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Community detection in large-scale complex networks has recently received significant attention as the volume of available data is becoming larger. The use of evolutionary algorithms (EAs) for community detection in large-scale networks has gained considerable popularity because these algorithms are fairly effective in networks with a relatively small number of nodes. In this paper, we propose a parallel multi-objective EA, called PMOEA, for community detection in large-scale networks, where the communities associated with key network nodes are detected in parallel. Specifically, we develop a multi-objective and a single-objective EA. The former is used to detect the communities of a key node instead of all communities in the network. The latter obtains the communities in the entire network using the previously detected communities of each key node. The performance of the proposed method was verified on both large-scale synthetic benchmark networks and real-world networks. The results demonstrated the superiority of PMOEA over six EA-based and two non-EA-based community-detection algorithms for large-scale networks.

OBJECTIVE: To evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on-the-road driving performance in participants with narcolepsy.METHODS: In this randomised, double-blind, placebo-controlled, crossover study, driving performance during a 1 h on-road driving test was assessed at 2 and 6 h post-dose following 7 days of treatment with solriamfetol (150 mg/day for 3 days, followed by 300 mg/day for 4 days) or placebo. The primary endpoint was standard deviation of lateral position (SDLP) at 2 h post-dose.RESULTS: The study included 24 participants (54% male; mean age, 40 years); 22 had evaluable SDLP data. At 2 h post-dose, median SDLP was significantly lower (improved) with solriamfetol compared with placebo (19.08 vs. 20.46 cm [median difference, -1.9 cm], p = 0.002). Four participants on solriamfetol and 7 on placebo had incomplete driving tests. At 6 h post-dose, median SDLP was not statistically significantly different with solriamfetol compared with placebo (19.59 vs. 19.78 cm [median difference, -1.1 cm], p = 0.125). Three participants on solriamfetol and 10 on placebo had incomplete driving tests. Common adverse events (≥5%) included headache, decreased appetite, and somnolence.CONCLUSIONS: Solriamfetol 300 mg/day improved on-the-road driving performance, at 2 h post-administration in participants with narcolepsy.

Recently, multi-objective evolutionary algorithms (MOEAs) have been shown promising performance for detecting overlapping community structure in complex networks. However, it is still challenging to design MOEAs for overlapping community detection on large-scale complex networks due to the curse of dimensionality. Along this avenue, this paper proposes a local-to-global scheme-based MOEA named LG-MOEA for overlapping community detection on large-scale complex networks, which mainly consists of two stages: a local community structure detection stage and a global community structure determination stage. To be specific, in the local community structure detection stage, the key nodes that are central to community and essential to the connectedness of community are firstly identified. Then for each key node, an MOEA with the proposed community boundary control strategy is suggested to detect a set of local overlapping communities through local expansion around the key node. In the global community structure determination stage, a single objective evolutionary algorithm is adopted to search for a suitable local overlapping community for each key node and combine them as one global community partition of the whole network. The proposed LG-MOEA is compared with several competitive overlapping community detection algorithms on both real-world small-scale and large-scale networks, and the experimental results show its superiority for overlapping community detection in terms of the generalized normalized mutual information gNMI and the extended modularity $$Q_{ov}$$ , especially has competitive superiority for large-scale complex networks.

Background Therapeutic advances have greatly extended survival times in patients with multiple myeloma, necessitating increasingly lengthy trials when using survival outcomes as primary endpoints. A surrogate endpoint that can more rapidly predict survival could accelerate drug development. We conducted a meta-analysis to evaluate minimal residual disease (MRD) status as a valid progression-free survival (PFS) surrogate in patients with newly diagnosed multiple myeloma (NDMM). Materials and Methods We searched abstracts in PubMed, The American Society of Hematology, and the European Hematology Association for “myeloma,” “minimal residual disease,” and “clinical trial.” Because of the need to evaluate the treatment effect on MRD response, only randomized studies for subjects with NDMM were included. Details on the MRD-tested populations were required. The meta-analysis was performed by principles outlined at the 2013 United States Food and Drug Administration workshop on MRD in acute myeloid leukemia. 42 For samples that were not measured for MRD and within the subset specified for MRD assessment, their MRD status was imputed from the samples that had known MRD status. Patients that were excluded from planned MRD assessment were considered MRD-positive. Results Six randomized studies, representing 3283 patients and 2208 MRD samples, met analysis inclusion criteria. MRD negativity rates ranged from 0.06 to 0.70. The treatment effect on the odds ratio for MRD-negative response strongly correlated with the hazard ratio for PFS with a coefficient of determination for the weighted regression line of 0.97. Our meta-analysis suggested that MRD status met both the Prentice criteria for PFS surrogacy. Conclusions These results support the claim that MRD status can be used as a surrogate for PFS in NDMM.

Background: Elevated circulating growth differentiation factor 15 (GDF15) and increased GDF15 expression in tumor tissues has been observed in patients with advanced pancreatic cancer (APC). These changes were correlated with poor survival. Effects of GDF15 on tumor progression, metastasis and immune escape may play a role. NGM120, a novel antibody to GFRAL that blocks the effects of GDF15, has resulted both in antitumor and anti-cachexia effects in experimental models. Here we report updated findings of the ongoing Phase 1b study with NGM120 in patients with APC. Methods: Metastatic pancreatic cancer patients with elevated serum GDF15 were treated with NGM120 (30 or 100 mg, s.c., q4wks) in a 1st line setting in combination with Gem/nab-paclitaxel. Primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetics, preliminary evidence of antitumor activity (RECIST) and anti-cachexia effects. Results: Eight patients received NGM120 in combination with Gem/nab-paclitaxel. Median age was 67 years, all patients had advanced disease. NGM120 was well tolerated with no dose-limiting toxicities. Most of the AEs or SAEs observed were Gem/nab-paclitaxel related and none of them attributed to NGM 120 treatment. As of data cut off on March 25, 2022, preliminary results include 3 patients with PR (extending >32 wks), 3 patients SD; 2 patients discontinued early (before first post-dose scan) due to toxicity attributed to Gem/nab-paclitaxel. Among the 6 evaluable patients, the disease control rate (DCR) is 100%, mPFS has not been reached, 12-month survival rate (12-month OS) is 83.3%. Over the course of the study, 5/6 of the patients gained or maintained their body weight (BW) and 5/6 of the patients gained or maintained their lean body mass (LBM) based on maximum change from baseline. Conclusions: NGM120 given in combination with Gem/nab-paclitaxel to patients with APC resulted in a 50% ORR (3 PR in 6 evaluable patients), 100% DCR, 83.3% 12-month OS and a “not reached” mPFS. Compared to historical Gem/nab-paclitaxel data, these findings are encouraging and support the potential role of NGM120 in the treatment of patients with APC. The positive effects on BW and LBM is also encouraging compared to the historical cachexia rate of 30% observed within 12 weeks of starting first-line chemotherapy in APC. A sign of NGM120 engages the GDF15-GFRAL pathway in managing body weight regulation. A Ph2a study is ongoing to further evaluate NGM120 in combination with Gem/nab-paclitaxel in the 1st line setting for the treatment of APC. Citation Format: Andrew Hendifar, Efrat Dotan, Benjamin Weinberg, Edward Kim, Peter Hosein, Jian Luo, Jiping Zha, Alex DePaoli, Vladimir Hanes, Cecilia Tranmuchowski, Kefei Zhou, Carol Tseng, Hsiao Lieu. Initial results of a cohort of advanced pancreatic cancer patients in a phase 1b Study of NGM120, a first-in-class anti-GDNF Family Receptor Alpha Like (GFRAL) antibody [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR006.

TD-0714 is an orally active, potent, and selective inhibitor of human neprilysin (NEP) in development for the treatment of chronic heart failure. Oral administration of TD-0714 in rats resulted in dose-dependent and sustained increases in plasma cyclic guanosine monophosphate (cGMP) over 24 hours consistent with NEP target engagement. Randomized, double-blind, placebo controlled, single ascending dose (50-600 mg TD-0714) and multiple ascending dose (10-200 mg TD-0714 q.d. for 14 days) studies were conducted in healthy volunteers. TD-0714 was generally well-tolerated and no serious adverse events or clinically significant effects on vital signs or electrocardiogram parameters were observed. TD-0714 exhibited dose-proportional pharmacokinetics (PKs) with high oral bioavailability, minimal accumulation after once daily dosing, and negligible renal elimination. Pharmacodynamic (PD) responses were observed at all dose levels studied, as reflected by statistically significant increases in plasma cGMP concentrations. The increases in cGMP were significantly above the baseline (~ 50-100%) on day 14 for the entire 24-hour interval indicating that sustained cGMP elevations are achieved at steady-state. Maximal steady-state cGMP response was observed in plasma and urine at doses ≥ 50 mg. The TD-0714 PK-PD relationship and safety profile were similar in elderly vs. younger adult subjects. The TD-0714 PK and PD profiles support further clinical development of TD-0714 and suggest the potential for once-daily administration and predictable exposure in patients with cardiorenal diseases regardless of their renal function.

Safety monitoring and reporting has achieved a greater level of attention in the past 15 years. Statisticians play an important role in learning about a drug's safety profile. An ASA safety monitoring working group was established with a goal to empower the biostatistics community to play a proactive role and better enable quantification in safety monitoring. As part of its effort, this article presents a systematic review and unique perspective on the existing methodology developments, which include Bayesian and frequentist, blinded versus unblinded safety monitoring, individual versus aggregate data meta-analyses, pre-, and post-marketing methods, static versus dynamic safety reviews, and methods of visualization. These perspectives may serve as a background for future statistical work, both in methodology development and its application.

In clinical trials, some patient subgroups are likely to demonstrate larger effect sizes than other subgroups. For example, the effect size, or informally the benefit with treatment, is often greater in patients with a moderate condition of a disease than in those with a mild condition. A limitation of the usual method of analysis is that it does not incorporate this ordering of effect size by patient subgroup. We propose a test statistic which supplements the conventional test by including this information and simultaneously tests the null hypothesis in pre-specified subgroups and in the overall sample. It results in more power than the conventional test when the differences in effect sizes across subgroups are at least moderately large; otherwise it loses power. The method involves combining p-values from models fit to pre-specified subgroups and the overall sample in a manner that assigns greater weight to subgroups in which a larger effect size is expected. Results are presented for randomized trials with two and three subgroups.

AIMS AMG 181 pharmacokinetics/pharmacodynamics (PK/PD), safety, tolerability and effects after single subcutaneous (s.c.) or intravenous (i.v.) administration were evaluated in a randomized, double-blind, placebo-controlled study. METHODS Healthy male subjects (n= 68) received a single dose of AMG 181 or placebo at 0.7, 2.1, 7, 21, 70 mg s.c. (or i.v.), 210 mg s.c. (or i.v.), 420 mg i.v. or placebo. Four ulcerative colitis (UC) subjects (n= 4, male : female 2:2) received 210 mg AMG 181 or placebo s.c. (3:1). AMG 181 concentration, anti-AMG 181-antibody (ADA), α4β7 receptor occupancy (RO), target cell counts, serum C-reactive protein, fecal biomarkers and Mayo score were measured. Subjects were followed 3-9 months after dose. RESULTS Following s.c. dosing, AMG 181 was absorbed with a median tmax ranging between 2-10 days and a bioavailability between 82% and 99%. Cmax and AUC increased dose-proportionally and approximately dose-proportionally, respectively, within the 70-210 mg s.c. and 70-420 mg i.v. ranges. The linear β-phase t1/2 was 31 (range 20-48) days. Target-mediated disposition occurred at serum AMG 181 concentrations of less than 1 μgml-1. The PD effect on α4β7 RO showed an EC50 of 0.01 μgml-1. Lymphocytes, eosinophils, CD4+ T cells and subset counts were unchanged. AMG 181-treated UC subjects were in remission with mucosal healing at weeks 6, 12 and/or 28. The placebo-treated UC subject experienced colitis flare at week 6. No ADA or AMG 181 treatment-related serious adverse events were observed. CONCLUSIONS AMG 181 has PK/PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases.

Background With blinded data, several authors have concluded that there is a negligible chance of inferring a non-null treatment effect. The recent Food and Drug Administration (FDA) draft guidance document on adaptive trials, by encouraging blinded sample size reestimation, implies the same. Purpose We derive methods to investigate whether the probability of inferring a treatment effect is much larger than previously thought, and whether that is of concern. Methods A statistic is developed that contributes to improving signal detection. Additionally, trials that are overpowered, for reasons external to powering the primary objective, further strengthen the chance of finding a signal. Results An example of data from a clinical trial shows how revealing a blinded analysis can be. The ability to infer a non-null effect while a blinded trial is ongoing is a serious matter. Limitations The methods apply to superiority trials and are of limited use for non-inferiority or equivalence trials. Conclusion It is important, therefore, that guidance documents include clear language to limit or prevent inference from blinded data to maintain trial integrity. Simple steps are proposed to make inference difficult.

For ethical reasons, group sequential trials were introduced to allow trials to stop early in the event of extreme results. Endpoints in such trials are usually mortality or irreversible morbidity. For a given endpoint, the norm is to use a single test statistic and to use that same statistic for each analysis. This approach is risky because the test statistic has to be specified before the study is unblinded, and there is loss in power if the assumptions that ensure optimality for each analysis are not met. To minimize the risk of moderate to substantial loss in power due to a suboptimal choice of a statistic, a robust method was developed for nonsequential trials. The concept is analogous to diversification of financial investments to minimize risk. The method is based on combining P values from multiple test statistics for formal inference while controlling the type I error rate at its designated value.This article evaluates the performance of 2 P value combining methods for group sequential trials. The emphasis is on time to event trials although results from less complex trials are also included. The gain or loss in power with the combination method relative to a single statistic is asymmetric in its favor. Depending on the power of each individual test, the combination method can give more power than any single test or give power that is closer to the test with the most power. The versatility of the method is that it can combine P values from different test statistics for analysis at different times. The robustness of results suggests that inference from group sequential trials can be strengthened with the use of combined tests.

Stratification is common in clinical trials because it can reduce the variance of the estimated treatment effect. The traditional demonstration of variance reduction relies on the assumption of stratum sizes being fixed quantities. However, in practice, to speed up enrollment, and to obtain a study population with a similar distribution as the overall population, the stratum sizes are allowed to vary. Under the condition that the total sample size is fixed and that the stratum sizes have a multinomial distribution, the criterion changes for achieving a reduction in variance. The relationship between the stratified and unstratified variances is established and shown to be approximately the same for prestratified and post-stratified trials. It is demonstrated why stratification may actually increase the variance compared with no stratification even when the mean square error is reduced on account of stratification. Data from a real clinical trial will be used for illustration. The benefit attributed to stratification needs to be re-examined in light of the findings presented, particularly given its widespread use. Copyright © 2011 John Wiley & Sons, Ltd.

OBJECTIVES: To examine the combined influence of alcohol use and comorbidity on 20-year mortality in older adults (average age 66 at the time of the baseline survey). DESIGN: Longitudinal analysis of a national probability sample‐based cohort study. SETTING: Data sources were the National Health and Nutrition Examination Survey I (NHANES I), 1971‐1974, and the NHANES Epidemiologic Followup Survey, 1992. PARTICIPANTS: Four thousand six hundred ninety-one adults aged 60 and older who provided data on alcohol use. MEASUREMENTS: The prevalence of at-risk drinking in older adults in the United States and the 20-year all-cause mortality risk associated with it. At-risk drinking status was determined from amount of alcohol consumed and comorbidities, using a previously validated method. RESULTS: The prevalence of at-risk drinking in the United States between 1971 and 1974 in older adults was 10% (18% of men, 5% of women). The majority of at-risk drinkers were identified as such because of their use of alcohol in amounts deemed risky in the presence of relevant comorbidities (69%) (e.g., drinking 2‐3 drinks per day and having gout or anxiety or taking a medication for pain). In men, at-risk drinking was associated with higher mortality rates than not-at-risk drinking (hazard ratio 51.20, 95% confidence interval 51.01‐1.41); abstinence was not associated with greater mortality. In women, neither abstinence nor at-risk drinking was associated with greater mortality rates. CONCLUSION: In this first, large population-based study of older adults examining the mortality risks of alcohol use and comorbidity, at-risk drinking was associated with greater mortality rates in men. These findings suggest that a lower threshold of alcohol use should be recommended for older adults with specific comorbidities to reduce mortality risks. J Am Geriatr Soc 54:757–762, 2006.

Aims To estimate age, period, cohort and other demographic influences on heavy alcohol consumption and trajectories of heavy drinking in American adults. Design Prospective cohort of 14 127 participants, aged 25–74 years at baseline. Generalized estimating equations to model longitudinal change in the probability of heavy drinking and its association with demographic factors. Setting National, population-based sample of non-institutionalized civilians. Measurements Heavy alcohol consumption (usual number of drinks per occasion ≥ five for men; ≥ four for women) at baseline (1971–74) and three follow-ups until 1992. Findings Heavy alcohol consumption declined with increasing age (age effect) and tracked national average consumption (period effect). There was no cohort effect. Higher probability of heavy drinking was associated with male gender (relative risk: RR = 2.4), being not married (RR = 1.4), having less than high school education (RR = 1.7), having annual income below the median (RR = 1.5), not living in the South-east (RR = 1.7), and smoking (RR = 3.4). Getting married and quitting smoking during the study were each associated with reduction in heavy drinking (RR = 0.55 and 0.61, respectively). Slower age-related decline in the probability of heavy drinking was seen in men (P

Objectives: To provide preliminary evidence on the effectiveness and optimal dosage of megestrol acetate for older persons with impaired appetite after hospitalization. Design: Randomized clinical trial. Setting: Acute care hospital. Participants: Forty-seven older persons (mean age 83) who were recently discharged from an acute care hospital and had fair or poor appetite. Intervention: Participants were randomized to placebo or megestrol acetate suspension 200 mg, 400 mg, or 800 mg daily for 9 weeks. Measurements: Appetite, health-related quality of life, and adverse effects were measured at baseline and 20, 42, and 63 days. Serum nutritional markers were measured at baseline and 20 and 63 days. Results: During the course of the study, there were no significant differences between treatment groups on any of the appetite questions, although participants in the 400-mg and 800-mg groups demonstrated significant improvement from baseline on some questions. At 20 days, prealbumin increased in a dose-response relationship across the four groups (by 0.4, 5.1, 7.5, and 9.0 mg/dL, respectively). Participants in the 400-mg and 800-mg groups demonstrated greater improvement in prealbumin levels at 20 days than those receiving placebo (P=.009 and P=.004, respectively) and those in the 400-mg group also demonstrated improvement at 63 days (P=.02). At 20 days, no participant taking placebo had a morning serum cortisol level less than 8 ng/mL (the lower limit of normal). In contrast, 33%, 70%, and 78% of those taking 200 mg, 400 mg and 800 mg, respectively, had values below this level; by 63 days, these percentages were 11%, 30%, 56%, and 37%, respectively. No patient reported clinical symptoms of adrenal insufficiency. Diarrhea developed in three subjects, and thromboembolism occurred in two receiving active treatment. Conclusion: Megestrol acetate at doses of 400 mg and 800 mg increases prealbumin in recently hospitalized older persons. Cortisol suppression is common at higher doses and may be persistent. In this small study, the drug did not confer benefit on other nutritional or clinical outcomes.

Background: The combination of carfilzomib with lenalidomide and dexamethasone (KRd) is approved in the United States and the European Union (EU) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). Under these approvals, carfilzomib is administered twice weekly as a 10-minute intravenous (IV) infusion at a dose of 20/27 mg/m2. The phase 1/2 CHAMPION-1 study showed that once-weekly carfilzomib (20/70 mg/m2; 30-minute IV infusion) with dexamethasone was well tolerated and active in patients with RRMM (Berenson et al. Blood. 2016;127:3360−3368). We present initial results from the dose evaluation component of a phase 1b study (NCT02335983) assessing the safety and efficacy of once-weekly carfilzomib with lenalidomide and dexamethasone in patients with MM. Methods: This is an open-label, multicenter, dose-finding, phase 1b study.The primary objective of the study is to evaluate the safety and tolerability of a once-weekly KRd regimen. Secondary objectives included evaluation of the efficacy of a once-weekly KRd regimen. This study consists of 2 parts: a dose-evaluation component in patients with RRMM and a dose-expansion component in both RRMM and newly diagnosed MM (NDMM). Results from the ongoing dose-evaluation component in RRMM are presented. There were 2 planned dose cohorts in the dose-evaluation portion of the study: carfilzomib 56 mg/m2 KRd cohort (56 mg/m2) and carfilzomib 70 mg/m2 KRdcohort (70 mg/m2). All patients received carfilzomib (days 1, 8, and 15), lenalidomide 25 mg (days 1 - 21), and dexamethasone 40 mg (days 1, 8, 15 and 22) on a 28-day cycle (dexamethasone was not administered on day 22 for cycles 9+). Carfilzomib was administered as a 30-minute IV infusion: 20 mg/m2 on cycle 1 day 1 with escalation to the assigned dose level (56 or 70 mg/m2) thereafter. The protocol allowed 8 DLT-evaluable patients to be treated in the 56 mg/m2 and 70 mg/m2 cohorts. Response was assessed by investigators using International Myeloma Working Group Uniform Response Criteria. The data cutoff date for this analysis was June 23, 2016. Results: A total of 22 patients (56 mg/m2, n=10; 70 mg/m2, n=12) with a median age of 69 (range, 50-87) years were enrolled in the dose evaluation component of the study. The median number of prior regimens was 1 (range, 1 - 3) in both cohorts. There were no dose-limiting toxicities observed in any of the 15 dose-evaluable RRMM patients (56 mg/m2 cohort, n=8; 70 mg/m2 cohort, n=7). The median number of cycles started as of data cutoff was 9.5 (range, 3-15) in the 56 mg/m2 cohort and 6.0 (range, 2-9) in the 70 mg/m2 cohort. All patients experienced at least 1 treatment-emergent adverse event (AE). Grade ≥3 AEs occurring in ≥9% of patients, and any AE of interest are shown in Table 1. The only grade ≥3 AEs to occur in ≥2 patients (≥9%) were thrombocytopenia (56 mg/m2, n=2; 70 mg/m2, n=1), decreased neutrophil count (56 mg/m2, n=2; 70 mg/m2, n=1), anemia (56 mg/m2, n=2), and hypertension (56 mg/m2, n=1; 70 mg/m2, n=1). Although the numbers were small, there was no apparent difference in the incidence of dyspnea or hypertension between the 56 and 70 mg/m2 cohorts. Cardiac or renal failure of any grade was not reported at the time of the database snapshot in these patients with RRMM. Response rates after 4 cycles, as assessed by investigators, are shown in Table 2. Two patients in the 56 mg/m2 cohort did not complete 4 cycles: an 87-year old patient developed asymptomatic pulmonary hypertension (detected on a required echocardiogram study) and was taken off therapy; another patient withdrew consent. One patient in the 70 mg/m2 cohort had a partial response after cycle 1 but was found to have progressive disease in cycle 3 (listed as did not complete 4 cycles in Table 2). After 4 cycles, the response rates (investigator assessed), were 70% and 75% in the 56 and 70 mg/m2 cohorts (response assessment for 2 patients in the 70 mg/m2 cohort was missing at the time of the data cutoff). Conclusions: These results demonstrate that carfilzomib administered in a convenient once-weekly schedule in combination with lenalidomide and dexamethasone in patients with RRMM is safe with promising efficacy. The 70 mg/m2 dosing was selected for dose-expansion cohorts in RRMM and NDMM. An update on the expansion cohorts will be presented at the meeting. Disclosures Biran: Onyx: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Siegel:Novartis: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Merck: Honoraria; BMS: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding. Faber:Celgene: Speakers Bureau; Cardinal Health: Honoraria; Gilead: Consultancy, Honoraria. Seneviratne:Novartis Pharmaceuticals: Speakers Bureau. Alsina:Onyx: Speakers Bureau; Millenium Pharmaceuticals: Research Funding; Novartis: Research Funding; Signal Genetics: Consultancy; Onyx: Consultancy. Bensinger:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau. Kimball:Amgen Inc.: Employment, Equity Ownership. Zhou:Amgen Inc.: Employment, Equity Ownership. Landgren:BMS: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

We present a unified approach to nonparametric comparisons of receiver operating characteristic (ROC) curves for a paired design with clustered data. Treating empirical ROC curves as stochastic processes, their asymptotic joint distribution is derived in the presence of both between-marker and within-subject correlations. A Monte Carlo method is developed to approximate their joint distribution without involving nonparametric density estimation. The developed theory is applied to derive new inferential procedures for comparing weighted areas under the ROC curves, confidence bands for the difference function of ROC curves, confidence intervals for the set of specificities at which one diagnostic test is more sensitive than the other, and multiple comparison procedures for comparing more than two diagnostic markers. Our methods demonstrate satisfactory small-sample performance in simulations. We illustrate our methods using clustered data from a glaucoma study and repeated-measurement data from a startle response study.

To examine the combined influence of alcohol use and comorbidity on 20-year mortality in older adults (average age 66 at the time of the baseline survey).Longitudinal analysis of a national probability sample-based cohort study.Data sources were the National Health and Nutrition Examination Survey I (NHANES I), 1971-1974, and the NHANES Epidemiologic Followup Survey, 1992.Four thousand six hundred ninety-one adults aged 60 and older who provided data on alcohol use.The prevalence of at-risk drinking in older adults in the United States and the 20-year all-cause mortality risk associated with it. At-risk drinking status was determined from amount of alcohol consumed and comorbidities, using a previously validated method.The prevalence of at-risk drinking in the United States between 1971 and 1974 in older adults was 10% (18% of men, 5% of women). The majority of at-risk drinkers were identified as such because of their use of alcohol in amounts deemed risky in the presence of relevant comorbidities (69%) (e.g., drinking 2-3 drinks per day and having gout or anxiety or taking a medication for pain). In men, at-risk drinking was associated with higher mortality rates than not-at-risk drinking (hazard ratio=1.20, 95% confidence interval=1.01-1.41); abstinence was not associated with greater mortality. In women, neither abstinence nor at-risk drinking was associated with greater mortality rates.In this first, large population-based study of older adults examining the mortality risks of alcohol use and comorbidity, at-risk drinking was associated with greater mortality rates in men. These findings suggest that a lower threshold of alcohol use should be recommended for older adults with specific comorbidities to reduce mortality risks.

To provide preliminary evidence on the effectiveness and optimal dosage of megestrol acetate for older persons with impaired appetite after hospitalization.Randomized clinical trial.Acute care hospital.Forty-seven older persons (mean age 83) who were recently discharged from an acute care hospital and had fair or poor appetite.Participants were randomized to placebo or megestrol acetate suspension 200 mg, 400 mg, or 800 mg daily for 9 weeks.Appetite, health-related quality of life, and adverse effects were measured at baseline and 20, 42, and 63 days. Serum nutritional markers were measured at baseline and 20 and 63 days.During the course of the study, there were no significant differences between treatment groups on any of the appetite questions, although participants in the 400-mg and 800-mg groups demonstrated significant improvement from baseline on some questions. At 20 days, prealbumin increased in a dose-response relationship across the four groups (by 0.4, 5.1, 7.5, and 9.0 mg/dL, respectively). Participants in the 400-mg and 800-mg groups demonstrated greater improvement in prealbumin levels at 20 days than those receiving placebo (P=.009 and P=.004, respectively) and those in the 400-mg group also demonstrated improvement at 63 days (P=.02). At 20 days, no participant taking placebo had a morning serum cortisol level less than 8 ng/mL (the lower limit of normal). In contrast, 33%, 70%, and 78% of those taking 200 mg, 400 mg and 800 mg, respectively, had values below this level; by 63 days, these percentages were 11%, 30%, 56%, and 37%, respectively. No patient reported clinical symptoms of adrenal insufficiency. Diarrhea developed in three subjects, and thromboembolism occurred in two receiving active treatment.Megestrol acetate at doses of 400 mg and 800 mg increases prealbumin in recently hospitalized older persons. Cortisol suppression is common at higher doses and may be persistent. In this small study, the drug did not confer benefit on other nutritional or clinical outcomes.

Objectives. We examined demographic predictors of longitudinal patterns in alcohol consumption. Methods. We used mixed-effects models to describe individual alcohol consumption and change in consumption with age, as well as the associations between consumption and birth year, national alcohol consumption, and demographic factors, among 14 105 adults from the National Health and Nutrition Examination Survey I Epidemiologic Follow-Up Study. Results. Alcohol consumption declined with increasing age, and individual consumption mirrored national consumption. Higher consumption was associated with male gender, being White, being married, having a higher educational level, having a higher income, being employed, and being a smoker. Faster age-related decline in consumption was associated with earlier cohorts, being male, being married, having a lower educational level, and being a smoker. Conclusions. Compared with alcohol consumption among earlier cohorts, that among recent cohorts declined more slowly with increasing age, suggesting that negative health effects of alcohol could increase in the future.

9501 Background: There is an interest in identifying patients at risk for SREs who may benefit most from treatment with bone-targeted agents (BTA). Previous results from a subgroup analysis of thre...

Pharmacokinetics (PK), Pharmacodynamics (PD), and Safety of Amg 181, a Fully Human Anti-α4β7 Antibody for Treating Inflammatory Bowel Diseases (IBD) Wei-Jian Pan, Barbara A. Sullivan, Christine M. Evangelista, David R. Doherty, Chi-Yan J. Tam, Sonal K. Patel, Peter J. Prince, Kai O. Reynhardt, William A. Rees, Hailing Hsu, Kefei Zhou, Wen Gu, Mark Yen, Christine A. Haller, Susanna Dodson, Zhigang Yu, Larry C. Wienkers, Dominique C. Borie