scholarly journals A class of two-sample nonparametric statistics for binary and time-to-event outcomes

2021 ◽  
pp. 096228022110480
Author(s):  
Marta Bofill Roig ◽  
Guadalupe Gómez Melis
Keyword(s):  
Proportional Hazards ◽  
Asymptotic Properties ◽  
Score Test ◽  
Vaccine Trial ◽  
R Package ◽  
Survival Outcome ◽  
Small Sample ◽  
Phase Iii ◽  
Survival Functions ◽  
The Difference

We propose a class of two-sample statistics for testing the equality of proportions and the equality of survival functions. We build our proposal on a weighted combination of a score test for the difference in proportions and a weighted Kaplan–Meier statistic-based test for the difference of survival functions. The proposed statistics are fully non-parametric and do not rely on the proportional hazards assumption for the survival outcome. We present the asymptotic distribution of these statistics, propose a variance estimator, and show their asymptotic properties under fixed and local alternatives. We discuss different choices of weights including those that control the relative relevance of each outcome and emphasize the type of difference to be detected in the survival outcome. We evaluate the performance of these statistics with small sample sizes through a simulation study and illustrate their use with a randomized phase III cancer vaccine trial. We have implemented the proposed statistics in the R package SurvBin, available on GitHub ( https://github.com/MartaBofillRoig/SurvBin ).

Activity of cetuximab (C) in head and neck squamous cell carcinoma (HNSCC) patients (pts) with PTEN loss or PIK3CA mutation treated on E5397, a phase III trial of cisplatin (CDDP) with placebo (P) or C.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6028-6028 ◽  
Author(s):  
Barbara Burtness ◽  
Ju-Whei Lee ◽  
Donghua Yang ◽  
Fang Zhu ◽  
Joaquin J. Garcia ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Pik3ca Mutation ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Small Sample ◽  
Pten Expression ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Pik3ca Mutations ◽  
Pten Loss

6028 Background: Abnormalities in EGFR signaling targets are associated with C resistance but no biomarker of C resistance has been identified in HNSCC. We hypothesized that cases with loss of PTEN protein expression (PTEN null) or PIK3CA mutation would display C resistance in HNSCC. Methods: E5397 was a phase III trial of CDDP plus P or CDDP plus C and enrolled 117 eligible and evaluable pts. PIK3CA and PTEN were analyzed for 52 and 67 consented pts, respectively. PTEN expression (PTEN Cell Signaling Technology, Cat. 9559) was determined by automated quantitative analysis (AQUA) on the PM-2000 (HistoRx, New Haven) using a cutpoint generated in 5 HNSCC tissue microarrays, each consisting of HNSCC as well as positive (small intestine, median AQUA score 2833.2) and negative controls (breast and colon carcinoma, median AQUA score 205.5). A cutpoint of 570 provides 100% specificity, 100% sensitivity, and identified 30% of the HNSCCs as PTEN null, consonant with the literature. The 3 most common PIK3CA mutations (E542K and E545K in exon 9 and H1047R in exon 20) were determined by BEAMing (Inostics, Heidelberg, Germany). Response, overall survival (OS) and progression-free survival (PFS) were compared between PTEN null or PIK3CA mutated pts and all others. Log rank and multivariable Cox proportional hazards modeling were used to calculate p values. Results: 23/67 (34%) tumors were PTEN null and 2/52 (4%) had PIK3CA mutations (E542K and E545K). Both tumors with PIK3CA mutation had PTEN expression. No statistically significant differences in response, OS or PFS were noted in this small sample. However, among PTEN expressing/PIK3CA WT pts, median PFS increased to 4.2 months (m) for C (N=22) from 2.9 m for P (N=26) (Wald p=0.07), compared with 4.6 m for C (N=12) and 3.5 m for P (n=13) among the PTEN null/PIK3CA mutated (Wald p=0.60). Conclusions: The PTEN loss or PIK3CA mutation signature warrants further investigation as a predictor of C resistance.

scholarly journals Estimating effect of environmental contaminants on women's subfecundity for the MoBa study data with an outcome-dependent sampling scheme

Biostatistics ◽  
2014 ◽  
Vol 15 (4) ◽  
pp. 636-650 ◽  
Author(s):  
Jieli Ding ◽  
Haibo Zhou ◽  
Yanyan Liu ◽  
Jianwen Cai ◽  
Matthew P. Longnecker
Keyword(s):  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Failure Time ◽  
Asymptotic Properties ◽  
Likelihood Estimation ◽  
Small Sample ◽  
Environmental Study ◽  
Time Data ◽  
Model Framework ◽  
Data Set

Abstract Motivated by the need from our on-going environmental study in the Norwegian Mother and Child Cohort (MoBa) study, we consider an outcome-dependent sampling (ODS) scheme for failure-time data with censoring. Like the case-cohort design, the ODS design enriches the observed sample by selectively including certain failure subjects. We present an estimated maximum semiparametric empirical likelihood estimation (EMSELE) under the proportional hazards model framework. The asymptotic properties of the proposed estimator were derived. Simulation studies were conducted to evaluate the small-sample performance of our proposed method. Our analyses show that the proposed estimator and design is more efficient than the current default approach and other competing approaches. Applying the proposed approach with the data set from the MoBa study, we found a significant effect of an environmental contaminant on fecundability.

scholarly journals Vaccine Efficacy at a Point in Time

2021 ◽  
Author(s):  
Dean Follmann ◽  
Michael Fay
Keyword(s):  
Vaccine Efficacy ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Vaccine Trial ◽  
Phase Iii ◽  
Cross Sectional ◽  
Transmission Potential ◽  
Viral Loads ◽  
Hazards Model ◽  
Vaccine Effect

AbstractVaccine trials are generally designed to assess efficacy on clinical disease. The vaccine effect on infection, while important both as a proxy for transmission and to describe a vaccine’s total effects, requires frequent longitudinal sampling to capture all infections. Such sampling may not always be feasible. A logistically easy approach is to collect a sample to test for infection at a regularly scheduled visit. Such point or cross-sectional sampling does not permit estimation of classic vaccine effiacy on infection, as long duration infections are sampled with higher probability. Building on work by Rinta-Kokko and others (2009) we evaluate proxies of the vaccine effect on transmission at a point in time; the vaccine efficacy on prevalent infection and on prevalent viral load, VEPI and VEPV L, respectively. Longer infections with higher viral loads should have more transmission potential and prevalent vaccine efficacy naturally captures this aspect. We apply a proportional hazards model for infection risk and show how these metrics can be estimated using longitudinal or cross-sectional sampling. We also introduce regression models for designs with multiple cross-sectional sampling. The methods are evaluated by simulation and a phase III vaccine trial with PCR cross-sectional sampling for subclinical infection is analyzed.

PETCO2 gradient: a novel prognostic parameter in cardiopulmonary exercise testing

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
I.D Poveda Pinedo ◽  
I Marco Clement ◽  
O Gonzalez ◽  
I Ponz ◽  
A.M Iniesta ◽  
...  
Keyword(s):  
Exercise Testing ◽  
Proportional Hazards ◽  
Cardiopulmonary Exercise Testing ◽  
Cox Proportional Hazards ◽  
Prognostic Parameter ◽  
Cardiopulmonary Exercise ◽  
Proportional Hazards Regression ◽  
Kaplan Meier ◽  
Baseline Characteristics ◽  
The Difference

Abstract Background Previous parameters such as peak VO2, VE/VCO2 slope and OUES have been described to be prognostic in heart failure (HF). The aim of this study was to identify further prognostic factors of cardiopulmonary exercise testing (CPET) in HF patients. Methods A retrospective analysis of HF patients who underwent CPET from January to November 2019 in a single centre was performed. PETCO2 gradient was defined by the difference between final PETCO2 and baseline PETCO2. HF events were defined as decompensated HF requiring hospital admission or IV diuretics, or decompensated HF resulting in death. Results A total of 64 HF patients were assessed by CPET, HF events occurred in 8 (12.5%) patients. Baseline characteristics are shown in table 1. Patients having HF events had a negative PETCO2 gradient while patients not having events showed a positive PETCO2 gradient (−1.5 [IQR −4.8, 2.3] vs 3 [IQR 1, 5] mmHg; p=0.004). A multivariate Cox proportional-hazards regression analysis revealed that PETCO2 gradient was an independent predictor of HF events (HR 0.74, 95% CI [0.61–0.89]; p=0.002). Kaplan-Meier curves showed a significantly higher incidence of HF events in patients having negative gradients, p=0.002 (figure 1). Conclusion PETCO2 gradient was demonstrated to be a prognostic parameter of CPET in HF patients in our study. Patients having negative gradients had worse outcomes by having more HF events. Time to first event, decompensated heart Funding Acknowledgement Type of funding source: None

Resiliency factors protecting against teenage alcohol use and smoking: influences of religion, religious involvement and values, and ethnicity in the Missouri Adolescent Female Twin Study

Twin Research ◽  
1999 ◽  
Vol 2 (2) ◽  
pp. 145-155 ◽  
Author(s):  
AC Heath ◽  
PAF Madden ◽  
JD Grant ◽  
TL McLaughlin ◽  
AA Todorov ◽  
...  
Keyword(s):  
African American ◽  
Alcohol Use ◽  
Proportional Hazards ◽  
Religious Affiliation ◽  
Religious Involvement ◽  
African American Adolescents ◽  
Religious Values ◽  
High Heritability ◽  
The Difference

AbstractThe objective of this study was to investigate the contribution of ethnicity (African American vs European/other ancestry), family religious affiliation, religious involvement, and religious values, to risk of alcohol and cigarette use in adolescent girls; and to estimate genetic and shared environmental effects on religious involvement and values. Telephone interviews were conducted with a sample of female like-sex twin pairs, aged 13–20 (n = 1687 pairs, including 220 minority pairs), as well as with one or both parents of twins aged 11–20 (n = 2111 families). These data, together with one-year follow-up twin questionnaire data, and two-year follow-up parent interview data, were used to compare ethnic differences. Proportional hazards regression models and genetic variance component models were fitted to the data. Despite higher levels of exposure to family, school and neighborhood environmental adversities, African American adolescents were less likely to become teenage drinkers or smokers. They showed greater religious involvement (frequency of attendance at religious services) and stronger religious values (eg belief in relying upon their religious beliefs to guide day-to-day living). Controlling for religious affiliation, involvement and values removed the ethnic difference in alcohol use, but had no effect on the difference in rates of smoking. Religious involvement and values exhibited high heritability in African Americans, but only modest heritability in EOAs. The strong protective effect of adolescent religious involvement and values, and its contribution to lower rates of African American alcohol use, was confirmed. We speculate about the possible association between high heritability of African American religious behavior and an accelerated maturation of religious values during adolescence.

scholarly journals Efficacy of BRAF and MEK Inhibition in Patients with BRAF-Mutant Advanced Melanoma and Germline CDKN2A Pathogenic Variants

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2440
Author(s):  
Francesco Spagnolo ◽  
Bruna Dalmasso ◽  
Enrica Tanda ◽  
Miriam Potrony ◽  
Susana Puig ◽  
...  
Keyword(s):  
Real World ◽  
Response Rate ◽  
Suppressor Gene ◽  
Phase Iii ◽  
Clinical Activity ◽  
P Value ◽  
Pathogenic Variants ◽  
Phase Iii Trials ◽  
The Difference ◽  
First Time

Inherited pathogenic variants (PVs) in the CDKN2A tumor suppressor gene are among the strongest risk factors for cutaneous melanoma. Dysregulation of the p16/RB1 pathway may intrinsically limit the activity of MAPK-directed therapy due to the interplay between the two pathways. In our study, we assessed, for the first time, whether patients with germline CDKN2A PVs achieve suboptimal results with BRAF inhibitors (BRAFi)+/−MEK inhibitors (MEKi). We compared the response rate of nineteen CDKN2A PVs carriers who received first-line treatment with BRAFi+/−MEKi with an expected rate derived from phase III trials and “real-world” studies. We observed partial response in 16/19 patients (84%), and no complete responses. The overall response rate was higher than that expected from phase III trials (66%), although not statistically significant (p-value = 0.143; 95% CI = 0.60–0.97); the difference was statistically significant (p-value = 0.019; 95% CI = 0.62–0.97) in the comparison with real-world studies (57%). The clinical activity of BRAFi+/−MEKi in patients with germline CDKN2A PV was not inferior to that of clinical trials and real-world studies, which is of primary importance for clinical management and genetic counseling of this subgroup of patients.

Fibroblast growth factor receptor alteration (FGFRa) status and progression outcomes of patients with advanced or metastatic urothelial cancer (mUC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4530-4530
Author(s):  
Sarah Fleming ◽  
Dina Gifkins ◽  
Waleed Shalaby ◽  
Jianjun Gao ◽  
Philip Rosenberg ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
The United States ◽  
Cox Proportional Hazards ◽  
Small Sample ◽  
Prognostic Impact ◽  
Patient Records ◽  
Front Line ◽  
Convenience Sample ◽  
Adjusted Risk ◽  
Metastatic Urothelial Cancer

4530 Background: FGFRa appear in approximately 15% of cases of mUC. Data on whether FGFRa in mUC have a prognostic impact or predictive benefit for particular treatments have been limited by small sample sizes. The objective of this study was to evaluate the association between tumor FGFRa and clinical outcomes of patients with advanced UC or mUC regardless of therapy type and status. Methods: A convenience sample of oncologists and urologists across the United States provided patient level data on 400 patients with stage IIIb or IV UC via a standardized questionnaire over a 1-month period (August 17, 2020 – September 20, 2020). Study design enriched for FGFRa by requiring physicians to provide ≥1 FGFRa patient record. The questionnaire included physician characteristics, patient demographic information, FGFR status, therapy given, response, and clinical and radiographic measures of progression. Patient records were eligible for inclusion if they were identified and treated during July 1, 2017, to June 30, 2019. Cox proportional hazards models were used to estimate adjusted risk of disease progression by FGFR status. Results: A total of 104 physicians (58.7% medical oncologists, 31.7% hematologic oncologists, and 9.6% urologic oncologists) contributed 414 patient records Overall, 73.9% of the patients were male and the average age was 64.5 years (SD ±10.6). Median follow-up was 15 months. Of the 414 patients, 218 (52.7%) had FGFRa and 196 (47.3%) had FGFR wild-type ( FGFRwt) mUC . Of the 218 patients with FGFRa, 47.2% were treated with front-line chemo, 27.5% with a programmed death-ligand 1 inhibitor (PD-L1), 11.5% with chemo + PD-L1, and 13.8% with other treatments. Of the 196 FGFRwt patients, 63.2% were treated with front-line chemo, 21.9% with PD-L1, 12.2% with chemo + PD-L1, and 2.6% with other treatments. There was no difference in response or progression status for those receiving front-line chemo (HR, 1.15; 95% CI, 0.86-1.55). Among 97 patients (55 FGFRa and 42 FGFRwt) who received PD-L1 alone as front-line therapy, those who had FGFRa had an adjusted risk of progression 2 times higher than their FGFRwt counterparts (HR, 2.12; 95% CI, 1.13-4.00). Conclusions: Patients with FGFRa mUC progressed earlier than FGFRwt patients treated with front-line PDL-1 inhibitors; however, there was no difference in progression in patients treated with chemo based upon FGFR status. This real-world study using a survey design efficiently generated a relatively large FGFRa dataset, mitigating a core limitation of other studies assessing the patient population with FGFRa. Further work is warranted to validate these results and determine the optimal strategy for treating the patient with FGFRa mUC. Gene expression profiling of FGFRa mUC samples from clinical trials will help determine the potential impact of subtype or other features that may associate with benefit from therapy.

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