Gamma frailty model for survival risk estimation: an application to cancer data

Abstract Objectives: In time to event analysis, the risk for an event is usually estimated using Cox proportional hazards (CPH) model. But CPH model has the limitation of biased estimate due to unobserved hidden heterogeneity among the covariates, which can be tackled using frailty models. The best models were usually being identified using Akaike information criteria (AIC). Apart from AIC, the present study aimed to assess predictability of risk models using survival concordance measure. Methods: CPH model and frailty models were used to estimate the risk for breast cancer patient survival, and the frailty variable was assumed to follow gamma distribution. Schoenfeld global test was used to check the proportionality assumption. Survival concordance, AIC and simulation studies were used to identify the significance of frailty. Results: From the univariate analysis it was observed that for the covariate age, the frailty has a significant role (θ = 2.758, p-value: 0.0004) and the corresponding hazard rate was 1.93 compared to that of 1.38 for CPH model (age > 50 vs. ≤ 40). Also the covariates radiotherapy and chemotherapy were found to be significant (θ = 5.944, p-value: <0.001 and θ = 16, p-value: <0.001 respectively). Even though there were only minor differences in hazard rates, the concordance was higher for frailty than CPH model for all the covariates. Further the simulation study showed that the bias and root mean square error (RMSE) obtained for both the methods was almost the same and the concordance measures were higher for frailty model by 12–15%. Conclusions: We conclude that the frailty model is better compared to CPH model as it can account for unobserved random heterogeneity, and if the frailty coefficient doesn’t have an effect it gives exactly the same risk as that of CPH model and this has been established using survival concordance.

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Regression standardization and attributable fraction estimation with between-within frailty models for clustered survival data

Statistical Methods in Medical Research ◽

10.1177/0962280217727558 ◽

2017 ◽

Vol 28 (2) ◽

pp. 462-485 ◽

Cited By ~ 6

Author(s):

Elisabeth Dahlqwist ◽

Yudi Pawitan ◽

Arvid Sjölander

Keyword(s):

Survival Time ◽

Survival Data ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Frailty Model ◽

Cox Proportional Hazards ◽

Attributable Fraction ◽

Cox Proportional Hazards Model ◽

Frailty Models ◽

Analysis Tool

The between-within frailty model has been proposed as a viable analysis tool for clustered survival time outcomes. Previous research has shown that this model gives consistent estimates of the exposure–outcome hazard ratio in the presence of unmeasured cluster-constant confounding, which the ordinary frailty model does not, and that estimates obtained from the between-within frailty model are often more efficient than estimates obtained from the stratified Cox proportional hazards model. In this paper, we derive novel estimation techniques for regression standardization with between-within frailty models. We also show how between-within frailty models can be used to estimate the attributable fraction function, which is a generalization of the attributable fraction for survival time outcomes. We illustrate the proposed methods by analyzing a large cohort on preterm birth and attention deficit hyperactivity disorder. To facilitate use of the proposed methods, we provide R code for all analyses.

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Anhedonia as a Potential Risk Factor of Alzheimer’s Disease in a Community-Dwelling Elderly Sample: Results from the ZARADEMP Project

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18041370 ◽

2021 ◽

Vol 18 (4) ◽

pp. 1370

Author(s):

David Vaquero-Puyuelo ◽

Concepción De-la-Cámara ◽

Beatriz Olaya ◽

Patricia Gracia-García ◽

Antonio Lobo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Potential Risk ◽

Proportional Hazards ◽

Univariate Analysis ◽

Population Sample ◽

Public Health Problem ◽

Cox Proportional Hazards ◽

Community Dwelling ◽

Major Public Health Problem

(1) Introduction: Dementia is a major public health problem, and Alzheimer’s disease (AD) is the most frequent subtype. Clarifying the potential risk factors is necessary in order to improve dementia-prevention strategies and quality of life. Here, our purpose was to investigate the role of the absence of hedonic tone; anhedonia, understood as the reduction on previous enjoyable daily activities, which occasionally is underdetected and underdiagnosed; and the risk of developing AD in a cognitively unimpaired and non-depressed population sample. (2) Method: We used data from the Zaragoza Dementia and Depression (ZARADEMP) project, a longitudinal epidemiological study on dementia and depression. After excluding subjects with dementia, a sample of 2830 dwellers aged ≥65 years was followed for 4.5 years. The geriatric mental state examination was used to identify cases of anhedonia. AD was diagnosed by a panel of research psychiatrists according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. A multivariate survival analysis and Cox proportional hazards regression model were performed, and the analysis was controlled by an analysis for the presence of clinically significant depression. (3) Results: We found a significant association between anhedonia cases and AD risk in the univariate analysis (hazard ratio (HR): 2.37; 95% CI: 1.04–5.40). This association persisted more strongly in the fully adjusted model. (4) Conclusions: Identifying cognitively intact individuals with anhedonia is a priority to implement preventive strategies that could delay the progression of cognitive and functional impairment in subjects at risk of AD.

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Antibiotic and acid-suppression medications during early childhood are associated with obesity

Gut ◽

10.1136/gutjnl-2017-314971 ◽

2018 ◽

Vol 68 (1) ◽

pp. 62-69 ◽

Cited By ~ 36

Author(s):

Christopher M Stark ◽

Apryl Susi ◽

Jill Emerick ◽

Cade M Nylund

Keyword(s):

Early Childhood ◽

Department Of Defense ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Event Analysis ◽

Early Exposure ◽

Single Event ◽

Inclusion Criteria ◽

Cox Proportional Hazards Regression ◽

Proportional Hazards Regression

ObjectiveGut microbiota alterations are associated with obesity. Early exposure to medications, including acid suppressants and antibiotics, can alter gut biota and may increase the likelihood of developing obesity. We investigated the association of antibiotic, histamine-2 receptor antagonist (H2RA) and proton pump inhibitor (PPI) prescriptions during early childhood with a diagnosis of obesity.DesignWe performed a cohort study of US Department of Defense TRICARE beneficiaries born from October 2006 to September 2013. Exposures were defined as having any dispensed prescription for antibiotic, H2RA or PPI medications in the first 2 years of life. A single event analysis of obesity was performed using Cox proportional hazards regression.Results333 353 children met inclusion criteria, with 241 502 (72.4%) children prescribed an antibiotic, 39 488 (11.8%) an H2RA and 11 089 (3.3%) a PPI. Antibiotic prescriptions were associated with obesity (HR 1.26; 95% CI 1.23 to 1.28). This association persisted regardless of antibiotic class and strengthened with each additional class of antibiotic prescribed. H2RA and PPI prescriptions were also associated with obesity, with a stronger association for each 30-day supply prescribed. The HR increased commensurately with exposure to each additional medication group prescribed.ConclusionsAntibiotics, acid suppressants and the combination of multiple medications in the first 2 years of life are associated with a diagnosis of childhood obesity. Microbiota-altering medications administered in early childhood may influence weight gain.

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Extraskeletal osteosarcoma: A large series treated at a single institution

Rare Tumors ◽

10.1177/2036361317749651 ◽

2018 ◽

Vol 10 ◽

pp. 203636131774965 ◽

Cited By ~ 3

Author(s):

Haotong Wang ◽

Ruoyu Miao ◽

Alex Jacobson ◽

David Harmon ◽

Edwin Choy ◽

...

Keyword(s):

Prognostic Factors ◽

Proportional Hazards ◽

Survival Curve ◽

Treatment Options ◽

Univariate Analysis ◽

Soft Tissue Sarcomas ◽

Cox Proportional Hazards ◽

Wide Resection ◽

Incomplete Resection ◽

Extraskeletal Osteosarcoma

Purpose: This study is to present a large cohort of extraskeletal osteosarcoma (ESOS) and evaluate prognostic factors and treatment options. Methods: Medical records were reviewed retrospectively for 41 patients with extraskeletal osteosarcoma that was diagnosed by pathology, and treated at our institution between 1960 and 2016. Kaplan-Meier analysis and Cox proportional hazards regression were used to identify variables that affect survival outcomes. Results: 41 patients were identified from 952 osteosarcomas. 32 patients had non-metastatic disease. Prognostic factors were identified by univariate analysis and multi-variate analysis. Surgery ( p<0.001), and surgery type ( p<0.001) both were shown to significantly affect overall survival (OS). Chemotherapy and radiation therapy (RT) did not show any significant effect on OS, local recurrence, or progression free survival as a whole. However for patients who had incomplete resection with residual tumor RT improved OS ( p=0.03). The survival curve for ESOS follows more closely that of non-rhabdomyosarcoma soft tissue sarcomas (NRSTS). Conclusions: ESOS is a very rare tumor. Attempt to achieve wide resection is the treatment of choice. However for patients who are not able to achieve complete resection, RT may improve OS. The behavior of ESOS more closely follows that of NRSTS than osteosarcoma of the bone.

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Prognostic Effect of Preoperative Psoas Muscle Hounsfield Unit at Radical Cystectomy for Bladder Cancer

Cancers ◽

10.3390/cancers13225629 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5629

Author(s):

Yusuke Sugino ◽

Takeshi Sasaki ◽

Manabu Kato ◽

Satoru Masui ◽

Kouhei Nishikawa ◽

...

Keyword(s):

Bladder Cancer ◽

Radical Cystectomy ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Univariate Analysis ◽

Psoas Muscle ◽

Hounsfield Unit ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Cross Sectional

Radical cystectomy (RC) is the standard treatment for patients with advanced bladder cancer. Since RC is a highly invasive procedure, the surgical indications in an aging society must be carefully judged. In recent years, the concept of “frailty” has been attracting attention as a term used to describe fragility due to aging. We focused on the psoas muscle Hounsfield unit (PMHU) and analyzed its appropriateness as a prognostic factor together with other clinical factors in patients after RC. We retrospectively analyzed the preoperative prognostic factors in 177 patients with bladder cancer who underwent RC between 2008 and 2020. Preoperative non-contrast computed tomography axial image at the third lumbar vertebral level was used to measure the mean Hounsfield unit (HU) and cross-sectional area (mm2) of the psoas muscle. Univariate analysis showed significant differences in age, sex, clinical T stage, and PMHU. In multivariate analysis using the Cox proportional hazards model, age (hazard ratio (HR) = 1.734), sex (HR = 2.116), cT stage (HR = 1.665), and PMHU (HR = 1.758) were significant predictors for overall survival. Furthermore, using these four predictors, it was possible to stratify the prognosis of patients after RC. Finally, PMHU was useful as a simple and significant preoperative factor that correlated with prognosis after RC.

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Lopinavir/Ritonavir and Darunavir/Cobicistat in Hospitalized COVID-19 Patients: Findings From the Multicenter Italian CORIST Study

Frontiers in Medicine ◽

10.3389/fmed.2021.639970 ◽

2021 ◽

Vol 8 ◽

Author(s):

Augusto Di Castelnuovo ◽

Simona Costanzo ◽

Andrea Antinori ◽

Nausicaa Berselli ◽

Lorenzo Blandi ◽

...

Keyword(s):

Observational Study ◽

Propensity Scores ◽

Proportional Hazards ◽

Real Life ◽

Cox Proportional Hazards ◽

Event Analysis ◽

Multicenter Observational Study ◽

Protein Levels ◽

Cox Proportional Hazards Models ◽

Increased Risk

Background: Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients.Objectives: To describe the association between lopinavir/ritonavir (LPV/r) or darunavir/cobicistat (DRV/c) use and in-hospital mortality in COVID-19 patients.Study Design: Multicenter observational study of COVID-19 patients admitted in 33 Italian hospitals. Medications, preexisting conditions, clinical measures, and outcomes were extracted from medical records. Patients were retrospectively divided in three groups, according to use of LPV/r, DRV/c or none of them. Primary outcome in a time-to event analysis was death. We used Cox proportional-hazards models with inverse probability of treatment weighting by multinomial propensity scores.Results: Out of 3,451 patients, 33.3% LPV/r and 13.9% received DRV/c. Patients receiving LPV/r or DRV/c were more likely younger, men, had higher C-reactive protein levels while less likely had hypertension, cardiovascular, pulmonary or kidney disease. After adjustment for propensity scores, LPV/r use was not associated with mortality (HR = 0.94, 95% CI 0.78 to 1.13), whereas treatment with DRV/c was associated with a higher death risk (HR = 1.89, 1.53 to 2.34, E-value = 2.43). This increased risk was more marked in women, in elderly, in patients with higher severity of COVID-19 and in patients receiving other COVID-19 drugs.Conclusions: In a large cohort of Italian patients hospitalized for COVID-19 in a real-life setting, the use of LPV/r treatment did not change death rate, while DRV/c was associated with increased mortality. Within the limits of an observational study, these data do not support the use of LPV/r or DRV/c in COVID-19 patients.

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Factors Influencing the Efficacy of Anti-PD-1 Therapy in Chinese Patients with Advanced Melanoma

Journal of Oncology ◽

10.1155/2019/6454989 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Lingdi Zhao ◽

Yonghao Yang ◽

Baozhen Ma ◽

Wei Li ◽

Tiepeng Li ◽

...

Keyword(s):

Proportional Hazards ◽

Univariate Analysis ◽

Objective Response ◽

Eastern Cooperative Oncology Group ◽

Cox Proportional Hazards ◽

Advanced Melanoma ◽

Chinese Patients ◽

Time To Progression ◽

Independent Predictive Factor ◽

Factors Influencing

Purpose. Anti-PD-1 antibody improves the survival of patients with advanced melanoma. However, the efficacy and safety of anti-programmed death protein 1 (PD-1) antibody have not been fully elucidated in Chinese melanoma patients, who show high frequency of mucosal and acral melanoma subtypes; besides, the factors influencing the efficacy of anti-PD-1 antibody have not been evaluated broadly. Patients and Methods. Patients with advanced melanoma treated with regimens containing anti-PD-1 antibody from June 2016 to January 2019 were evaluated. Baseline characteristics and blood parameters were assessed, and outcome and adverse events were evaluated according to different regimens. The Cox proportional hazards regression model was used for univariate and multivariate analyses. Results. A total of 51 patients with advanced melanoma were included in this study. The overall objective response rate (ORR) was 17.6%, the disease control rate was 58.5%, and the median time to progression was 5.2 months. The ORR of patients with PD-1 blockade-based combination therapy, without liver metastases and higher level of C-reactive protein (CRP) before PD-1 blockade, is higher than that of those not. Univariate analysis based on clinical features showed that ECOG scores, liver metastasis, elevated lactate dehydrogenase (LDH), and CRP levels were the factors affecting time to progression (TTP). Multivariate analysis showed that elevated CRP before PD-1 blockade was an independent predictive factor for ORR of PD-1 blockade therapy (P=0.009), while only Eastern Cooperative Oncology Group (ECOG) score was an independent predictor for TTP (P=0.032). The treatment was well tolerated in these cohort patients, and there was no treatment-related death. Conclusion. Anti-PD-1 antibody-containing regimen was safe and effective in Chinese patients with advanced melanoma, and elevated CRP and ECOG score were independent factors predicting the efficacy of anti-PD-1 therapy.

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The Effect of Diagnostic Ureterorenoscopy on Intravesical Recurrence in Patients Undergoing Nephroureterectomy for Primary Upper Tract Urinary Carcinoma

Urologia Internationalis ◽

10.1159/000511650 ◽

2020 ◽

pp. 1-7

Author(s):

Volkan İzol ◽

Mutlu Deger ◽

Ender Ozden ◽

Deniz Bolat ◽

Burak Argun ◽

...

Keyword(s):

Proportional Hazards ◽

Proportional Hazards Model ◽

Univariate Analysis ◽

Upper Urinary Tract ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Recurrence Time ◽

Tumor Biopsy ◽

Group 2 ◽

Group 1

Objective: The objective of this study is to evaluate the effect of diagnostic ureterorenoscopy (URS) prior to radical nephroureterectomy (RNU) on intravesical recurrence (IVR), in patients with primary upper urinary tract urothelial carcinoma (UTUC). Materials and Methods: Retrospective analysis of 354 patients, who underwent RNU for UTUC from 10 urology centers between 2005 and 2019, was performed. The primary endpoint was the occurrence of IVR after RNU. Patients were divided into URS prior to RNU (Group 1) and no URS prior to RNU (Group 2). Rates of IVR after RNU were compared, and a Cox proportional hazards model was used to evaluate potential predictors of IVR. Results: After exclusion, a total of 194 patients were analyzed: Group 1 n = 95 (49.0%) and Group 2 n = 99 (51.0%). In Group 1, a tumor biopsy and histopathological confirmation during URS were performed in 58 (61.1%). The mean follow-up was 39.17 ± 39.3 (range 12–250) months. In 54 (27.8%) patients, IVR was recorded after RNU, and the median recurrence time within the bladder was 10.0 (3–144) months. IVR rate was 38.9% in Group 1 versus 17.2% in Group 2 (p = 0.001). In Group 1, IVR rate was 43.1% in those undergoing intraoperative biopsy versus 32.4% of patients without biopsy during diagnostic URS (p =0.29). Intravesical recurrence-free survival (IRFS) was longer in Group 2 compared to Group 1 (median IRFS was 111 vs. 60 months in Groups 2 and 1, respectively (p< 0.001)). Univariate analysis revealed that IRFS was significantly associated with URS prior to RNU (HR: 2.9, 95% CI 1.65–5.41; p < 0.001). In multivariate analysis, URS prior to RNU (HR: 3.5, 95% CI 1.74–7.16; p < 0.001) was found to be an independent prognostic factor for IRFS. Conclusion: Diagnostic URS was associated with the poor IRFS following RNU for primary UTUC. The decision for a diagnostic URS with or without tumor biopsy should be reserved for cases where this information might influence further treatment decisions.

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Risk Factors for Adverse Events in Household Contacts Prescribed Preventive Treatment for Drug-resistant Tuberculosis Exposure

Clinical Infectious Diseases ◽

10.1093/cid/ciaa327 ◽

2020 ◽

Author(s):

Amyn A Malik ◽

Mercedes C Becerra ◽

Timothy L Lash ◽

Lisa M Cranmer ◽

Saad B Omer ◽

...

Keyword(s):

Risk Factors ◽

Adverse Events ◽

Proportional Hazards ◽

Multivariable Analysis ◽

Preventive Treatment ◽

Cox Proportional Hazards ◽

Drug Resistant ◽

Event Analysis ◽

Crude Odds Ratio ◽

Household Contacts

Abstract Background Completion of tuberculosis (TB) preventive treatment is important to optimize efficacy; treatment-related adverse events (AEs) sometimes result in discontinuation. This study describes the occurrence of AEs and their risk factors during a 6-month, 2-drug, fluoroquinolone-based preventive treatment for household contacts of patients with drug-resistant TB in Karachi, Pakistan. Methods The primary outcome was development of any clinical AE during preventive treatment. Adverse events were categorized using the AE grading tables of the National Institutes of Health. Time-to-event analysis with Kaplan-Meier curves and Cox proportional hazards models accounting for recurrence were used to analyze associated risk factors. Results Of the 172 household contacts on preventive treatment, 36 (21%) developed 64 AEs during 813 months of treatment. The incidence of AEs over 6 months of treatment was 7.9 per 100 person-months; 16 per 100 person-months with a fluoroquinolone and ethionamide, and 4.4 per 100 person-months with a fluoroquinolone and ethambutol. There were 53 (83%) grade 1 and 11 grade 2 AEs, with no grade 3 or 4 AEs. In multivariable analysis, the risk of AEs was higher in contacts prescribed ethionamide as compared to ethambutol adjusting for age, sex, and body mass index (adjusted hazard ratio, 2.1 [95% confidence interval {CI}, 1.2–3.6]). Overall, there was no notable difference in treatment completion among the contacts who experienced an AE and those who did not (crude odds ratio, 1.1 [95% CI, .52–2.5]). Conclusions A fluoroquinolone-based preventive treatment regimen for drug-resistant TB exposure is well tolerated. Regimens with ethionamide are more likely to result in AEs.

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Disparity in outcomes of melanoma adjuvant immunotherapy by demographic profile

Melanoma Management ◽

10.2217/mmt-2020-0002 ◽

2020 ◽

Vol 7 (2) ◽

pp. MMT43

Author(s):

Alexandra Ikeguchi ◽

Michael Machiorlatti ◽

Sara K Vesely

Keyword(s):

Survival Benefit ◽

Proportional Hazards ◽

Univariate Analysis ◽

Multivariable Analysis ◽

Demographic Factors ◽

Cox Proportional Hazards ◽

Adjuvant Immunotherapy ◽

Node Positive ◽

Melanoma Patients ◽

The Impact

Background: Randomized comparisons have demonstrated survival benefit of adjuvant immunotherapy in node-positive melanoma patients but have limited power to determine if this benefit persists across various demographic factors. Materials & methods: We assessed the impact of demographic factors on the survival benefit of adjuvant immunotherapy in a database of 38,189 node-positive melanoma patients using the Kaplan–Meier method and Cox proportional hazards models. Results: All assessed demographic factors other than race significantly impacted survival of node-positive melanoma patients in univariate analysis. In multivariable analysis, only the age group interacted with immunotherapy. Conclusion: Analysis of this large database of unselected node-positive melanoma patients demonstrated a positive survival benefit of immunotherapy across all demographic factors assessed and the impact was greater for patients 65 years of age and older.

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