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Advances in statistical modeling and analysis technology have improved our ability to derive valid inferences from tumor xenograft experiments. Further challenges in this area include the modeling of intertumor heterogeneity and the development of robust statistical models that describe key parameters in the underlying tumor biology., (©2011 AACR.)

Unlabelled: Comparative effectiveness research has become an integral part of health care planning in most developed countries. In a simulated cohort of women, aged 30-65, who tested positive for BRCA1 or BRCA2 mutations, we compared outcomes of mammography with and without MRI, prophylactic oophorectomy with and without mastectomy, mastectomy alone, and chemoprevention., Methods: Using Treeage 9.02 software, we developed Markov models with 25,000 Monte Carlo simulations and conducted probabilistic sensitivity analysis. We based mutation penetrance rates, breast and ovarian cancer incidence, and mortality rates, and costs in terms of 2009 dollars, on published studies and data from the Surveillance, Epidemiology, and End RESULTS (SEER) Program and the Centers for Medicare and Medicaid Services. We used preference ratings obtained from mutation carriers and controls to adjust survival for quality of life (QALYs)., Results: For BRCA1 mutation carriers, prophylactic oophorectomy at $1,741 per QALY, was more cost effective than both surgeries and dominated all other interventions. For BRCA2 carriers, prophylactic oophorectomy, at $4,587 per QALY, was more cost effective than both surgeries. Without quality adjustment, both mastectomy and BSO surgeries dominated all other interventions. In all simulations, preventive surgeries or chemoprevention dominated or were more cost effective than screening because screening modalities were costly., Conclusion: Our analysis suggested that among BRCA1/2 mutation carriers, prophylactic surgery would dominate or be cost effective compared to chemoprevention and screening. Annual screening with MRI and mammography was the most effective strategy because it was associated with the longest quality-adjusted survival, but it was also very expensive.

When testing multiple hypotheses simultaneously, there is a need to adjust the levels of the individual tests to effect control of the family-wise error rate (FWER). Standard frequentist adjustments control the error rate but are typically both conservative and oblivious to prior information. We propose a Bayesian testing approach-multiplicity-calibrated Bayesian hypothesis testing-that sets individual critical values to reflect prior information while controlling the FWER via the Bonferroni inequality. If the prior information is specified correctly, in the sense that those null hypotheses considered most likely to be false in fact are false, the power of our method is substantially greater than that of standard frequentist approaches. We illustrate our method using data from a pharmacogenetic trial and a preclinical cancer study. We demonstrate its error rate control and power advantage by simulation.

The ability to quit smoking is heritable, yet few genetic studies have investigated prospective smoking cessation. We conducted a systems-based genetic association analysis in a sample of 472 treatment-seeking smokers of European ancestry after 8 weeks of transdermal nicotine therapy for smoking cessation. The genotyping panel included 169 single-nucleotide polymorphisms (SNPs) in 7 nicotinic acetylcholine receptor subunit genes and 4 genes in the endogenous cholinergic system. The primary outcome was smoking cessation (biochemically confirmed) at the end of treatment. SNPs clustered in the choline acetyltransferase (ChAT) gene were individually identified as nominally significant, and a 5-SNP haplotype (block 6) in ChAT was found to be significantly associated with quitting success. Single SNPs in ChAT haplotype block 2 were also associated with pretreatment levels of nicotine dependence in this cohort. To replicate associations of SNPs in haplotype blocks 2 and 6 of ChAT with nicotine dependence in a non-treatment-seeking cohort, we used data from an independent community-based sample of 629 smokers representing 200 families of European ancestry. Significant SNP and haplotype associations were identified for multiple measures of nicotine dependence. Although the effect sizes in both cohorts are modest, converging data across cohorts and phenotypes suggest that ChAT may be involved in nicotine dependence and ability to quit smoking. Additional sequencing and characterization of ChAT may reveal functional variants that contribute to nicotine dependence and smoking cessation.

Background: Hospitalized patients who develop febrile neutropenia (FN) are treated empirically with antibiotics due to a high risk of developing septic shock. Currently, there is no method to predict which patients are at greatest risk. This study was designed to determine whether serum lactate, measured at the time of FN, is associated with the development of septic shock in hospitalized hematologic malignancy (HM) patients., Results: Of the 547 patients enrolled, 46 (8.4%; 95% CI 6.2-10.9) developed septic shock. Baseline characteristics were similar between the groups. In univariate analysis, tachypnea (OR 5.9; 95% CI: 2.0-16.9, p = 0.001) and lactate (OR 18.4; 95% CI: 4.1-81.6, p < 0.001) were significantly associated with the development of septic shock. In multivariate analysis, lactate and tachypnea remained independently associated with the development of septic shock. By ROC analysis, lactate provided incremental prognostic value compared to vital signs alone., Methods: Vital signs and lactate were measured during episodes of FN. The primary endpoint was the development of septic shock. Using a prospective, nested, case-control design, controls were matched on length of stay at the time of septic shock to achieve 80% power to detect an OR of >or=2.5. Using logistic regression, we evaluated the association of vital signs and lactate with the subsequent development of septic shock., Conclusions: In FN patients, measurement of lactate during FN adds significant prognostic information about the risk of developing septic shock. Routine measurement of lactate may help identify patients who may benefit from increased monitoring and early intervention strategies.

We previously showed that a single intrapleural dose of an adenoviral vector expressing interferon-beta (Ad.IFN-beta) in patients with malignant pleural mesothelioma (MPM) or malignant pleural effusions (MPE) resulted in gene transfer, humoral antitumor immune responses, and anecdotal clinical responses manifested by modified Response Evaluation Criteria in Solid Tumors (RECIST) disease stability in 3 of 10 patients at 2 months and an additional patient with significant metabolic response on positron emission tomography (PET) imaging. This phase I trial was conducted to determine whether using two doses of Ad.IFN-beta vector would be superior. Ten patients with MPM and seven with MPE received two doses of Ad.IFN-beta through an indwelling pleural catheter. Repeated doses were generally well tolerated. High levels of IFN-beta were detected in pleural fluid after the first dose; however, only minimal levels were seen after the second dose of vector. Lack of expression correlated with the rapid induction of neutralizing Ad antibodies (Nabs). Antibody responses against tumor antigens were induced in most patients. At 2 months, modified RECIST responses were as follows: one partial response, two stable disease, nine progressive disease, and two nonmeasurable disease. One patient died after 1 month. By PET scanning, 2 patients had mixed responses and 11 had stable disease. There were seven patients with survival times longer than 18 months. This approach was safe, induced immune responses and disease stability. However, rapid development of Nabs prevented effective gene transfer after the second dose, even with a dose interval as short as 7 days.

We propose a flexible parametric model to describe alternating states recurrent-event data where there is a possibility of cure with each type of event. We begin by introducing a novel cure model in which a common frailty influences both the cure probability and the hazard function given not cured. We then extend our model to data with recurring events of two alternating types. We assume that each type of event has a gamma frailty, and we link the frailties by a Clayton copula. We illustrate the model with an analysis of data from two smoking cessation trials comparing bupropion and placebo, in which each subject potentially experienced a series of lapse and recovery events. Our analysis suggests that bupropion increases the probability of permanent cure and decreases the hazard of lapse, but does not affect the distribution of time to recovery during a lapse. The data suggest a positive but non-significant association between the lapse and recovery frailties. A simulation study suggests that the estimates have little bias and that their 95 per cent confidence intervals have nearly nominal coverage in samples of practical size., (Copyright (c) 2010 John Wiley & Sons, Ltd.)

Background: Tobacco dependence is a chronic, relapsing condition that may require extended treatment., Objective: To assess whether extended-duration transdermal nicotine therapy increases abstinence from tobacco more than standard-duration therapy in adult smokers., Design: Parallel randomized, placebo-controlled trial from September 2004 to February 2008. Participants and all research personnel except the database manager were blinded to randomization. (ClinicalTrials.gov registration number: NCT00364156), Setting: Academic center., Participants: 568 adult smokers., Intervention: In an unstratified small block-randomization scheme, participants were randomly assigned to standard therapy (Nicoderm CQ [GlaxoSmithKline, Research Triangle Park, North Carolina], 21 mg, for 8 weeks and placebo for 16 weeks) or extended therapy (Nicoderm CQ, 21 mg, for 24 weeks)., Measurements: The primary outcome was biochemically confirmed point-prevalence abstinence at weeks 24 and 52. Secondary outcomes were continuous and prolonged abstinence, lapse and recovery events, cost per additional quitter, and side effects and adherence., Results: At week 24, extended therapy produced higher rates of point-prevalence abstinence (31.6% vs. 20.3%; odds ratio, 1.81 [95% CI, 1.23 to 2.66]; P = 0.002), prolonged abstinence (41.5% vs. 26.9%; odds ratio, 1.97 [CI, 1.38 to 2.82]; P = 0.001), and continuous abstinence (19.2% vs. 12.6%; odds ratio, 1.64 [CI, 1.04 to 2.60]; P = 0.032) versus standard therapy. Extended therapy reduced the risk for lapse (hazard ratio, 0.77 [CI, 0.63 to 0.95]; P = 0.013) and increased the chances of recovery from lapses (hazard ratio, 1.47 [CI, 1.17 to 1.84]; P = 0.001). Time to relapse was slower with extended versus standard therapy (hazard ratio, 0.50 [CI, 0.35 to 0.73]; P < 0.001). At week 52, extended therapy produced higher quit rates for prolonged abstinence only (P = 0.027). No differences in side effects and adverse events between groups were found at the extended-treatment assessment., Limitation: The generalizability of the findings may be limited because participants were smokers without medical comorbid conditions who were seeking treatment, and differences in adherence across treatment groups were detected., Conclusion: Transdermal nicotine for 24 weeks increased biochemically confirmed point-prevalence abstinence and continuous abstinence at week 24, reduced the risk for smoking lapses, and increased the likelihood of recovery to abstinence after a lapse compared with 8 weeks of transdermal nicotine therapy., Primary Funding Source: National Institutes of Health.

Objective: The role of serum uric acid as an independent risk factor for cardiovascular disease remains unclear, although hyperuricemia is associated with cardiovascular disease such as coronary heart disease (CHD), stroke, and hypertension., Methods: A systematic review and meta-analysis using a random-effects model was conducted to determine the risk of CHD associated with hyperuricemia in adults. Studies of hyperuricemia and CHD were identified by searching major electronic databases using the medical subject headings and keywords without language restriction (through February 2009). Only prospective cohort studies were included if they had data on CHD incidences or mortalities related to serum uric acid levels in adults., Results: Twenty-six eligible studies of 402,997 adults were identified. Hyperuricemia was associated with an increased risk of CHD incidence (unadjusted risk ratio [RR] 1.34, 95% confidence interval [95% CI] 1.19-1.49) and mortality (unadjusted RR 1.46, 95% CI 1.20-1.73). When adjusted for potential confounding, the pooled RR was 1.09 (95% CI 1.03-1.16) for CHD incidence and 1.16 (95% CI 1.01-1.30) for CHD mortality. For each increase of 1 mg/dl in uric acid level, the pooled multivariate RR for CHD mortality was 1.12 (95% CI 1.05-1.19). Subgroup analyses showed no significant association between hyperuricemia and CHD incidence/mortality in men, but an increased risk for CHD mortality in women (RR 1.67, 95% CI 1.30-2.04)., Conclusion: Hyperuricemia may marginally increase the risk of CHD events, independently of traditional CHD risk factors. A more pronounced increased risk for CHD mortality in women should be investigated in future research.

Introduction: Uncertainty exists about how best to measure daily cigarette consumption. Two common measures are timeline followback (TLFB), which involves structured, prompted recall, and ecological momentary assessment (EMA), which involves recording consumption, as it occurs, on a handheld electronic device., Methods: We evaluated the agreement between TLFB and EMA measures collected for 14 days prior to the target quit date from 236 smokers in a smoking cessation program. We performed a Bland-Altman analysis to assess agreement of TLFB and EMA using a regression-based model that allows for a nonuniform difference between methods and limits of agreement that can vary with the number of cigarettes smoked., Results: For pairs of measurements taken on the same smoker, TLFB counts were on average 3.2 cigarettes higher than EMA counts; this difference increased for larger numbers of cigarettes. Using a model that allows for variable limits of agreement, the width of the 95% interval ranged from 8.7 to 61.8 cigarettes, with an average of 26.4 cigarettes. Variation between the methods increased substantially for larger cigarette counts, leading to wider limits and poorer agreement for heavy smokers., Discussion: Throughout the measurement range, the estimated limits of agreement were far wider than the limits of clinical significance, defined a priori to be 20% of the number of cigarettes smoked. We conclude that TLFB and EMA cannot be considered equivalent for the assessment of daily cigarette consumption, especially for heavy smokers.

Objective: To assess the association between hyperuricemia and risk of stroke incidence and mortality because hyperuricemia is hypothesized to be a risk factor for stroke and other cardiovascular disease, but, to date, results from observational studies are conflicting., Methods: A systematic review and meta-analysis were conducted. Studies were identified by searching major electronic databases using the Medical Subject Headings and keywords without restriction in languages. Prospective cohort studies were included only if they contained data on stroke incidences or mortalities related to serum uric acid levels in adults. Pooled risk ratios (RRs) for the association of stroke incidence and mortality with serum uric acid levels were calculated., Results: A total of 16 studies including 238,449 adults were eligible and abstracted. Hyperuricemia was associated with a significantly higher risk of both stroke incidence (6 studies; RR 1.41, 95% confidence interval [95% CI] 1.05, 1.76) and mortality (6 studies; RR 1.36, 95% CI 1.03, 1.69) in our meta-analyses of unadjusted study estimates. Subgroup analyses of studies adjusting for known risk factors such as age, hypertension, diabetes mellitus, and cholesterol still showed that hyperuricemia was significantly associated with both stroke incidence (4 studies; RR 1.47, 95% CI 1.19, 1.76) and mortality (6 studies; RR 1.26, 95% CI 1.12, 1.39). The pooled estimate of multivariate RRs did not differ significantly by sex., Conclusion: Hyperuricemia may modestly increase the risks of both stroke incidence and mortality. Future research is needed to determine whether lowering uric acid level has any beneficial effects on stroke.

Background: The systemic inflammatory response syndrome (SIRS) criteria have not been validated in patients with hematologic malignancies (HM)., Objective: To determine whether daily assessment of SIRS criteria allows early identification of HM patients who will develop septic shock (SS)., Design: Observational, single-center,nested case-control study., Setting: Oncology unit of a tertiary care center., Patients: 547 consecutive, hospitalized, HM subject were enrolled. Using incidence-density sampling, 184 controls were matched to 46 SS cases., Measurements: The study exposure was the SIRS score. The study outcome was the development of SS during the hospitalization., Main Results: 8.4% of subjects developed SS. SIRS scores measured 24 hours prior to SS were significantly higher in cases than in controls (2.1 vs. 1.4,p<0.0001). Using standard SIRS cutpoints, fever, tachypnea and tachycardia were each associated with the onset of SS. Population-specific SIRS criteria were empirically derived., Limitations: Single-center study. Further validation is warranted., Conclusions: SIRS can identify HM patients at risk for SS at least 24 hours before SS onset. These data may lead to evidence-based guidelines using routine vital signs to risk-stratify HM patients for SS.

Mesothelin is a cell-surface molecule over-expressed on a large fraction of carcinomas, and thus is an attractive target of immunotherapy. A molecularly targeted therapy for these cancers was created by engineering T cells to express a chimeric receptor with high affinity for human mesothelin. Lentiviral vectors were used to express a single-chain variable fragment that binds mesothelin and that is fused to signaling domains derived from T-cell receptor zeta, CD28, and CD137 (4-1BB). When stimulated by mesothelin, lentivirally transduced T cells were induced to proliferate, express the antiapoptotic gene Bcl-X(L), and secrete multiple cytokines, all features characteristic of central memory T cells. When transferred intratumorally or intravenously into NOD/scid/IL2rgamma(-/-) mice engrafted with large pre-established tumors, the engineered T cells reduced the tumor burden, and in some cases resulted in complete eradication of the tumors at low effector-to-target ratios. Incorporation of the CD137 signaling domain specifically reprogrammed cells for multifunctional cytokine secretion and enhanced persistence of T cells. These findings have important implications for adoptive immunotherapy of cancer, especially in the context of poorly immunogenic tumors. Genetically redirected T cells have promise of targeting T lymphocytes to tumor antigens, confer resistance to the tumor microenvironment, and providing immunosurveillance.

Background: Nicotine deprivation symptoms, including fatigue and attentional deficits, predict relapse following smoking cessation. Modafinil (Provigil), a wakefulness medication shown to have efficacy for the treatment of cocaine addiction, was tested as a novel therapy for nicotine dependence in a double-blind placebo-controlled trial., Methods: One hundred and fifty-seven treatment-seeking smokers received brief smoking cessation counseling and were randomized to: (1) 8 weeks of modafinil (200mg/day), or (2) 8 weeks of placebo. The primary outcome was biochemically verified 7-day point prevalence abstinence at the end of treatment (EOT). Secondary outcomes included cigarette smoking rate and post-quit nicotine deprivation symptoms (e.g., negative affect, withdrawal)., Results: In this interim study analysis, EOT quit rates did not differ between treatment arms (42% for placebo vs. 34% for modafinil; OR=0.67 [0.34-1.31], p=0.24). Further, from the target quit date to EOT, the daily smoking rate was 44% higher among non-abstainers in the modafinil arm, compared to non-abstainers in the placebo arm (IRR=1.44, CI95=1.09-1.89, p<0.01). Modafinil-treated participants also reported greater increases in negative affect and withdrawal symptoms, vs. participants randomized to placebo (ps<0.05)., Conclusions: These data do not support the use of modafinil for the treatment of nicotine dependence and, as a consequence, this trial was discontinued. Cigarette smoking should be considered when modafinil is prescribed, particularly among those with psychiatric conditions that have high comorbidity with nicotine dependence.

Pharmacogenetic clinical trials seek to identify genetic modifiers of treatment effects. When a trial has collected data on many potential genetic markers, a first step in analysis is to screen for evidence of pharmacogenetic effects by testing for treatment-by-marker interactions in a statistical model for the outcome of interest. This approach is potentially problematic because (i) individual significance tests can be overly sensitive, particularly when sample sizes are large; and (ii) standard significance tests fail to distinguish between markers that are likely, on biological grounds, to have an effect, and those that are not. One way to address these concerns is to perform Bayesian hypothesis tests [Berger (1985) Statistical decision theory and Bayesian analysis. New York: Springer; Kass and Raftery (1995) J Am Stat Assoc 90:773-795], which are typically more conservative than standard uncorrected frequentist tests, less conservative than multiplicity-corrected tests, and make explicit use of relevant biological information through specification of the prior distribution. In this article we use a Bayesian testing approach to screen a panel of genetic markers recorded in a randomized clinical trial of bupropion versus placebo for smoking cessation. From a panel of 59 single-nucleotide polymorphisms (SNPs) located on 11 candidate genes, we identify four SNPs (one each on CHRNA5 and CHRNA2 and two on CHAT) that appear to have pharmacogenetic relevance. Of these, the SNP on CHRNA5 is most robust to specification of the prior. An unadjusted frequentist test identifies seven SNPs, including these four, none of which remains significant upon correction for multiplicity. In a panel of 43 randomly selected control SNPs, none is significant by either the Bayesian or the corrected frequentist test., (2007 Wiley-Liss, Inc.)

In studies of smoking behavior, some subjects report exact cigarette counts, whereas others report rounded-off counts, particularly multiples of 20, 10 or 5. This form of data reporting error, known as heaping, can bias the estimation of parameters of interest such as mean cigarette consumption. We present a model to describe heaped count data from a randomized trial of bupropion treatment for smoking cessation. The model posits that the reported cigarette count is a deterministic function of an underlying precise cigarette count variable and a heaping behavior variable, both of which are at best partially observed. To account for an excess of zeros, as would likely occur in a smoking cessation study where some subjects successfully quit, we model the underlying count variable with zero-inflated count distributions. We study the sensitivity of the inference on smoking cessation by fitting various models that either do or do not account for heaping and zero inflation, comparing the models by means of Bayes factors. Our results suggest that sufficiently rich models for both the underlying distribution and the heaping behavior are indispensable to obtaining a good fit with heaped smoking data. The analyses moreover reveal that bupropion has a significant effect on the fraction abstinent, but not on mean cigarette consumption among the non-abstinent.

Purpose: Adoptive cellular immunotherapy is a promising approach to eradicate established tumors. However, a significant hurdle in the success of cellular immunotherapy involves recently identified mechanisms of immune suppression on cytotoxic T cells at the effector phase. Transforming growth factor-beta (TGF-beta) is one of the most important of these immunosuppressive factors because it affects both T-cell and macrophage functions. We thus hypothesized that systemic blockade of TGF-beta signaling combined with adoptive T-cell transfer would enhance the effectiveness of the therapy., Experimental Design: Flank tumors were generated in mice using the chicken ovalbumin-expressing thymoma cell line, EG7. Splenocytes from transgenic OT-1 mice (whose CD8 T cells recognize an immunodominant peptide in chicken ovalbumin) were activated in vitro and adoptively transferred into mice bearing large tumors in the presence or absence of an orally available TGF-beta receptor-I kinase blocker (SM16)., Results: We observed markedly smaller tumors in the group receiving the combination of SM16 chow and adoptive transfer. Additional investigation revealed that TGF-beta receptor blockade increased the persistence of adoptively transferred T cells in the spleen and lymph nodes, increased numbers of adoptively transferred T cells within tumors, increased activation of these infiltrating T cells, and altered the tumor microenvironment with a significant increase in tumor necrosis factor-alpha and decrease in arginase mRNA expression., Conclusions: We found that systemic blockade of TGF-beta receptor activity augmented the antitumor activity of adoptively transferred T cells and may thus be a useful adjunct in future clinical trials.

Objective: To evaluate whether specific preoperative variables might better predict the concordance between biopsy and radical prostatectomy (RP) Gleason grade, and to assess the effect of the biopsy Gleason score (bGS) when controlling for the pathological GS (pGS) on clinical outcomes in patients undergoing RP., Patients and Methods: Between 1989 and 1998, 1088 men had RP at our institution, with a median follow-up of 56 months. To evaluate the independent effect of bGS within categories of pGS, we stratified the sample by pGS (three categories;

Background: The investigation of angiogenesis inhibitors is of particular interest in renal cell carcinoma (RCC), in which dysregulated blood vessel formation has been correlated with shortened survival. Sorafenib is a novel RAF and VEGF receptor tyrosine kinase inhibitor. We conducted this study to (a) determine if sorafenib is anti-angiogenic, and (b) to relate anti-angiogenic effect to outcome., Results: Four patients achieved partial response by WHO criteria (ORR 24%). Median time to progression (TTP) was 12.9 months. K(trans) decreased significantly during treatment with sorafenib (60.3% decline, 95% CI 46.1-74.6%). The percent decline in K(trans) and change in tumor size by CT scan were significantly associated with progression-free survival (p = 0.01 and 0.05, respectively). In addition, K(trans) at baseline was also significantly associated with progress-free survival (p = 0.02)., Patients and Methods: Seventeen patients with metastatic RCC underwent dynamic-contrast enhanced magnetic resonance imaging (DCE-MRI). DCE-MRI was used to calculate the gadolinium exchange constant between blood and tumor interstitial tissue, K(trans)., Conclusions: In patients with RCC, inhibition of tumor vascular permeability by sorafenib was associated with improved outcome. Moreover, baseline tumor vascular permeability, expected to be a poor prognosis factor, was a predictive marker of favorable response to therapy.

In clinical trials with interim analyses planned at pre-specified event counts, one may wish to predict the times of these landmark events as a tool for logistical planning. Currently available methods use either a parametric approach based on an exponential model for survival (Bagiella and Heitjan, Statistics in Medicine 2001; 20:2055) or a non-parametric approach based on the Kaplan-Meier estimate (Ying et al., Clinical Trials 2004; 1:352). Ying et al. (2004) demonstrated the trade-off between bias and variance in these models; the exponential method is highly efficient when its assumptions hold but potentially biased when they do not, whereas the non-parametric method has minimal bias and is well calibrated under a range of survival models but typically gives wider prediction intervals and may fail to produce useful predictions early in the trial. As a potential compromise, we propose here to make predictions under a Weibull survival model. Computations are somewhat more difficult than with the simpler exponential model, but Monte Carlo studies show that predictions are robust under a broader range of assumptions. We demonstrate the method using data from a trial of immunotherapy for chronic granulomatous disease., (Copyright 2007 John Wiley & Sons, Ltd.)

The coarse data model of Heitjan and Rubin (1991) generalizes the missing data model of Rubin (1976) to cover other forms of incompleteness such as censoring and grouping. The model has 2 components: an ideal data model describing the distribution of the quantity of interest and a coarsening mechanism that describes a distribution over degrees of coarsening given the ideal data. The coarsening mechanism is said to be nonignorable when the degree of coarsening depends on an incompletely observed ideal outcome, in which case failure to properly account for it can spoil inferences. A theme in recent research is to measure sensitivity to nonignorability by evaluating the effect of a small departure from ignorability on the maximum likelihood estimate (MLE) of a parameter of the ideal data model. One such construct is the "index of local sensitivity to nonignorability" (ISNI) (Troxel and others, 2004), which is the derivative of the MLE with respect to a nonignorability parameter evaluated at the ignorable model. In this paper, we adapt ISNI to Bayesian modeling by instead defining it as the derivative of the posterior expectation. We propose the application of ISNI as a first step in judging the robustness of a Bayesian analysis to nonignorable coarsening. We derive formulas for a range of models and apply the method to evaluate sensitivity to nonignorable coarsening in 2 real data examples, one involving missing CD4 counts in an HIV trial and the other involving potentially informatively censored relapse times in a leukemia trial.

Purpose: This phase 1 dose escalation study evaluated the safety and feasibility of single-dose intrapleural IFN-beta gene transfer using an adenoviral vector (Ad.IFN-beta) in patients with malignant pleural mesothelioma (MPM) and metastatic pleural effusions (MPE)., Experimental Design: Ad.IFN-beta was administered through an indwelling pleural catheter in doses ranging from 9 x 10(11) to 3 x 10(12) viral particles (vp) in two cohorts of patients with MPM (7 patients) and MPE (3 patients). Subjects were evaluated for (a) toxicity, (b) gene transfer, (c) humoral, cellular, and cytokine-mediated immune responses, and (d) tumor responses via 18-fluorodeoxyglucose-positron emission tomography scans and chest computed tomography scans., Results: Intrapleural Ad.IFN-beta was generally well tolerated with transient lymphopenia as the most common side effect. The maximally tolerated dose achieved was 9 x 10(11) vp secondary to idiosyncratic dose-limiting toxicities (hypoxia and liver function abnormalities) in two patients treated at 3 x 10(12) vp. The presence of the vector did not elicit a marked cellular infiltrate in the pleural space. Intrapleural levels of cytokines were highly variable at baseline and after response to gene transfer. Gene transfer was documented in 7 of the 10 patients by demonstration of IFN-beta message or protein. Antitumor immune responses were elicited in 7 of the 10 patients and included the detection of cytotoxic T cells (1 patient), activation of circulating natural killer cells (2 patients), and humoral responses to known (Simian virus 40 large T antigen and mesothelin) and unknown tumor antigens (7 patients). Four of 10 patients showed meaningful clinical responses defined as disease stability and/or regression on 18-fluorodeoxyglucose-positron emission tomography and computed tomography scans at day 60 after vector infusion., Conclusions: Intrapleural instillation of Ad.IFN-beta is a potentially useful approach for the generation of antitumor immune responses in MPM and MPE patients and should be investigated further for overall clinical efficacy.

In non-randomized studies, estimation of treatment effects generally requires adjustment for imbalances in observed covariates. One such method, based on the propensity score, is useful in many applications but may be biased when the assumption of strongly ignorable treatment assignment is violated. Because it is not possible to evaluate this assumption from the data, it is advisable to assess the sensitivity of conclusions to violations of strong ignorability. Lin et al. (Biomet. 1998; 54:948-963) have implemented this idea by investigating how an unmeasured covariate may affect the conclusions of an observational study. We extend their method to assess sensitivity of the treatment hazard ratio to hidden bias under a range of covariate distributions. We derive simple formulas for approximating the true from the apparent treatment hazard ratio estimated under a specific survival model, and assess the validity of these formulas in simulation studies. We demonstrate the method in an analysis of SEER-Medicare data on the effects of chemotherapy in elderly colon cancer patients., (Copyright (c) 2006 John Wiley & Sons, Ltd.)

Background: Timing for interim or final analysis of data in an event-based trial is often determined by the accrual of events during the study. Existing Bayesian methods may be used to predict the date of the landmark event using observed enrollment, event, and loss times when treatment arm information is masked., Purpose: For event-based trials with a blocked randomization, knowledge of blocks in which patients are enrolled can provide additional information to improve predictions versus models that only assume a known treatment allocation proportion. We therefore propose to incorporate blocking information into existing methods for prediction., Methods: We derive a latent variable (LV) extension of a mixture model used in Donovan JM, Elliott MR, Heitjan DF. Predicting Event Times in Clinical Trials When Treatment Arm is Masked. J Biopharmaceut Stat 2006; 16:343-56 to incorporate block randomization (constrained LV) for predicting the landmark event and compare this model with (a) methods where blocking information is ignored (unconstrained LV), and (b) methods assuming a single population (SP)., Results: Comparison of the constrained and unconstrained LV models in our application shows that the constrained LV model has narrower prediction intervals. Simulation studies show that the constrained LV model can have better coverage probabilities for the prediction intervals than SP models if a treatment effect is present, and prediction intervals from the constrained LV model are narrower than those for the unconstrained LV model. These differences varied by block size and prediction time., Limitations: We have limited focus to the exponential model for events. Coverage for the LV models may be somewhat reduced if no treatment effect is present., Conclusions: Extra information provided by knowledge of blocking can be used to decrease prediction interval width versus the unconstrained LV model, while providing better coverage properties than the SP model if a treatment effect is present.

Right- and interval-censored data are common special cases of coarsened data (Heitjan and Rubin, 1991, Annals of Statistics19, 2244-2253). As with missing data, standard statistical methods that ignore the random nature of the coarsening mechanism may lead to incorrect inferences. We extend a simple sensitivity analysis tool, the index of local sensitivity to nonignorability (Troxel, Ma, and Heitjan, 2004, Statistica Sinica14, 1221-1237), to the evaluation of nonignorability of the coarsening process in the general coarse-data model. By converting this index into a simple graphical display one can easily assess the sensitivity of key inferences to nonignorable coarsening. We illustrate the validity of the method with a simulated example, and apply it to right-censored data from an observational study of cardiac transplantation and to interval-censored data on time to detectable viral load from a clinical trial in HIV disease.

We propose a pattern-mixture model for describing the joint distribution of incomplete repeated measurements of quality of life (QoL) and right-censored survival times. The model assumes that the survival times follow a multinomial distribution and that the quality of life outcome follows a multivariate normal distribution conditional on the survival time. We estimate the model using a Bayesian approach by importance sampling. We then use simulated parameters to create multiple imputations of the censored QoL outcomes, which can then be used to calculate individual values of quality-adjusted life-years (QALYs). We apply the method to data from the Randomized Evaluation of Mechanical Assistance in the Treatment of Congestive Heart Failure (REMATCH) clinical trial.

Tumor lysis syndrome (TLS) is defined by metabolic derangements occurring in the setting of rapid tumor destruction. In acute myelogenous leukemia (AML), TLS frequency, risk stratification, monitoring, and management strategies are based largely on case series and data from other malignancies. A single-center, retrospective cohort study was conducted to estimate TLS incidence and identify TLS predictive factors in a patient population undergoing myeloid leukemia induction chemotherapy. This study included 194 patients, aged 18-86 years, with AML or advanced myelodysplastic syndrome undergoing primary myeloid leukemia induction chemotherapy. Nineteen patients (9.8%) developed TLS. In univariate analysis, elevated pre-chemotherapy values for uric acid (P < 0.0001), creatinine (P = 0.0025), lactate dehydrogenase (LDH) (P = 0.0001), white blood cell (P = 0.0058), gender (P = 0.0064) and chronic myelomonocytic leukemia history (P = 0.0292) were significant predictors. In multivariate analysis, LDH (P = 0.0042), uric acid (P < 0.0001) and gender (P = 0.0073) remained significant TLS predictors. A predictive model was then designed using a scoring system based on these factors. This analysis may lay the groundwork for the development of the first evidence-based guidelines for TLS monitoring and management in this patient population.

Because power is primarily determined by the number of events in event-based clinical trials, the timing for interim or final analysis of data is often determined based on the accrual of events during the course of the study. Thus, it is of interest to predict early and accurately the time of a landmark interim or terminating event. Existing Bayesian methods may be used to predict the date of the landmark event, based on current enrollment, event, and loss to follow-up, if treatment arms are known. This work extends these methods to the case where the treatment arms are masked by using a parametric mixture model with a known mixture proportion. Posterior simulation using the mixture model is compared with methods assuming a single population. Comparison of the mixture model with the single-population approach shows that with few events, these approaches produce substantially different results and that these results converge as the prediction time is closer to the landmark event. Simulations show that the mixture model with diffuse priors can have better coverage probabilities for the prediction interval than the nonmixture models if a treatment effect is present.

Background: For BRCA1 or BRCA2 mutation carriers, decision analysis indicates that prophylactic surgery or chemoprevention leads to better survival than surveillance alone., Objective: To evaluate the cost-effectiveness of the preventive strategies that are available to unaffected women carrying a single BRCA1 or BRCA2 mutation with high cancer penetrance., Design: Markov modeling with Monte Carlo simulations and probabilistic sensitivity analyses., Data Sources: Breast and ovarian cancer incidence and mortality rates, preference ratings, and costs derived from the literature; the Surveillance, Epidemiology, and End Results (SEER) Program; and the Health Care Financing Administration (now the Centers for Medicare & Medicaid Services)., Target Population: Unaffected carriers of a single BRCA1 or BRCA2 mutation 35 to 50 years of age., Time Horizon: Lifetime., Perspective: Health policy, societal., Interventions: Tamoxifen, oral contraceptives, bilateral salpingo-oophorectomy, mastectomy, both surgeries, or surveillance., Outcome Measures: Cost-effectiveness., Results of Base-Case Analysis: For mutation carriers 35 years of age, both surgeries (prophylactic bilateral mastectomy and oophorectomy) had an incremental cost-effectiveness ratio over oophorectomy alone of 2352 dollars per life-year for BRCA1 and 100 dollars per life-year for BRCA2. With quality adjustment, oophorectomy dominated all other strategies for BRCA1 and had an incremental cost-effectiveness ratio of 2281 dollars per life-year for BRCA2., Results of Sensitivity Analysis: Older age at intervention increased the cost-effectiveness of prophylactic mastectomy for BRCA1 mutation carriers to 73,755 dollars per life-year. Varying the penetrance, mortality rates, costs, discount rates, and preferences had minimal effects on outcomes., Limitations: Results are dependent on the accuracy of model assumptions., Conclusion: On the basis of this model, the most cost-effective strategies for BRCA mutation carriers, with and without quality adjustment, were oophorectomy alone and oophorectomy and mastectomy, respectively.

Purpose: Anal intraepithelial neoplasia is associated with human papillomavirus infection and may progress to invasive squamous cell carcinoma (SCC), which is increasing in immunocompromised patients. We hypothesize that anal intraepithelial neoplasia is associated with abnormal DNA methylation and that detection of these events may be used to improve screening programs., Experimental Design: Seventy-six patients were identified who underwent anal cytology screening and subsequent biopsy at our institution between 1999 and 2004. The specimens from these patients included 184 anal biopsies [normal, n = 57; low-grade squamous intraepithelial lesion (LSIL), n = 74; high-grade squamous intraepithelial lesion (HSIL), n = 41; and invasive SCC, n = 12] and 37 residual liquid-based anal cytology specimens (normal, n = 11; LSIL, n = 12; HSIL, n = 14). The methylation status of the following genes was determined for each biopsy and cytology sample using real-time methylation-specific PCR: HIC1, RASSF1, RARB, CDKN2A, p14, TP73, APC, MLH1, MGMT, DAPK1, and IGSF4., Results: Methylation-specific PCR analysis of biopsy samples revealed that DNA methylation was more common in SCC and HSIL than LSIL and normal mucosa. Specifically, methylation of IGSF4 and DAPK1 was prevalent in SCC (75% and 75% of cases, respectively) and HSIL (59% and 71%, respectively) but was absent in LSIL and normal biopsy samples. Methylation profiles of cytologic samples were similar to those found in the biopsy samples., Conclusions: Aberrant DNA methylation is a frequent event in anal HSIL and SCC. Methylation of IGSF4 and DAPK1 is specific for HSIL and SCC, and may serve as a useful molecular biomarker.

Background: Isolated hepatic perfusion has been used in patients with colorectal cancer (CRC) metastatic to the liver. We sought to determine whether perfusion with antisense oligodeoxynucleotides results in the downregulation of beta-catenin and whether this improves tumor response to isolated limb perfusion (ILP) in a heterotopic model of human CRC., Methods: Adenomatous polyposis coli-mutant human CRC xenografts were implanted into athymic rats. Animals were randomized to the following groups: (1) no treatment, (2) control ILP, (3) melphalan ILP, (4) ILP with antisense specific for beta-catenin, (5) ILP with nonspecific antisense, and (6) melphalan plus beta-catenin-specific antisense ILP. Tumor response and Western blot analysis of protein expression were evaluated., Results: The maximal decrease (mean +/- SE) in tumor volume was 0% +/- 10% for no treatment, 19% +/- 14% for control ILP, 58% +/- 3% for melphalan ILP, 58% +/- 9% for beta-catenin-specific ILP, 13% +/- 19% for nonspecific antisense ILP, and 73% +/- 6% for melphalan plus beta-catenin-specific ILP (P < .05 for melphalan ILP, beta-catenin-specific ILP, and melphalan plus antisense ILP). Tumor regrowth was delayed for 6 days after control ILP, 24 days after melphalan ILP, 20 days after beta-catenin-specific ILP, 10 days after nonspecific antisense ILP, and 60 days after melphalan plus beta-catenin-specific ILP (P < .05 for melphalan plus beta-catenin-specific ILP compared with all others). Western blotting revealed prolonged suppression of beta-catenin expression after beta-catenin-specific ILP., Conclusions: Short-term beta-catenin antisense treatment improves tumor response rates after ILP in a rodent model of human CRC.

In longitudinal studies with potentially nonignorable drop-out, one can assess the likely effect of the nonignorability in a sensitivity analysis. Troxel et al. proposed a general index of sensitivity to nonignorability, or ISNI, to measure sensitivity of key inferences in a neighbourhood of the ignorable, missing at random (MAR) model. They derived detailed formulas for ISNI in the special case of the generalized linear model with a potentially missing univariate outcome. In this paper, we extend the method to longitudinal modelling. We use a multivariate normal model for the outcomes and a regression model for the drop-out process, allowing missingness probabilities to depend on an unobserved response. The computation is straightforward, and merely involves estimating a mixed-effects model and a selection model for the drop-out, together with some simple arithmetic calculations. We illustrate the method with three examples., (Copyright 2005 John Wiley & Sons, Ltd)

In problems with missing or latent data, a standard approach is to first impute the unobserved data, then perform all statistical analyses on the completed dataset--corresponding to the observed data and imputed unobserved data--using standard procedures for complete-data inference. Here, we extend this approach to model checking by demonstrating the advantages of the use of completed-data model diagnostics on imputed completed datasets. The approach is set in the theoretical framework of Bayesian posterior predictive checks (but, as with missing-data imputation, our methods of missing-data model checking can also be interpreted as "predictive inference" in a non-Bayesian context). We consider the graphical diagnostics within this framework. Advantages of the completed-data approach include: (1) One can often check model fit in terms of quantities that are of key substantive interest in a natural way, which is not always possible using observed data alone. (2) In problems with missing data, checks may be devised that do not require to model the missingness or inclusion mechanism; the latter is useful for the analysis of ignorable but unknown data collection mechanisms, such as are often assumed in the analysis of sample surveys and observational studies. (3) In many problems with latent data, it is possible to check qualitative features of the model (for example, independence of two variables) that can be naturally formalized with the help of the latent data. We illustrate with several applied examples.

Background: In a clinical trial, survival may be censored by the end of the study, especially for subjects who enter later in the enrollment period. If there is a trend toward better survival over time then longer survivors experience shorter censoring times (heavier censoring). In such a case, the censoring and survival times are correlated, and thus the censoring is nonignorable in the sense that standard survival models that assume independent censoring could yield incorrect inferences. We will demonstrate a graphical method for analyzing sensitivity of estimates of survival model parameters to small departures from nonignorable censoring., Methods: We assume a parametric model of survival together with a scaled beta model for the censoring process that incorporates the dependence of censoring time on survival time. We assess sensitivity using an index of local sensitivity to nonignorability (Troxel et al.). High sensitivity indicates a large impact of nonignorable censoring on the parameter of interest and a need for additional modeling., Results: A simulation study shows that the approach is valid for practical use. We apply our method to a clinical trial evaluating the survival benefit of a surgically implanted left ventricular assist device in subjects with end-stage heart failure. Sensitivity is somewhat larger in estimates of the mean survival in the device arm, where survival is better and the fraction censored is therefore larger. The degree of nonignorability required to substantially affect estimates is larger than seems plausible, however., Conclusions: Our results illustrate how one can apply sensitivity analysis to evaluate the reliability of survival parameter estimates in a clinical trial.

Background: Cervical carcinoma is a common malignancy among women worldwide, and its pathogenesis is related causally to human papillomavirus infection. The progression from precursor squamous intraepithelial lesions to cervical carcinoma requires additional genetic and epigenetic alterations that have not been characterized fully. The authors examined aberrant promoter methylation of multiple tumor suppressor genes in precursor squamous intraepithelial lesions., Methods: A multiplex, nested, methylation-specific polymerase chain reaction approach was used to examine promoter methylation of 15 tumor suppressor genes in high-grade squamous intraepithelial lesions (HSIL, n = 11), low-grade squamous intraepithelial lesions (LSIL, n = 17), and negative tissues (n = 11) from liquid-based cytology samples. The area under the receiver-operating characteristic (ROC) curve was determined for individual methylated tumor suppressor genes and for gene combinations to evaluate test performance for the ability of methylation profiles to distinguish HSIL cytology samples from combined LSIL/negative cytology samples., Results: Aberrant promoter methylation of DAPK1 and IGSF4 occurred at a high frequency in HSIL samples and was absent in LSIL and negative samples. There was a significant trend toward increased methylation with the increased severity of lesions, and the mean number of methylated genes was significantly higher in HSIL samples compared with LSIL and negative samples. Using the area under the ROC curve as a measure of test performance, the methylation of IGSF4 and DAPK1 had areas that were significantly greater than 0.5; thus, each had the ability to distinguish HSIL samples from combined LSIL/negative samples. The areas under the curve for the best two-gene combination (IGSF4/DAPK1) and the best three-gene combination (IGSF4/DAPK1/HIC1) were not statistically different from the best individual tumor suppressor gene (IGSF4) in distinguishing HSIL samples from combined LSIL/negative samples., Conclusions: Aberrant promoter methylation of tumor suppressor genes is an epigenetic alteration that occurs during neoplastic progression to cervical carcinoma. The methylation status of multiple tumor suppressor genes can be evaluated using ROC analysis to determine methylation profiles that can distinguish HSIL samples from combined LSIL/negative samples.

We describe a Bayesian methodology for estimating the cost-effectiveness of a new treatment compared to a standard in a clinical trial, when censoring of survival, the effectiveness variable, induces censoring of total cost. The statistical model assumes that survival follows a Weibull distribution and that total health care cost follows a gamma distribution whose mean has a linear regression on survival time. We summarize the posterior distributions of key parameters by importance sampling. We illustrate the method with an analysis of data from a randomized clinical trial of a treatment for cardiovascular disease., (Copyright 2004 John Wiley & Sons, Ltd.)

Background: Perfusate acidification with dilute hydrochloric acid augments tumor response rates in a rodent model of isolated limb perfusion (ILP). This study investigates the combination of metaiodobenzylguanidine (MIBG), a mitochondrial inhibitor, and systemic hyperglycemia as a strategy to selectively acidify tumors and thereby sensitize them to ILP., Methods: Human melanoma xenografts were implanted into the hind limbs of athymic rats. When tumors reached 12 to 15 mm in diameter, animals were randomized to ILP with or without melphalan, with or without systemic MIBG, and hyperglycemia of 485 +/- 35 mg/dL. Intratumoral pH was measured during MIBG and glucose treatment by using magnetic resonance spectroscopy., Results: MIBG at 30 mg/kg plus hyperglycemia decreased intracellular pH by.6 units and extracellular pH by.8 units. MIBG at 22.5 mg/kg plus hyperglycemia decreased intracellular and extracellular pH by.4 and.5 units, respectively. Tumor growth was unaffected by systemic MIBG and hyperglycemia alone. When MIBG at 30 mg/kg and hyperglycemia were combined with ILP, tumor growth was delayed for 33 days after control ILP and for 44 days after melphalan ILP. However, this dose of MIBG was complicated by a 40% mortality rate after ILP. MIBG at 22.5 mg/kg, in combination with MIBG in the perfusate, did not cause mortality and delayed tumor growth by 51 days after melphalan ILP., Conclusions: MIBG and hyperglycemia improve tumor response rates after ILP in a rodent model of human melanoma. Selective tumor acidification with MIBG and hyperglycemia may offer added benefit to current regional perfusion strategies.

In many clinical trials it is possible for some subjects to cross over between treatment arms. One can evaluate the effect of crossover by modeling it as a missing-data problem, where for subjects who cross over, one treats the unobserved value of the outcome in the original randomization arm as the missing data. The as-treated analysis is invalid if the crossover is nonignorable, in the sense that the crossovers represent a nonrandom sample of the randomized subjects. A recent area of general interest is the development of methods for measuring the sensitivity of inferences to nonignorability in the missing-data mechanism; one such approach is that of Troxel et al. In this paper we apply their method to the problem of measuring sensitivity to nonignorable crossover in randomized trials, extending it to the case where the crossover mechanism may differ between arms. Our method allows us to identify circumstances under which the as-treated analysis may be more or less sensitive to nonignorable crossover. We illustrate it with the example of a randomized clinical trial (RCT) in multiple sclerosis and a study of the effect of military service on income.

We describe a method for estimating the cost-effectiveness of a new treatment compared to a standard, using data from a comparative clinical trial. We quantify the clinical effectiveness as a binary variable indicating success or failure. The underlying statistical model assumes that costs are uncensored and follow separate gamma distributions in each of the groups defined by the four possible combinations of treatment arm and effectiveness outcome. The method is subjectivist, in that it represents prior uncertainty about model parameters with a probability distribution, which we update via Bayes's theorem to produce a posterior distribution. We approximate the posterior by importance sampling, a straightforward simulation method. We illustrate the method with an analysis of cost (derived from resource usage data) and effectiveness (measured by one-year survival) in a clinical trial in heart disease. The example demonstrates that the method is practical and provides for a flexible data analysis., (Copyright 2003 John Wiley & Sons, Ltd.)

In clinical trials with planned interim analysis, it can be valuable for logistical reasons to predict the times of landmark events such as the 50th and 100th event. Bagiella and Heitjan (Stat Med 2001; 20: 2055-63) proposed a parametric prediction model for failure-time outcomes assuming exponential survival and Poisson enrollment. When little is known about the distributions of interest, there is concern that parametric prediction methods may be biased and inefficient if their underlying distributional assumptions are invalid. We propose nonparametric approaches to make point and interval predictions for landmark dates during the course of the trial. We obtain point predictions using the Kaplan-Meier estimator to extrapolate the survival probability into the future, selecting the time when the expected number of events is equal to the landmark number. To construct prediction intervals, we use a simulation strategy based on the Bayesian bootstrap. Monte Carlo results demonstrate the superiority of the nonparametric method when the assumptions underlying the parametric model are incorrect. We demonstrate the methods using data from a trial of immunotherapy of chronic granulomatous disease.

Purpose: Combined adjuvant fluorouracil (5-FU)-based chemotherapy with radiation is now the standard of care for locally advanced rectal cancer in the United States. We investigated the use of these treatments for stages II and III rectal cancer among the elderly and the effectiveness of these treatments on a population-based scale., Patients and Methods: The linked Surveillance, Epidemiology, and End-Results-Medicare database was used to identify 1,807 Medicare beneficiaries > or = 65 years of age with stage II or III rectal cancer who underwent surgical resection between 1992 and 1996. We excluded members of a health maintenance organization in the 12 months before or 4 months after their diagnosis and those who died within 4 months of diagnosis. We used multivariate analysis to identify factors associated with combined 5-FU and radiation therapy, and propensity score methodology to determine survival benefit for those treated., Results: We found that 37% of patients received both adjuvant 5-FU and radiation therapy, 11% 5-FU alone, and 14% radiation alone. Decreasing age, increasing lymph node positivity, comorbid conditions, and nonblack race were associated with increased probability of treatment with 5-FU and radiation. Combined chemotherapy/radiation therapy was associated with improved survival for stage III (relative risk, 0.71; 95% confidence interval, 0.56 to 0.90), but not for stage II rectal cancer (relative risk, 0.89; 95% confidence interval, 0.70 to 1.14)., Conclusion: The association of combined treatment with improved survival in node-positive disease was similar to that observed in other studies. In the absence of data from well-designed randomized controlled trials, our observational data support efforts on the part of clinicians to make appropriate referrals and provide combined treatment for elderly patients with stage III rectal cancer.

Purpose: This study updates findings regarding the effects of prophylactic surgery, chemoprevention, and surveillance on the survival and quality-adjusted survival of women who test positive for BRCA1/2 mutations., Materials and Methods: Markov modeling of outcomes was performed in a simulated cohort of 30-year-old women who tested positive for BRCA1/2 mutations. The model incorporated breast and ovarian cancer incidence rates from the literature and mortality rates from the Surveillance, Epidemiology, and End Results Program. Quality adjustment of survival estimates were obtained from a survey of women aged 33 to 50 years. Sensitivity analyses were performed of varied assumptions regarding timing and effects of preventive measures on cancer incidence and adverse effects., Results: A 30-year-old woman could prolong her survival beyond that associated with surveillance alone by use of preventive measures: 1.8 years with tamoxifen, 2.6 years with prophylactic oophorectomy, 4.6 years with both tamoxifen and prophylactic oophorectomy, 3.5 years with prophylactic mastectomy, and 4.9 years with both surgeries. She could prolong her quality-adjusted survival by 2.8 years with tamoxifen, 4.4 years with prophylactic oophorectomy, 6.3 years with tamoxifen and oophorectomy, and 2.6 years with mastectomy, or with both surgeries. The benefits of all of these strategies would decrease if they were initiated at later ages., Conclusion: Women who test positive for BRCA1/2 mutations may derive greater survival and quality adjusted survival benefits than previously reported from chemoprevention, prophylactic surgery, or a combination. Observational studies and clinical trials are needed to verify the results of this analysis of the long-term benefits of preventive strategies among BRCA1/2-positive women.

In medical informatics research, study questions frequently involve individuals who are grouped into clusters. For example, an intervention may be aimed at a clinician (who treats a cluster of patients) with the intention of improving the health of individual patients. Correlation among individuals within a cluster can lead to incorrect estimates of the sample size required to detect an effect and inappropriate estimates of the confidence intervals and the statistical significance of the intervention effects. Contamination, which is the spread of the effect of an intervention or control treatment to the opposite group, often occurs between individuals within clusters. It leads to an attenuation of the effect of the intervention and reduced power to detect a difference. If individuals are randomized in a clinical trial (individual-randomized trial), then correlation must be taken into account in the analysis, and the sample size may need to be increased to compensate for contamination. Randomizing clusters rather than individuals (cluster-randomized trials) can eliminate contamination and may be preferred for logistical reasons. Cluster-randomized trials are generally less efficient than individual-randomized trials, so the tradeoffs must be assessed. Correlation must be taken into account in the analysis and in the sample-size calculations for cluster-randomized trials.

Agreement measures are used frequently in reliability studies that involve categorical data. Simple measures like observed agreement and specific agreement can reveal a good deal about the sample. Chance-corrected agreement in the form of the kappa statistic is used frequently based on its correspondence to an intraclass correlation coefficient and the ease of calculating it, but its magnitude depends on the tasks and categories in the experiment. It is helpful to separate the components of disagreement when the goal is to improve the reliability of an instrument or of the raters. Approaches based on modeling the decision making process can be helpful here, including tetrachoric correlation, polychoric correlation, latent trait models, and latent class models. Decision making models can also be used to better understand the behavior of different agreement metrics. For example, if the observed prevalence of responses in one of two available categories is low, then there is insufficient information in the sample to judge raters' ability to discriminate cases, and kappa may underestimate the true agreement and observed agreement may overestimate it.

Background: Randomized clinical trials have demonstrated the efficacy of adjuvant 5-fluorouracil (5-FU)-based chemotherapy after surgical resection of node-positive colon cancer. Although this treatment became the standard in 1990 following a National Institutes of Health Consensus Conference, among those at least 65 years of age it is less likely to be offered to older or nonwhite patients., Objective: To determine the association between 5-fu-based chemotherapy and survival in older patients., Design: Retrospective cohort study., Setting: Combined database of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program and Medicare., Patients: 4768 patients 65 years of age or older who received a diagnosis of node-positive colon cancer from 1992 to 1996, were covered by Medicare Parts A and B, and resided in the population covered by the SEER program., Measurements: Propensity scores to control for known predictors of receiving treatment, Cox proportional hazards models to assess the association of 5-FU therapy with survival, and sensitivity analyses to estimate the possible effects of unknown confounders., Results: Fifty-two percent of patients received 5-FU therapy. For this sample, the hazard ratio for death associated with 5-FU therapy was 0.66 (95% CI, 0.60 to 0.73). Confounding could have accounted for this association only if an unmeasured confounder were extremely unequally distributed between the treated and untreated groups or increased mortality by at least 50%., Conclusions: 5-Fluorouracil adjuvant therapy is significantly associated with reduced mortality in older patients, similar to the association found in randomized, controlled trials among younger patients. More frequent use of 5-FU therapy in older patients would probably reduce death from colon cancer.

Purpose: To estimate the effects on survival, quality-adjusted survival, and health care costs of using tamoxifen for primary prevention in subgroups of women at very high risk for breast cancer., Patients and Methods: A decision analysis was performed using a hypothetical cohort of women that included subgroups with atypical hyperplasia, Gail risk greater than 5, lobular carcinoma-in-situ, or two or more first-degree relatives with breast cancer. Data sources were the Breast Cancer Prevention Trial, the Surveillance, Epidemiology, and End-Results program, time trade-off preference ratings, the Group Health Cooperative of Puget Sound, and the United States Health Care Financing Administration., Results: Our model predicted that tamoxifen would prolong the average survival of cohort members initiating use at ages 35, 50, and 60 years by 70, 42, and 27 days, respectively. It would prolong survival even more for those in the higher-risk groups, especially those with atypical hyperplasia (202, 89, and 45 days). Tamoxifen use was also projected to extend quality-adjusted survival by 158, 80, and 50 days in the atypical hyperplasia group. For younger women in the highest risk groups, chemoprevention with tamoxifen was estimated to have cost savings or be cost-effective, both with and without quality adjustments., Conclusion: Chemoprevention with tamoxifen may be particularly beneficial to women with atypical hyperplasia, 5-year Gail model risk greater than 5%, lobular carcinoma-in-situ, or two or more first-degree relatives with breast cancer. The benefits may be greater if tamoxifen is initiated before age 50 years rather than after and if the breast cancer risk reduction conferred by tamoxifen lasts longer than 5 years. For women with a very high risk of invasive breast cancer, chemoprevention with tamoxifen seems to be cost-effective.