Statistical issues in breast cancer screening and clustered survival data analysis

This dissertation addresses certain statistical issues in two biomedical fields, namely, modeling breast cancer screening program and correlated survival data analysis. For the breast cancer screening project, this study investigates statistical approaches to quantitatively describing the age effect on screening sensitivity and sojourn time distribution. Such an investigation is directly motivated by the need to understand the inherent relationships between age and these important quantities. Age effect is incorporated through generalized linear models under a progressive disease modeling framework. Parameter estimates are obtained by maximizing conditional likelihood functions. Among a set of potential models, the Akeike's information criterion and likelihood ratio test are used in model selection and inferences. Extensive simulation studies show that the estimators have reasonable accuracy and the model selection criterion works well. The proposed methods are illustrated using data from two large breast cancer screening trials. For correlated survival data analysis, an interesting yet often ignored problem is considered, that is when cluster sizes may be informative to the outcome of interest, based on a within-cluster resampling approach and a weighted marginal model. Large sample properties for the within-cluster resampling estimators are derived under the Cox proportional hazards model, including the consistency and asymptotic normality of the regression coefficient estimators and the weak convergence property of the estimated baseline cumulative hazard function. The weighted marginal model is constructed by incorporating the inverse of cluster sizes as weights in the estimating equations. Simulation studies are conducted to assess and compare the finite-sample behaviors of the estimators and the proposed methods are applied to a dental data example as an illustration

Assessing the causal effects of adipokines on uric acid and gout: A two-sample mendelian randomization study

Previous observational studies have highlighted associations between adipokines and hyperuricemia, as well as gout, but the causality and direction of these associations are not clear. Therefore, we attempted to assess whether there are causal effects of specific adipokines (such as adiponectin (ADP) and soluble leptin receptors (sOB-R)) on uric acid (UA) or gout in a two-sample Mendelian randomization (MR) analysis, based on summary statistics from large genome-wide association studies. The inverse-variance weighted (IVW) method was performed as the primary analysis. Sensitivity analyses (including MR-Egger regression, weighted median, penalized weighted median, and MR pleiotropy residual sum and outlier methods) were also performed, to ensure reliable results. In the IVW models, no causal effect was found for sOB-R (odds ratios (OR), 1.002; 95% confidence intervals (CI), 0.999–1.004; p = 0.274) on UA, or ADP (OR, 1.198; 95% CI, 0.865–1.659; p = 0.277) or sOB-R (OR, 0.988; 95% CI, 0.940–1.037; p = 0.616) on gout. The results were confirmed in sensitivity analyses. There was no notable directional pleiotropy or heterogeneity. This study suggests that these specific adipokines may not play causal roles in UA or gout development

Assessing the Causal Effects of Adipokines on Uric Acid and Gout: A Two-Sample Mendelian Randomization Study

Previous observational studies have highlighted associations between adipokines and hyperuricemia, as well as gout, but the causality and direction of these associations are not clear. Therefore, we attempted to assess whether there are causal effects of specific adipokines (such as adiponectin (ADP) and soluble leptin receptors (sOB-R)) on uric acid (UA) or gout in a two-sample Mendelian randomization (MR) analysis, based on summary statistics from large genome-wide association studies. The inverse-variance weighted (IVW) method was performed as the primary analysis. Sensitivity analyses (including MR-Egger regression, weighted median, penalized weighted median, and MR pleiotropy residual sum and outlier methods) were also performed, to ensure reliable results. In the IVW models, no causal effect was found for sOB-R (odds ratios (OR), 1.002; 95% confidence intervals (CI), 0.999–1.004; p = 0.274) on UA, or ADP (OR, 1.198; 95% CI, 0.865–1.659; p = 0.277) or sOB-R (OR, 0.988; 95% CI, 0.940–1.037; p = 0.616) on gout. The results were confirmed in sensitivity analyses. There was no notable directional pleiotropy or heterogeneity. This study suggests that these specific adipokines may not play causal roles in UA or gout development

Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial

Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) progressing after first-line platinum regimens have a poor prognosis and few treatment options. Afatinib, an irreversible ERBB family blocker, has shown efficacy in a phase 2 study in this setting. We aimed to assess the efficacy and safety of afatinib compared with methotrexate as second-line treatment in patients with recurrent or metastatic HNSCC progressing on or after platinum-based therapy.status: publishe

Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1) : an open-label, randomised phase 3 trial

Background Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) progressing after first-line platinum regimens have a poor prognosis and few treatment options. Afatinib, an irreversible ERBB family blocker, has shown efficacy in a phase 2 study in this setting. We aimed to assess the efficacy and safety of afatinib compared with methotrexate as second-line treatment in patients with recurrent or metastatic HNSCC progressing on or after platinum-based therapy. Methods In this open-label, phase 3, randomised controlled trial conducted in 101 centres in 19 countries, we enrolled patients aged 18 years or older with histologically or cytologically confirmed HNSCC that was recurrent, metastatic, or both who had progressed on or after first-line platinum-based therapy, were not amenable for salvage surgery or radiotherapy, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Previous treatment with more than one systemic regimen in this setting was not allowed; previous treatment with EGFR-targeted antibody therapy (but not EGFR-targeted tyrosine-kinase inhibitors) was allowed. We randomly assigned eligible patients in a 2: 1 ratio to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m(2) per week), stratified by ECOG performance status and previous EGFR-targeted antibody therapy for recurrent or metastatic disease. Randomisation was done centrally with an interactive voice or web-based response system. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. The primary endpoint was progression-free survival as assessed by an independent, central imaging review committee. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01345682. Findings Between Jan 10, 2012, and Dec 12, 2013, we enrolled 483 patients and randomly assigned 322 to afatinib and 161 to methotrexate. After a median follow-up of 6.7 months (IQR 3.1-9.0), progression-free survival was longer in the afatinib group than in the methotrexate group (median 2.6 months [95% CI 2.0-2.7] for the afatinib group vs 1.7 months [1.5-2.4] for the methotrexate group; hazard ratio [HR] 0.80 [95% CI 0.65-0.98], p=0.030). The most frequent grade 3 or 4 drug-related adverse events were rash or acne (31 [10%] of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group), diarrhoea (30 [9%] vs three [2%]), stomatitis (20 [6%] vs 13 [8%]), fatigue (18 [6%] vs five [3%]), and neutropenia (1 [<1%] vs 11 [7%]); serious adverse events occurred in 44 (14%) of afatinib-treated patients and 18 (11%) of methotrexate-treated patients. Interpretation Afatinib was associated with significant improvements in progression-free survival and had a manageable safety profile. These findings provide important new insights into the treatment of this patient population and support further investigations with irreversible ERBB family blockers in HNSCC