gov Identifier NCT0083658 (ATMOSPHERE) and NCT01035255 (PARADIGM-HF).

Prediction of dementia risk in low-income and middle-income countries (the 10/66 Study): an independent external validation of existing models

SummaryBackgroundTo date, dementia prediction models have been exclusively developed and tested in high-income countries (HICs). However, most people with dementia live in low-income and middle-income countries (LMICs), where dementia risk prediction research is almost non-existent and the ability of current models to predict dementia is unknown. This study investigated whether dementia prediction models developed in HICs are applicable to LMICs.MethodsData were from the 10/66 Study. Individuals aged 65 years or older and without dementia at baseline were selected from China, Cuba, the Dominican Republic, Mexico, Peru, Puerto Rico, and Venezuela. Dementia incidence was assessed over 3–5 years, with diagnosis according to the 10/66 Study diagnostic algorithm. Discrimination and calibration were tested for five models: the Cardiovascular Risk Factors, Aging and Dementia risk score (CAIDE); the Study on Aging, Cognition and Dementia (AgeCoDe) model; the Australian National University Alzheimer's Disease Risk Index (ANU-ADRI); the Brief Dementia Screening Indicator (BDSI); and the Rotterdam Study Basic Dementia Risk Model (BDRM). Models were tested with use of Cox regression. The discriminative accuracy of each model was assessed using Harrell's concordance (c)-statistic, with a value of 0·70 or higher considered to indicate acceptable discriminative ability. Calibration (model fit) was assessed statistically using the Grønnesby and Borgan test.Findings11 143 individuals without baseline dementia and with available follow-up data were included in the analysis. During follow-up (mean 3·8 years [SD 1·3]), 1069 people progressed to dementia across all sites (incidence rate 24·9 cases per 1000 person-years). Performance of the models varied. Across countries, the discriminative ability of the CAIDE (0·52≤c≤0·63) and AgeCoDe (0·57≤c≤0·74) models was poor. By contrast, the ANU-ADRI (0·66≤c≤0·78), BDSI (0·62≤c≤0·78), and BDRM (0·66≤c≤0·78) models showed similar levels of discriminative ability to those of the development cohorts. All models showed good calibration, especially at low and intermediate levels of predicted risk. The models validated best in Peru and poorest in the Dominican Republic and China.InterpretationNot all dementia prediction models developed in HICs can be simply extrapolated to LMICs. Further work defining what number and which combination of risk variables works best for predicting risk of dementia in LMICs is needed. However, models that transport well could be used immediately for dementia prevention research and targeted risk reduction in LMICs.FundingNational Institute for Health Research, Wellcome Trust, WHO, US Alzheimer's Association, and European Research Council.

The Effect of Surgeon Caseload on the Relative Revision Rate of Cemented and Cementless Unicompartmental Knee Replacements: An Analysis from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man.

Unicompartmental knee replacement (UKR) offers substantial benefits compared with total knee replacement (TKR) but is associated with higher revision rates. Data from registries suggest that revision rates for cementless UKR implants are lower than those for cemented implants. It is not known how much of this difference is due to the implant or to other factors, such as a greater proportion of high-volume surgeons using cementless implants. We aimed to determine the effect of surgeon caseload on the revision rate of matched cemented and cementless UKRs. From a group of 40,522 Oxford (Zimmer Biomet) UKR implants (30,814 cemented, 9,708 cementless) recorded in the National Joint Registry, 14,814 (7,407 cemented, 7,407 cementless) were propensity-score matched. Surgeons were categorized into 3 groups: low volume (<10 cases/year), medium volume (10 to <30 cases/year), and high volume (≥30 cases/year). The effect of caseload on the relative risk of revision was assessed with use of Cox regression. The 10-year survival rates for unmatched cementless and cemented UKR implants were 93.3% (95% confidence interval [CI] = 89.8% to 95.7%) and 89.1% (95% CI = 88.6% to 89.6%), respectively, with the difference being significant (hazard ratio [HR] = 0.59; p < 0.001). Cementless UKR implants had a greater proportion of high-volume surgeon users than cemented implants (30.4% compared with 15.1%). Following matching, the 10-year survival rates were 93.2% (95% CI = 89.7% to 95.6%) and 90.2% (95% CI = 87.5% to 92.3%), which were still significantly different (HR = 0.76; p = 0.002). The 10-year survival rates for matched cementless and cemented UKR implants were 86.8% (95% CI = 73.6% to 93.7%) and 81.8% (95% CI = 73.0% to 88.0%) for low-volume surgeons, 94.3% (95% CI = 92.2% to 95.9%) and 92.5% (95% CI = 89.9% to 94.5%) for medium-volume surgeons, and 97.5% (95% CI = 96.5% to 98.2%) and 94.2% (95% CI = 90.8% to 96.4%) for high-volume surgeons. The revision rate for cementless implants was lower for surgeons in all 3 caseload groups (HR = 0.74, 0.79, 0.80, respectively). Cementless fixation decreased the revision rate by about a quarter, whatever the surgeon caseload. Caseload had a profound effect on implant survival. Low-volume surgeons had a high revision rate with cemented or cementless fixation and therefore should consider either stopping or doing more UKR procedures. High-volume surgeons performing cementless UKR demonstrated a 10-year survival rate of 97.5%, which was similar to that reported in registries for the best-performing TKRs. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Dietary Patterns May Be Nonproportional Hazards for the Incidence of Type 2 Diabetes: Evidence from Korean Adult Females.

This study aimed to examine the association between the incidence of type 2 diabetes and various risk factors including dietary patterns based on the rigorous proportional hazards assumption tests. Data for 3335 female subjects aged 40–69 years from the Korea Genome and Epidemiology Study were used. The assumption of proportional hazards was tested using the scaled Schoenfeld test. The stratified Cox regression was used to adjust the nonproportionality of diabetic risk factors, and the regression was adjusted for potential confounding variables, such as age, marital status, physical activity, drinking, smoking, BMI, etc. Metabolic syndrome and meat and fish pattern variables were positively associated with diabetes. However, dietary patterns and metabolic syndrome variables violated the proportional hazards assumption; therefore, the stratified Cox regression with the interaction terms was applied to adjust the nonproportionality and to allow the possible different parameters over each stratum. The highest quartile of meat and fish pattern was associated with diabetes only in subjects aged over 60 years. Moreover, subjects who were obese and had metabolic syndrome had higher risk in bread and snacks (HR: 1.85; 95% CI: 1.00–3.40) and meat and fish pattern (HR: 1.82; 95% CI: 1.01–3.26), respectively. In conclusion, a quantitative proportional hazards assumption test should always be conducted before the use of Cox regression because nonproportionality of risk factors could induce limited effect on diabetes incidence.

Postcoronary Artery Bypass Graft Atrial Fibrillation Event Count and Survival: Differences by Sex

New-onset atrial fibrillation (AF) after coronary artery bypass graft surgery (CABG) is associated with poor outcomes, but data on the effects of its characteristics are lacking and conflicting. We examined the effect number of post-CABG AF events has on long-term mortality risk, and whether this is sex dependent. Routinely collected Society of Thoracic Surgeons (STS) data were supplemented with details on new-onset post-CABG AF (detected in-hospital by continuous electrocardiogram/telemetry monitoring) and long-term survival for 9203 consecutive patients with isolated-CABG (2002-2010). With the use of Cox regression, we determined the propensity-adjusted (STS-recognized risk factors) effect of number of AF events on survival, testing for effect modification by sex and controlling for AF duration. AF occurred in 739 women (29.4%) and 2157 men (32.3%) (P < .001). Adjusted results showed 2 or more AF events significantly (P < .001) increased 5-year mortality risk, independently of total AF duration. However, mortality risk differed between the sexes (P<.001): women with 2 AF episodes had the greatest increase (hazard ratio [HR]= 2.98; 95% confidence interval [CI], 1.43-4.83; versus women without AF), followed by women and men with 4 or more AF events (HR= 2.76 [95% CI, 1.27-4.55] and HR= 2.73 [95% CI,2.30-3.19], respectively). A single post-CABG AF episode was not associated with increased mortality risk. Both men and women who experienced 2 or more post-CABG AF episodes showed increased risk of 5-year mortality, independent of total AF duration. Although men's risk increased as the number of AF events increased, women's risk peaked at 2 AF events. Future research needs to determine whether this divergence stems from differences in treatment/management or underlying biology.

Right Ventricular Outflow Tract Doppler Notching Predicts Survival in Patients with Pulmonary Hypertension and Heart Failure with Preserved Ejection Fraction

Background Pulmonary hypertension (PH) in the setting of left heart disease (PH-LHD) is the most common cause of PH in the general population, with a prevalence of up to 80% and is associated with high morbidity and mortality. We have previously demonstrated the utility of right ventricular outflow tract (RVOT) Doppler notching as a composite marker of pulmonary vascular disease (PVD) in patients with PH-associated with heart failure with preserved ejection fraction (HFpEF). Our study examines the ability of RVOT Doppler notching to predict survival in patients with PH-HFpEF. Methods We retrospectively evaluated consecutive patients referred to the Penn PH program between January 2007 and March 2013 diagnosed with PH-HFpEF. Patients were included who had right heart catheterization with mean pulmonary artery pressure ≥ 25mmHg and pulmonary artery wedge pressure > 15 mmHg. All patients underwent echocardiographic and hemodynamic assessment as indicated clinically. Statistical analysis included student's t-test and chi-squared to assess continuous and categorical variables, respectively, along with use of Cox regression and the Kaplan-Meier estimator to evaluate survival. Results Of 86 patients, 53 had notching and 33 did not. Baseline characteristics were similar across both groups. Patients with notching had higher diastolic pulmonary gradient (8.2±6.4 vs 1.4±4.3, p Conclusions In PH-HFpEF, RVOT Doppler notching is a composite marker of PVD and is a strong predictor of long-term survival. Further work is needed to validate this marker in larger cohorts.

On the use of Cox regression to examine the temporal clustering of flooding and heavy precipitation across the central United States

The central United States is plagued by frequent catastrophic flooding, such as the flood events of 1993, 2008, 2011, 2013, 2014 and 2016. The goal of this study is to examine whether it is possible to describe the occurrence of flood and heavy precipitation events at the sub-seasonal scale in terms of variations in the climate system. Daily streamflow and precipitation time series over the central United States (defined here to include North Dakota, South Dakota, Nebraska, Kansas, Missouri, Iowa, Minnesota, Wisconsin, Illinois, West Virginia, Kentucky, Ohio, Indiana, and Michigan) are used in this study. We model the occurrence/non-occurrence of a flood and heavy precipitation event over time using regression models based on Cox processes, which can be viewed as a generalization of Poisson processes. Rather than assuming that an event (i.e., flooding or precipitation) occurs independently of the occurrence of the previous one (as in Poisson processes), Cox processes allow us to account for the potential presence of temporal clustering, which manifests itself in an alternation of quiet and active periods. Here we model the occurrence/non-occurrence of flood and heavy precipitation events using two climate indices as time-varying covariates: the Arctic Oscillation (AO) and the Pacific-North American pattern (PNA). We find that AO and/or PNA are important predictors in explaining the temporal clustering in flood occurrences in over 78% of the stream gages we considered. Similar results are obtained when working with heavy precipitation events. Analyses of the sensitivity of the results to different thresholds used to identify events lead to the same conclusions. The findings of this work highlight that variations in the climate system play a critical role in explaining the occurrence of flood and heavy precipitation events at the sub-seasonal scale over the central United States.

Vitamin B-6 catabolism and long-term mortality risk in patients with coronary artery disease

Low vitamin B-6 status has been related to increased risk of coronary artery disease (CAD), which is a condition that is associated with inflammation. The most common status marker, plasma pyridoxal 5'-phosphate (PLP), decreases during inflammation; therefore, causal relations are uncertain. We evaluated the vitamin B-6 biomarkers PLP, pyridoxal, and pyridoxic acid (PA) and the pyridoxic acid:(pyridoxal + PLP) ratio (PAr), a proposed marker of vitamin B-6 catabolism during activated cellular immunity, as predictors of mortality. Associations with risks of long-term all-cause mortality and cardiovascular mortality were evaluated with the use of Cox regression in patients who were undergoing elective coronary angiography for suspected stable angina pectoris (SAP) (n = 4131) and an independent cohort of patients who were hospitalized for acute myocardial infarction (AMI) (n = 3665). Plasma PLP (AMI patients only) and PA predicted all-cause mortality in models that were adjusted for established risk predictors, but associations were attenuated or nonsignificant after additional adjustment for inflammatory markers. PAr was correlated with biomarkers of inflammation (Pearson's r ≥ 0.37) and predicted all-cause mortality and cardiovascular mortality after adjustment for established risk predictors. In SAP patients, PAr had greater predictive strength than did current smoking, diabetes, hypertension, apolipoproteins, or C-reactive protein. PAr provided multiadjusted HRs per SD of 1.45 (95% CI: 1.30, 1.63) and 1.31 (95% CI: 1.21, 1.41) in SAP and AMI patients, respectively. In both cohorts, PAr was a particularly strong predictor of all-cause mortality for patients with no previous CAD history (P-interaction ≤ 0.04). PAr may capture unique aspects of inflammatory activation and thus provide new insights into disease mechanisms that may aid in identifying patients at increased risk of future fatal events.

Using cumulative sums of martingale residuals for model checking in nested case-control studies.

Standard use of Cox regression requires collection of covariate information for all individuals in a cohort even when only a small fraction of them experiences the event of interest (fail). This may be very expensive for large cohorts. Further in biomarker studies, it will imply a waste of valuable biological material that one may want to save for future studies. A nested case-control study offers a useful alternative. For this design, covariate information is only needed for the failing individuals (cases) and a sample of controls selected from the cases' at-risk sets. Methods based on martingale residuals are useful for checking the fit of Cox's regression model for cohort data. But similar methods have so far not been developed for nested case-control data. In this article, it is described how one may define martingale residuals for nested case-control data, and it is shown how plots and tests based on cumulative sums of martingale residuals may be used to check model fit. The plots and tests may be obtained using available software.

Prenatal smoking and age at menarche: influence of the prenatal environment on the timing of puberty.

Do prenatal exposure to cigarette smoking and birthweight influence age at menarche (AAM) in a cohort of Australian girls? We find that prenatal smoke exposure and lower birthweight increase the chance of earlier menarche in accordance with theoretical predictions as do confounding factors of maternal AAM and higher BMI of the girls. Much prior research focuses on the role of the early childhood environment in determining AAM but fewer studies consider the role of the prenatal environment. Those studies that examine the prenatal period find an acceleration of maturation associated with maternal smoking and low birthweight. Life history theory predicts that early life exposure to stressful environments should promote more rapid maturation and that this timing can be established before birth, making the prenatal environment particularly important. Statistical analysis of longitudinal survey data collected from a large cohort (n = 2446) of Australian children using data from birth to 12-13 years of age. Owing to missing data, 1493 girls were included in the final analysis. Using cox regression, we examine how (i) maternal cigarette smoking during gestation and (ii) birthweight influence girls' AAM. Cox regression was used because not all girls had reached menarche. We find that older maternal AAM (hazards ratio (HR): 0.75, confidence interval (CI) (95%): 0.71-0.79) and higher birthweight (HR: 0.86, CI (95%): 0.75-0.97) lower the chance of earlier menarche; while higher girls' BMI at 8-9 years (HR: 1.12, CI (95%): 1.10-1.15), and maternal cigarette smoking on 'most days' during gestation (HR: 1.40, CI (95%): 1.10-1.79 with 'no smoking' as the reference level) increased the chance of earlier menarche. All factors were statistically significant at P = 0.05. Not all girls had reached menarche, necessitating the use of cox regression. As with other longitudinal studies, there was study sample attrition and some missing data, particularly in reports of maternal smoking. In addition, as the degree of bias in the missing data is unknown, possible inaccurate reporting of maternal smoking may influence the results of birthweight on AAM. Because of the association between younger AAM and higher risk of uterine, endometrial and breast cancer development, our finding adds to the need to consider the stress caused by prenatal smoke exposure as an important health risk. In addition, this study needs to be extended, when the same girls are 14-15 years of age, and on a larger dataset from a younger cohort within the same Australian Government project. No funding was received for this study and there are no competing interests to declare.

Dietary Intake of Saturated Fat Is Not Associated with Risk of Coronary Events or Mortality in Patients with Established Coronary Artery Disease1–3

AbstractBackground: Data from recent meta-analyses question an association between dietary intake of saturated fatty acids (SFAs) and risk of cardiovascular disease (CVD). Moreover, the prognostic effect of dietary SFA in patients with established CVD treated with modern conventional medication has not been extensively studied.Objective: We investigated the associations between self-reported dietary SFA intake and risk of subsequent coronary events and mortality in patients with coronary artery disease (CAD).Methods: This study included patients who participated in the Western Norway B-Vitamin Intervention Trial and completed a 169-item semiquantitative food-frequency questionnaire after coronary angiography. Quartiles of estimated daily intakes of SFA were related to risk of a primary composite endpoint of coronary events (unstable angina pectoris, nonfatal acute myocardial infarction, and coronary death) and separate secondary endpoints (total acute myocardial infarction, fatal coronary events, and all-cause death) with use of Cox-regression analyses.Results: This study included 2412 patients (81% men, mean age: 61.7 y). After a median follow-up of 4.8 y, a total of 292 (12%) patients experienced at least one major coronary event during follow-up. High intake of SFAs was associated with a number of risk factors at baseline. However, there were no significant associations between SFA intake and risk of coronary events [age- and sex-adjusted HR (95% CI) was 0.85 (0.61, 1.18) for the upper vs. lower SFA quartile] or any secondary endpoint. Estimates were not appreciably changed after multivariate adjustments.Conclusions: There was no association between dietary intake of SFAs and incident coronary events or mortality in patients with established CAD.

A non-parametric approach for detecting gene-gene interactions associated with age-at-onset outcomes.

BackgroundCox-regression-based methods have been commonly used for the analyses of survival outcomes, such as age-at-disease-onset. These methods generally assume the hazard functions are proportional among various risk groups. However, such an assumption may not be valid in genetic association studies, especially when complex interactions are involved. In addition, genetic association studies commonly adopt case-control designs. Direct use of Cox regression to case-control data may yield biased estimators and incorrect statistical inference.ResultsWe propose a non-parametric approach, the weighted Nelson-Aalen (WNA) approach, for detecting genetic variants that are associated with age-dependent outcomes. The proposed approach can be directly applied to prospective cohort studies, and can be easily extended for population-based case-control studies. Moreover, it does not rely on any assumptions of the disease inheritance models, and is able to capture high-order gene-gene interactions. Through simulations, we show the proposed approach outperforms Cox-regression-based methods in various scenarios. We also conduct an empirical study of progression of nicotine dependence by applying the WNA approach to three independent datasets from the Study of Addiction: Genetics and Environment. In the initial dataset, two SNPs, rs6570989 and rs2930357, located in genes GRIK2 and CSMD1, are found to be significantly associated with the progression of nicotine dependence (ND). The joint association is further replicated in two independent datasets. Further analysis suggests that these two genes may interact and be associated with the progression of ND.ConclusionsAs demonstrated by the simulation studies and real data analysis, the proposed approach provides an efficient tool for detecting genetic interactions associated with age-at-onset outcomes.

Adenoma Detection Rate and Risk of Colorectal Cancer and Death

BackgroundThe proportion of screening colonoscopic examinations performed by a physician that detect one or more adenomas (the adenoma detection rate) is a recommended quality measure. However, little is known about the association between this rate and patients' risks of a subsequent colorectal cancer (interval cancer) and death.MethodsUsing data from an integrated health care delivery organization, we evaluated the associations between the adenoma detection rate and the risks of colorectal cancer diagnosed 6 months to 10 years after colonoscopy and of cancer-related death. With the use of Cox regression, our estimates of attributable risk were adjusted for the demographic characteristics of the patients, indications for colonoscopy, and coexisting conditions.ResultsWe evaluated 314,872 colonoscopies performed by 136 gastroenterologists; the adenoma detection rates ranged from 7.4 to 52.5%. During the follow-up period, we identified 712 interval colorectal adenocarcinomas, including 255 advanced-stage cancers, and 147 deaths from interval colorectal cancer. The unadjusted risks of interval cancer according to quintiles of adenoma detection rates, from lowest to highest, were 9.8, 8.6, 8.0, 7.0, and 4.8 cases per 10,000 person-years of follow-up, respectively. Among patients of physicians with adenoma detection rates in the highest quintile, as compared with patients of physicians with detection rates in the lowest quintile, the adjusted hazard ratio for any interval cancer was 0.52 (95% confidence interval [CI], 0.39 to 0.69), for advanced-stage interval cancer, 0.43 (95% CI, 0.29 to 0.64), and for fatal interval cancer, 0.38 (95% CI, 0.22 to 0.65). Each 1.0% increase in the adenoma detection rate was associated with a 3.0% decrease in the risk of cancer (hazard ratio, 0.97; 95% CI, 0.96 to 0.98).ConclusionsThe adenoma detection rate was inversely associated with the risks of interval colorectal cancer, advanced-stage interval cancer, and fatal interval cancer. (Funded by the Kaiser Permanente Community Benefit program and the National Cancer Institute.)

Outcomes and Toxicity for Hypofractionated and Single-Fraction Image-Guided Stereotactic Radiosurgery for Sarcomas Metastasizing to the Spine

Conventional radiation treatment (20-40 Gy in 5-20 fractions, 2-5 Gy per fraction) for sarcoma metastatic to the spine provides subtherapeutic doses, resulting in poor durable local control (LC) (50%-77% at 1 year). Hypofractionated (HF) and/or single-fraction (SF) image-guided stereotactic radiosurgery (IG-SRS) may provide a more effective means of managing these lesions. Patients with pathologically proven high-grade sarcoma metastatic to the spine treated with HF and SF IG-SRS were included. LC and overall survival (OS) were analyzed by the use of Kaplan-Meier statistics. Univariate and multivariate analyses were performed by the use of Cox regression with competing-risks analysis; all confidence intervals are 95%. Toxicities were assessed according to Common Terminology Criteria for Adverse Events, version 4.0. From May 2005 to November 11, 2012, 88 patients with 120 discrete metastases received HF (3-6 fractions; median dose, 28.5 Gy; n=52, 43.3%) or SF IG-SRS (median dose, 24 Gy; n=68, 56.7%). The median follow-up time was 12.3 months. At 12 months, LC was 87.9% (confidence interval [CI], 81.3%-94.5%), OS was 60.6% (CI, 49.6%-71.6%), and median survival was 16.9 months. SF IG-SRS demonstrated superior LC to HF IG-SRS (12-month LC of 90.8% [CI, 83%-98.6%] vs 84.1% [CI, 72.9%-95.3%] P=.007) and retained significance on multivariate analysis (P=.030, hazard ratio 0.345; CI, 0.132-0.901]. Treatment was well tolerated, with 1% acute grade 3 toxicity, 4.5% chronic grade 3 toxicity, and no grade >3 toxicities. In the largest series of metastatic sarcoma to the spine to date, IG-SRS provides excellent LC in the setting of an aggressive disease with low radiation sensitivity and poor prognosis. Single-fraction IG-SRS is associated with the highest rates of LC with minimal toxicity.