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1.  A Bayesian approach for unplanned sample sizes in phase II cancer clinical trials 
Phase II cancer clinical trials commonly employ two-stage designs that incorporate a single interim analysis for lack of efficacy and are designed to achieve specified frequentist properties. The requirement to examine the outcome at a prespecified sample size (SS) can be problematic, because the attained SS often differs from the planned SS.
We propose to address unplanned SSs achieved at either stage by means of a Bayesian approach that approximately preserves the original design’s properties.
Our approach translates the rejection rule of the original frequentist design into equivalent statements about the posterior distribution of the response rate and applies this Bayesian criterion to the analysis with any realized SS.
The results demonstrate that our approach approximately maintains operating characteristics of the original frequentist design including type I and type II error rates, probability of early termination, and expected SS under the null hypothesis.
Designs attained under this approach may not satisfy target limits for type I error rate and power.
Our method offers a coherent analysis plan when the attained SS at either stage deviates from that specified in the original design. The price of its flexibility, in terms of erosion of the desired frequentist properties, is modest.
PMCID: PMC4283461  PMID: 22523304
2.  Assessing the fit of parametric cure models 
Biostatistics (Oxford, England)  2012;14(2):340-350.
Survival data can contain an unknown fraction of subjects who are “cured” in the sense of not being at risk of failure. We describe such data with cure-mixture models, which separately model cure status and the hazard of failure among non-cured subjects. No diagnostic currently exists for evaluating the fit of such models; the popular Schoenfeld residual (Schoenfeld, 1982. Partial residuals for the proportional hazards regression-model. Biometrika 69, 239–241) is not applicable to data with cures. In this article, we propose a pseudo-residual, modeled on Schoenfeld's, to assess the fit of the survival regression in the non-cured fraction. Unlike Schoenfeld's approach, which tests the validity of the proportional hazards (PH) assumption, our method uses the full hazard and is thus also applicable to non-PH models. We derive the asymptotic distribution of the residuals and evaluate their performance by simulation in a range of parametric models. We apply our approach to data from a smoking cessation drug trial.
PMCID: PMC3695652  PMID: 23197383
Accelerated failure time; Long-term survivors; Proportional hazards; Residual analysis
3.  An Active Learning Approach for Rapid Characterization of Endothelial Cells in Human Tumors 
PLoS ONE  2014;9(3):e90495.
Currently, no available pathological or molecular measures of tumor angiogenesis predict response to antiangiogenic therapies used in clinical practice. Recognizing that tumor endothelial cells (EC) and EC activation and survival signaling are the direct targets of these therapies, we sought to develop an automated platform for quantifying activity of critical signaling pathways and other biological events in EC of patient tumors by histopathology. Computer image analysis of EC in highly heterogeneous human tumors by a statistical classifier trained using examples selected by human experts performed poorly due to subjectivity and selection bias. We hypothesized that the analysis can be optimized by a more active process to aid experts in identifying informative training examples. To test this hypothesis, we incorporated a novel active learning (AL) algorithm into FARSIGHT image analysis software that aids the expert by seeking out informative examples for the operator to label. The resulting FARSIGHT-AL system identified EC with specificity and sensitivity consistently greater than 0.9 and outperformed traditional supervised classification algorithms. The system modeled individual operator preferences and generated reproducible results. Using the results of EC classification, we also quantified proliferation (Ki67) and activity in important signal transduction pathways (MAP kinase, STAT3) in immunostained human clear cell renal cell carcinoma and other tumors. FARSIGHT-AL enables characterization of EC in conventionally preserved human tumors in a more automated process suitable for testing and validating in clinical trials. The results of our study support a unique opportunity for quantifying angiogenesis in a manner that can now be tested for its ability to identify novel predictive and response biomarkers.
PMCID: PMC3946171  PMID: 24603893
The annals of applied statistics  2013;7(4):2062-2080.
Estimates of the effects of treatment on cost from observational studies are subject to bias if there are unmeasured confounders. It is therefore advisable in practice to assess the potential magnitude of such biases. We derive a general adjustment formula for loglinear models of mean cost and explore special cases under plausible assumptions about the distribution of the unmeasured confounder. We assess the performance of the adjustment by simulation, in particular, examining robustness to a key assumption of conditional independence between the unmeasured and measured covariates given the treatment indicator. We apply our method to SEER-Medicare cost data for a stage II/III muscle-invasive bladder cancer cohort. We evaluate the costs for radical cystectomy vs. combined radiation/chemotherapy, and find that the significance of the treatment effect is sensitive to plausible unmeasured Bernoulli, Poisson and Gamma confounders.
PMCID: PMC3935434  PMID: 24587844
Sensitivity analysis; censored costs; SEER-Medicare
5.  Truth and Memory: Linking Instantaneous and Retrospective Self-Reported Cigarette Consumption 
The annals of applied statistics  2012;6(4):1689-1706.
Studies of smoking behavior commonly use the time-line follow-back (TLFB) method, or periodic retrospective recall, to gather data on daily cigarette consumption. TLFB is considered adequate for identifying periods of abstinence and lapse but not for measurement of daily cigarette consumption, thanks to substantial recall and digit preference biases. With the development of the hand-held electronic diary (ED), it has become possible to collect cigarette consumption data using ecological momentary assessment (EMA), or the instantaneous recording of each cigarette as it is smoked. EMA data, because they do not rely on retrospective recall, are thought to more accurately measure cigarette consumption. In this article we present an analysis of consumption data collected simultaneously by both methods from 236 active smokers in the pre-quit phase of a smoking cessation study. We define a statistical model that describes the genesis of the TLFB records as a two-stage process of mis-remembering and rounding, including fixed and random effects at each stage. We use Bayesian methods to estimate the model, and we evaluate its adequacy by studying histograms of imputed values of the latent remembered cigarette count. Our analysis suggests that both mis-remembering and heaping contribute substantially to the distortion of self-reported cigarette counts. Higher nicotine dependence, white ethnicity and male sex are associated with greater remembered smoking given the EMA count. The model is potentially useful in other applications where it is desirable to understand the process by which subjects remember and report true observations.
PMCID: PMC3889075  PMID: 24432181
Bayesian analysis; heaping; latent variables; longitudinal data; smoking cessation
6.  31P and 1H MRS of DB-1 Melanoma Xenografts: Lonidamine Selectively Decreases Tumor Intracellular pH and Energy Status and Sensitizes Tumors to Melphalan 
NMR in biomedicine  2012;26(1):98-105.
In vivo 31P MRS demonstrates that human melanoma xenografts in immunosuppressed mice treated with lonidamine (LND, 100 mg/kg, i.p.) exhibit a decrease in intracellular pH (pHi) from 6.90 ± 0.05 to 6.33 ± 0.10 (p < 0.001), a slight decrease in extracellular pH (pHe) from 7.00 ± 0.04 to 6.80 ± 0.07 (p > 0.05), and a monotonic decline in bioenergetics (NTP/Pi) by 66.8 ± 5.7% (p < 0.001) relative to the baseline level. Both bioenergetics and pHi decreases were sustained for at least 3 hr following LND treatment. Liver exhibited a transient intracellular acidification by 0.2 ± 0.1 pH units (p > 0.05) at 20 min post-LND with no significant change in pHe and a small transient decrease in bioenergetics, 32.9 ± 10.6 % (p > 0.05), at 40 min post-LND. No changes in pHi or ATP/Pi were detected in the brain (pHi, bioenergetics; p > 0.1) or skeletal muscle (pHi, pHe, bioenergetics; p > 0.1) for at least 120 min post-LND. Steady-state tumor lactate monitored by 1H MRS with a selective multiquantum pulse sequence with Hadamard localization increased ~3-fold (p = 0.009). Treatment with LND increased systemic melanoma response to melphalan (LPAM; 7.5 mg/kg, i.v.) producing a growth delay of 19.9 ± 2.0 d (tumor doubling time = 6.15 ± 0.31d, log10 cell-kill = 0.975 ± 0.110, cell-kill = 89.4 ± 2.2%) compared to LND alone of 1.1 ± 0.1 d and LPAM alone of 4.0 ± 0.0 d. The study demonstrates that the effects of LND on tumor pHi and bioenergetics may sensitize melanoma to pH-dependent therapeutics such as chemotherapy with alkylating agents or hyperthermia.
PMCID: PMC3465621  PMID: 22745015
Phosphorus-31 MRS; Lonidamine; Monocarboxylate transporter; Tumor acidification; Melphalan; Melanoma
7.  Sensitivity of the discrete-time Kaplan-Meier estimate to nonignorable censoring: Application in a clinical trial 
Statistics in medicine  2012;31(25):10.1002/sim.5454.
Untestable assumptions about association between survival and censoring times can affect the validity of estimates of the survival distribution, including the Kaplan-Meier (KM) nonparametric MLE. This article explores the sensitivity of the KM curve to nonignorable censoring by extending the index of local sensitivity to nonignorability (ISNI) (Troxel et al. 2004, Zhang and Heitjan 2006) to the case of a nonparametric survival model. The method involves first specifying a coarse-data selection model to describe the association between the failure and censoring processes, then evaluating the slope of the nonparametric survival MLE ordinate with respect to a nonignorability parameter in the neighborhood of the ignorable model. We define the nonparametric MLE of the survival curve for a fixed value of the nonignorability parameter, and show in a simulation that ISNI analysis effectively captures local sensitivity to nonignorability. The method measures sensitivity in the sense of identifying functionals of the nonparametric MLE that nonignorability, if present, can affect substantially. We demonstrate the method with an application to a trial comparing mechanical assistance to optimal medical management in the treatment of end-stage heart failure.
PMCID: PMC3876928  PMID: 22806989
Coarse-data model; ignorability; informative censoring; ISNI; sensitivity analysis
8.  Efficacy of Extended Duration Transdermal Nicotine Therapy: A Randomized Trial 
Annals of internal medicine  2010;152(3):144-151.
Background: Tobacco dependence is a chronic, relapsing condition that may require extended treatment.
Objective: To assess whether extended 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 (small block randomization scheme, not stratified). Study participants and all research personnel except for the database manager were blinded to randomization. (NCT00364156)
Setting: Academic center.
Participants: 568 adult smokers.
Intervention: Participants were randomized to: standard (8 weeks 21mg Nicoderm CQ, 16 weeks placebo) or extended (24 weeks 21mg Nicoderm CQ) therapy.
Measurements: The primary outcome was biochemically-verified point prevalence abstinence at weeks 24 and 52. Secondary outcomes were continuous and prolonged abstinence, lapse and recovery events, cost/additional quitter, and side effects and adherence.
Results: At 24 weeks, extended therapy produced higher rates of point prevalence abstinence (31.6% versus 20.3%; Odds Ratio [OR] = 1.81 [1.23-2.66], p = 0.002), prolonged abstinence (41.5% versus 26.9%; OR = 1.97 [1.38-2.82] p = 0.001), and continuous abstinence (19.2% versus 12.6%; OR = 1.64 [1.04-2.60] p = 0.032), versus standard therapy. Extended therapy reduced the risk for a lapse (Hazard Ratio [HR] = 0.77 [0.63-0.95], p = 0.013) and increased the chances of recovery from lapses (HR = 1.47 [1.17-1.84], p = 0.001). Time to relapse was slower with extended versus standard therapy (HR = 0.50 [0.35-0.73], p < 0.001). At week 52, extended therapy produced higher quit rates for prolonged abstinence only (p = 0.027). There were no group differences in side effects and adverse events at the extended treatment phase assessment.
Limitations: The generalizability of the findings may be limited because participants were treatment-seeking smokers without medical comorbidity and differences in adherence across treatment arms were detected.
Conclusion: Compared to 8 weeks of transdermal nicotine, 24 weeks of transdermal nicotine increased biochemically-confirmed point prevalence abstinence and continuous abstinence at week 24, reduced the risk of smoking lapses, and increased the likelihood of post-lapse recovery to abstinence.
PMCID: PMC3782858  PMID: 20124230
9.  Immunological effects of the TGFβ-blocking antibody GC1008 in malignant pleural mesothelioma patients 
Oncoimmunology  2013;2(8):e26218.
We evaluated a neutralizing anti-TGFβ antibody (GC1008) in cancer patients with malignant pleura mesothelioma (MPM). The goal of this study was to assess immunoregulatory effects in relation to clinical safety and clinical response. Patients with progressive MPM and 1–2 prior systemic therapies received GC1008 at 3mg/kg IV over 90 min every 21 d as part of an open-label, two-center Phase II trial. Following TGFβ blockade therapy, clinical safety and patient survival were monitored along with the effects of anti-TGFβ antibodies on serum biomarkers and peripheral blood mononuclear cells (PBMC). Although designed as a larger trial, only 13 patients were enrolled when the manufacturer discontinued further development of the antibody for oncology indications. All participants tolerated therapy. Although partial or complete radiographic responses were not observed, three patients showed stable disease at 3 mo. GC1008 had no effect in the expression of NK, CD4+, or CD8+ T cell activating and inhibitory markers, other than a decrease in the expression of 2B4 and DNAM-1 on NK cells. However, serum from 5 patients showed new or enhanced levels of antibodies against MPM tumor lysates as measured by immunoblotting. Patients who produced anti-tumor antibodies had increased median overall survival (OS) (15 vs 7.5 mo, p < 0.03) compared with those who did not. To our knowledge, these data represent the first immune analysis of TGFβ- blockade in human cancer patients.
PMCID: PMC3812201  PMID: 24179709
GC1008; anti-TGFβ antibody; antibody therapy; clinical trial; immunotherapy; malignant mesothelioma
10.  Reproducibility of the Nicotine Metabolite Ratio in Cigarette Smokers 
The nicotine metabolite ratio (NMR or 3-hydroxycotinine/cotinine) has been used to phenotype CYP2A6-mediated nicotine metabolism. Our objectives were to analyze (a) the stability of NMR in plasma, saliva, and blood in various storage conditions, (b) the relationship between NMRs derived from blood, plasma, saliva, and urine, and (c) the reproducibility of plasma NMR in ad libitum cigarette smokers.
We analyzed data from four clinical studies. In studies 1 and 2, we assessed NMR stability in saliva and plasma samples at room temperature (~22°C) over 14 days and in blood at 4°C for up to 72 hours. In studies 2 and 3, we used Bland-Altman analysis to assess agreement between blood, plasma, saliva, and urine NMRs. In study 4, plasma NMR was measured on 6 occasions over 44 weeks in 43 ad libitum smokers.
Reliability coefficients for stability tests of NMR in plasma and saliva at room temperature were 0.97 and 0.98, respectively, and 0.92 for blood at 4°C. Blood NMR agreed consistently with saliva and plasma NMRs but showed more variability in relation to urine NMR. The reliability coefficient for repeated plasma NMR measurements in smokers was 0.85.
The NMR is stable in blood, plasma, and saliva at the conditions tested. Blood, plasma, and saliva NMRs are similar while urine NMR is a good proxy for these NMR measures. Plasma NMR was reproducible over time in smokers.
One measurement may reliably estimate a smoker’s NMR for use as an estimate of the rate of nicotine metabolism.
PMCID: PMC3392523  PMID: 22552800
Nicotine metabolite ratio (NMR); cotinine; 3-hydroxycotinine; biological stability; chemical stability
11.  Comparative effectiveness of screening and prevention strategies among BRCA1/2-affected mutation carriers 
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.
PMCID: PMC3615889  PMID: 20644999
Comparative effectiveness; Cost-effectiveness; Mastectomy; Oophorectomy or both; Tamoxifen; Screening with MRI and mammography; BRCA1/BRCA2
12.  Blockade of Lymphocyte Chemotaxis in Visceral Graft-versus-Host Disease 
The New England journal of medicine  2012;367(2):135-145.
Graft-versus-host disease (GVHD) is a major barrier to successful allogeneic hematopoietic stem-cell transplantation (HSCT). The chemokine receptor CCR5 appears to play a role in alloreactivity. We tested whether CCR5 blockade would be safe and limit GVHD in humans.
We tested the in vitro effect of the CCR5 antagonist maraviroc on lymphocyte function and chemotaxis. We then enrolled 38 high-risk patients in a single-group phase 1 and 2 study of reduced-intensity allogeneic HSCT that combined maraviroc with standard GVHD prophylaxis.
Maraviroc inhibited CCR5 internalization and lymphocyte chemotaxis in vitro without impairing T-cell function or formation of hematopoietic-cell colonies. In 35 patients who could be evaluated, the cumulative incidence rate (±SE) of grade II to IV acute GVHD was low at 14.7±6.2% on day 100 and 23.6±7.4% on day 180. Acute liver and gut GVHD were not observed before day 100 and remained uncommon before day 180, resulting in a low cumulative incidence of grade III or IV GVHD on day 180 (5.9±4.1%). The 1-year rate of death that was not preceded by disease relapse was 11.7±5.6% without excessive rates of relapse or infection. Serum from patients receiving maraviroc prevented CCR5 internalization by CCL5 and blocked T-cell chemotaxis in vitro, providing evidence of antichemotactic activity.
In this study, inhibition of lymphocyte trafficking was a specific and potentially effective new strategy to prevent visceral acute GVHD. (Funded by Pfizer and others; number, NCT00948753.)
PMCID: PMC3568501  PMID: 22784116
13.  A Trial of Intrapleural Adenoviral-mediated Interferon-α2b Gene Transfer for Malignant Pleural Mesothelioma 
New therapeutic strategies are needed for malignant pleural mesothelioma (MPM). We conducted a single-center, open-label, nonrandomized, pilot and feasibility trial using two intrapleural doses of an adenoviral vector encoding human IFN-α (Ad.IFN-α2b). Nine subjects were enrolled at two dose levels. The first three subjects had very high pleural and systemic IFN-α concentrations resulting in severe “flu-like” symptoms necessitating dose de-escalation. The next six patients had reduced (but still significant) pleural and serum IFN-α levels, but with tolerable symptoms. Repeated vector administration appeared to prolong IFN-α expression levels. Anti-tumor humoral immune responses against mesothelioma cell lines were seen in seven of the eight subjects evaluated. No clinical responses were seen in the four subjects with advanced disease. However, evidence of disease stability or tumor regression was seen in the remaining five patients, including one dramatic example of partial tumor regression at sites not in contiguity with vector infusion. These data show that Ad.IFN-α2b has potential therapeutic benefit in MPM and that it generates anti-tumor immune responses that may induce anatomic and/or metabolic reductions in distant tumor.
Clinical trial registered with (NCT 01212367).
PMCID: PMC3262033  PMID: 21642245
clinical trials; immunotherapy; gene therapy
Obesity has implications for chemotherapy dosing and selection of patients for therapy. Autologous hematopoietic stem cell transplant (AutoHCT) improves outcomes for patients with multiple myeloma, but optimal chemotherapy dosing for obese patients is poorly defined. We analyzed the outcomes of 1087 recipients of AutoHCT for myeloma reported to the CIBMTR between 1995 and 2003 receiving high-dose melphalan conditioning, with or without total body irradiation (TBI). We categorized patients by body mass index (BMI) as normal, overweight, obese, or severely obese. There was no overall effect of BMI on progression-free survival (PFS), overall survival (OS), progression, or non-relapse mortality (NRM). In patients receiving melphalan and TBI conditioning, obese and severely obese patients had superior PFS and OS compared with normal and overweight patients, but the clinical significance of this finding is unclear. More obese patients were more likely to receive a reduced dose of melphalan, but there was no evidence that melphalan or TBI dosing variability affected PFS.
Therefore, current common strategies of dosing melphalan do not impair outcomes for obese patients, and obesity should not exclude patients from consideration of autologous transplantation. Further research is necessary to optimize dosing of both chemotherapy and radiation in obese patients.
PMCID: PMC3175301  PMID: 21624486
obesity; myeloma; autologous transplantation; chemotherapy; radiation therapy; melphalan
15.  Statistical Analysis of Daily Smoking Status in Smoking Cessation Clinical Trials 
Addiction (Abingdon, England)  2011;106(11):2039-2046.
Smoking cessation trials generally record information on daily smoking behavior, but base analyses on measures of smoking status at the end of treatment (EOT). We present an alternative approach that analyzes the entire sequence of daily smoking status observations.
We analyzed daily abstinence data from a smoking cessation trial, using two longitudinal logistic regression methods: A mixed-effects (ME) model and a generalized estimating equations (GEE) model. We compared results to a standard analysis that takes as outcome abstinence status at EOT. We evaluated time-varying covariates (smoking history and time-varying drug effect) in the longitudinal analysis and compared ME and GEE approaches.
We observed some differences in the estimated treatment effect odds ratios across models, with narrower confidence intervals under the longitudinal models. GEE yields similar results to ME when only baseline factors appear in the model, but gives biased results when one includes time-varying covariates. The longitudinal models indicate that the quit probability declines and the drug effect varies over time. Both the previous day’s smoking status and recent smoking history predict quit probability, independently of the drug effect.
When analysing outcomes of studies from smoking cessation interventions, longitudinal models with multiple outcome data points, rather than just end of treatment, can makes efficient use of the data and incorporate time-varying covariates. The generalized estimating equations approach should be avoided when using time-varying predictors.
PMCID: PMC3197211  PMID: 21631623
Generalized estimating equations; longitudinal analysis; mixed-effects model
16.  Incomplete Data: What You Don't Know Might Hurt You 
Molecular epidemiology studies commonly exhibit missing observations. Methods for extracting correct and efficient analyses from incomplete data are well known in statistics, but relatively few such methods have diffused into applications. I review some areas of incomplete-data research that are relevant to molecular epidemiology, and appeal for greater efforts by statisticians to translate their methods into practice.
PMCID: PMC3153574  PMID: 21750173
17.  Biology, Models and the Analysis of Tumor Xenograft Experiments 
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 inter-tumor heterogeneity and the development of robust statistical models that describe key parameters in the underlying tumor biology.
PMCID: PMC3079203  PMID: 21224374
18.  Hyperuricemia and Coronary Heart Disease: A Systematic Review and Meta-Analysis 
Arthritis care & research  2010;62(2):170-180.
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.
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.
26 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 (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 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).
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.
PMCID: PMC3156692  PMID: 20191515
hyperuricemia; coronary heart disease; meta-analysis
19.  Multiplicity-calibrated Bayesian hypothesis tests 
Biostatistics (Oxford, England)  2010;11(3):473-483.
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.
PMCID: PMC2912702  PMID: 20212321
Bayes factor; Bonferroni inequality; Frequentist calibration; Multiplicity
20.  Dietary flaxseed administered post thoracic radiation treatment improves survival and mitigates radiation-induced pneumonopathy in mice 
BMC Cancer  2011;11:269.
Flaxseed (FS) is a dietary supplement known for its antioxidant and anti-inflammatory properties. Radiation exposure of lung tissues occurs either when given therapeutically to treat intrathoracic malignancies or incidentally, such as in the case of exposure from inhaled radioisotopes released after the detonation of a radiological dispersion devise (RDD). Such exposure is associated with pulmonary inflammation, oxidative tissue damage and irreversible lung fibrosis. We previously reported that dietary FS prevents pneumonopathy in a rodent model of thoracic X-ray radiation therapy (XRT). However, flaxseed's therapeutic usefulness in mitigating radiation effects post-exposure has never been evaluated.
We evaluated the effects of a 10%FS or isocaloric control diet given to mice (C57/BL6) in 2 separate experiments (n = 15-25 mice/group) on 0, 2, 4, 6 weeks post a single dose 13.5 Gy thoracic XRT and compared it to an established radiation-protective diet given preventively, starting at 3 weeks prior to XRT. Lungs were evaluated four months post-XRT for blood oxygenation levels, inflammation and fibrosis.
Irradiated mice fed a 0%FS diet had a 4-month survival rate of 40% as compared to 70-88% survival in irradiated FS-fed mouse groups. Additionally, all irradiated FS-fed mice had decreased fibrosis compared to those fed 0%FS. Lung OH-Proline content ranged from 96.5 ± 7.1 to 110.2 ± 7.7 μg/ml (Mean ± SEM) in all irradiated FS-fed mouse groups, as compared to 138 ± 10.8 μg/ml for mice on 0%FS. Concomitantly, bronchoalveolar lavage (BAL) protein and weight loss associated with radiation cachexia was significantly decreased in all FS-fed groups. Inflammatory cell influx to lungs also decreased significantly except when FS diet was delayed by 4 and 6 weeks post XRT. All FS-fed mice (irradiated or not), maintained a higher blood oxygenation level as compared to mice on 0%FS. Similarly, multiplex cytokine analysis in the BAL fluid revealed a significant decrease of specific inflammatory cytokines in FS-fed mice.
Dietary FS given post-XRT mitigates radiation effects by decreasing pulmonary fibrosis, inflammation, cytokine secretion and lung damage while enhancing mouse survival. Dietary supplementation of FS may be a useful adjuvant treatment mitigating adverse effects of radiation in individuals exposed to inhaled radioisotopes or incidental radiation.
PMCID: PMC3146937  PMID: 21702963
Flaxseed; radiation pneumonopathy; mitigation; lung fibrosis; antioxidant; flaxseed lignans; SDG; lung injury; ROS; inflammation; bronchoalveolar lavage; survival; cytokines; mouse model
21.  Convergent Evidence that Choline Acetyltransferase Gene Variation is Associated with Prospective Smoking Cessation and Nicotine Dependence 
Neuropsychopharmacology  2010;35(6):1374-1382.
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.
PMCID: PMC2855736  PMID: 20147892
nicotine; smoking cessation; choline acetyltransferase ChAT; pharmacogenetics; addiction; Pharmacogenetics/Pharmacogenomics; Addiction & Substance Abuse; Clinical Pharmacology/Trials; Psychiatry & Behavioral Sciences; Nicotine; Smoking Cessation; choline acetyltransferase ChAT
22.  CCL2 Blockade Augments Cancer Immunotherapy 
Cancer research  2009;70(1):109.
Since an immuno-inhibitory environment exists within tumors, successful vaccines will likely require additional approaches to alter the tumor microenvironment. Monocyte chemoattractant proteins (such as CCL2) are produced by many tumors and have both direct and indirect immuno-inhibitory effects. We hypothesized that CCL2 blockade would reduce immunosuppression and augment vaccine immunotherapy. Anti-murine-CCL2/CCL12 monoclonal antibodies were administered in three immunotherapy models: one aimed at the HPV-E7 antigen expressed by a non-small cell lung cancer line, one targeted to mesothelin expressed by a mesothelioma cell line, and one using an adenovirus expressing Interferon-α to treat a non-immunogenic, non-small cell lung cancer line. We evaluated the effect of the combination treatment on tumor growth and assessed the mechanism of these changes by evaluating cytotoxic T cells, immunosuppressive cells, and the tumor microenvironment. Administration of anti-CCL2/CCL12 antibodies along with the vaccines markedly augmented efficacy with enhanced reduction in tumor volume and cures of approximately half of the tumors. The combined treatment generated more total intra-tumoral CD8+ T-cells that were more activated and more anti-tumor antigen specific, as measured by tetramer evaluation. Another important potential mechanism was reduction in intratumoral T-regulatory (T-reg) cells. CCL2 appears to be a key proximal cytokine mediating immunosuppression in tumors. Its blockade augments CD8+ T cell immune response to tumors elicited by vaccines via multifactorial mechanisms. These observations suggest that combining CCL2 neutralization with vaccines should be considered in future immunotherapy trials.
PMCID: PMC2821565  PMID: 20028856
CCL2; Cancer immunotherapy; Lung Cancer; Mesothelioma; T-lymphocytes
23.  A method comparison study of timeline followback and ecological momentary assessment of daily cigarette consumption 
Nicotine & Tobacco Research  2009;11(11):1368-1373.
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.
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.
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.
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.
PMCID: PMC2762933  PMID: 19808861
24.  Hyperuricemia and Risk of Stroke: A Systematic Review and Meta-analysis 
Arthritis and rheumatism  2009;61(7):885-892.
Hyperuricemia is hypothesized to be a risk factor for stroke and other cardiovascular disease, but to date results from observational studies are conflicting.
We conducted a systematic review and meta-analysis to assess the association between hyperuricemia and risk of stroke incidence and mortality. Studies were identified by searching major electronic databases using the Medical Subject Headings and keywords without restriction in languages. Only prospective cohort studies were included if they had 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.
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 [N=6 studies, RR 1.41, 95% confidence interval (CI): 1.05–1.76] and mortality [N=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, and cholesterol still showed that hyperuricemia was significantly associated with both stroke incidence [N=4 studies, RR 1.47, 95% CI: 1.19–1.76] and mortality [N=6 studies, RR 1.26, 95% CI: 1.12–1.39]. The pooled estimate of multivariate RRs did not differ much by gender.
Our study suggests that 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.
PMCID: PMC2714267  PMID: 19565556
hyperuricemia; stroke; systematic review; meta-analysis
25.  A Placebo-Controlled Trial of Modafinil for Nicotine Dependence 
Drug and alcohol dependence  2008;98(1-2):86-93.
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.
157 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. Secondary outcomes included cigarette smoking rate and post-quit nicotine deprivation symptoms (e.g., negative affect, withdrawal).
In this interim study analysis, end of treatment (EOT) quit rates did not differ between treatment arms (42% for placebo vs. 34% for modafinil; OR = 0.67 [0.34 – 1.31], p = .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 < .01). Modafinil-treated participants also reported greater increases in negative affect and withdrawal symptoms, vs. participants randomized to placebo (ps < .05).
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.
PMCID: PMC2610628  PMID: 18541389
nicotine dependence; smoking cessation; addiction; modafinil

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