Multicenter Comparison of Lung and Oral Microbiomes of HIV-infected and HIV-uninfected Individuals.

RATIONALE: Improved understanding of the lung microbiome in HIV-infected individuals could lead to better strategies for diagnosis, therapy, and prophylaxis of HIV-associated pneumonias. Differences in the oral and lung microbiomes in HIV-infected and HIV-uninfected individuals are not well defined. Whether highly active antiretroviral therapy influences these microbiomes is unclear. OBJECTIVES: We determined whether oral and lung microbiomes differed in clinically healthy groups of HIV-infected and HIV-uninfected subjects. METHODS: Participating sites in the Lung HIV Microbiome Project contributed bacterial 16S rRNA sequencing data from oral washes and bronchoalveolar lavages (BALs) obtained from HIV-uninfected individuals (n = 86), HIV-infected individuals who were treatment naive (n = 18), and HIV-infected individuals receiving antiretroviral therapy (n = 38). MEASUREMENTS AND MAIN RESULTS: Microbial populations differed in the oral washes among the subject groups (Streptococcus, Actinomyces, Rothia, and Atopobium), but there were no individual taxa that differed among the BALs. Comparison of oral washes and BALs demonstrated similar patterns from HIV-uninfected individuals and HIV-infected individuals receiving antiretroviral therapy, with multiple taxa differing in abundance. The pattern observed from HIV-infected individuals who were treatment naive differed from the other two groups, with differences limited to Veillonella, Rothia, and Granulicatella. CD4 cell counts did not influence the oral or BAL microbiome in these relatively healthy, HIV-infected subjects. CONCLUSIONS: The overall similarity of the microbiomes in participants with and without HIV infection was unexpected, because HIV-infected individuals with relatively preserved CD4 cell counts are at higher risk for lower respiratory tract infections, indicating impaired local immune function.

A review of software for analyzing molecular sequences.

BACKGROUND: Over the past ten years, there has been an explosion of microbiome research. Many software packages for analyzing microbial sequences such as the 16S gene from 454 sequencers and Illumina platforms are available. But for a new researcher, it is difficult to know which package to choose. We present a systematic review of packages for the analysis of molecular sequences used to describe and compare microbial communities. This review gives students and researchers information to help choose the best analytic pipeline for their project. To the best of our knowledge, this is the first review of such software. FINDINGS: Seven software packages met our inclusion criteria of being cost free and publically available, offering analysis functions from platform sequencing to results presentation, and included documentation and data security. We installed and executed each of the software packages and describe the installation, documentation, features, and functions of each. CONCLUSIONS: For the user, pipeline choices may be limited because some packages only run on select operating systems. Users should be aware of the availability of features and functions of each package. Of utmost importance is that the user must be aware of the default settings and underlying assumptions of each function. All packages are lacking sufficient methods for longitudinal analysis.Researchers can do well using any one of these seven packages. However, two packages are outstanding; mothur and QIIME, due not only to the comprehensive suite of functions and procedures incorporated into the pipelines but also because of the accompanying documentation.

Effectiveness and cost-effectiveness of diabetes prevention among adherent participants.

OBJECTIVES: We report the 10-year effectiveness and within-trial cost-effectiveness of the Diabetes Prevention Program (DPP) and its Outcomes Study (DPPOS) interventions among participants who were adherent to the interventions. STUDY DESIGN: DPP was a 3-year randomized clinical trial followed by 7 years of open-label modified intervention follow-up. METHODS: Data on resource utilization, cost, and quality of life were collected prospectively. Economic analyses were performed from health system and societal perspectives. Lifestyle adherence was defined as achieving and maintaining a 5% reduction in initial body weight, and metformin adherence as taking metformin at 80% of study visits. RESULTS: The relative risk reduction was 49.4% among adherent lifestyle participants and 20.8% among adherent metformin participants compared with placebo. Over 10 years, the cumulative, undiscounted, per capita direct medical costs of the interventions, as implemented during the DPP, were greater for adherent lifestyle participants ($4810) than adherent metformin participants ($2934) or placebo ($768). Over 10 years, the cumulative, per capita non-interventionrelated direct medical costs were $4250 greater for placebo participants compared with adherent lifestyle participants and $3251 greater compared with adherent metformin participants. The cumulative quality-adjusted life-years (QALYs) accrued over 10 years were greater for lifestyle (6.80) than metformin (6.74) or placebo (6.67). Without discounting, from a modified societal perspective (excluding participant time) and a full societal perspective (including participant time), lifestyle cost < $5000 per QALY-gained and metformin was cost saving compared with placebo. CONCLUSIONS: Over 10 years, lifestyle intervention and metformin were cost-effective or cost saving compared with placebo. These analyses confirm that lifestyle and metformin represent a good value for money.

Clinical research enrolling pregnant women: a workshop summary.

Clinical research investigates mechanisms of human disease, interventions, or new technologies, but pregnant women are often excluded from clinical studies. Few studies, beyond research on pregnancy, are designed to address questions relevant to pregnant women. A recent National Institutes of Health workshop considered the barriers and opportunities in conducting clinical research studies enrolling pregnant women.

After inclusion, information and inference: reporting on clinical trials results after 15 years of monitoring inclusion of women.

OBJECTIVE: The objectives of this report are to review the publications resulting from National Institutes of Health (NIH)-funded phase 3 trials monitored by NIH for inclusion and to address the quality of the research conducted and the validity of the sex/gender-specific or sex/gender difference analyses reported. METHODS: For intervention trials enrolling both women and men, this review links reports to NIH of completed enrollment to publications of trial results. Each publication was then reviewed for a variety of reported characteristics based on established measures of quality, bearing on whether or not the research will permit valid analyses of sex/gender differences. RESULTS: Publications from 268 trials reported an overall average enrollment of 37% (±6% standard deviation [SD]) women, at an increasing rate over the years 1995-2010. Only 28% of the publications either made some reference to sex/gender-specific results in the text or provided detailed results including sex/gender-specific estimates of effect or tests of interaction. CONCLUSIONS: Efforts at including women in clinical research have increased the information captured relative to women's health. Sex/gender-specific information has been captured and should be available to other researchers for further analysis, including individual patient data meta-analyses. Improved reporting and disseminating sex/gender-specific results will allow sex/gender-specific inferences and healthcare decisions.

Menopause and risk of diabetes in the Diabetes Prevention Program.

OBJECTIVE: The study objectives were to examine the association between menopause status and diabetes risk among women with glucose intolerance and to determine if menopause status modifies response to diabetes prevention interventions. METHODS: The study population included women in premenopause (n = 708), women in natural postmenopause (n = 328), and women with bilateral oophorectomy (n = 201) in the Diabetes Prevention Program, a randomized placebo-controlled trial of lifestyle intervention and metformin among glucose-intolerant adults. Associations between menopause and diabetes risk were evaluated using Cox proportional hazard models that adjusted for demographic variables (age, race/ethnicity, family history of diabetes, history of gestational diabetes mellitus), waist circumference, insulin resistance, and corrected insulin response. Similar models were constructed after stratification by menopause type and hormone therapy use. RESULTS: After adjustment for age, there was no association between natural menopause or bilateral oophorectomy and diabetes risk. Differences by study arm were observed in women who reported bilateral oophorectomy. In the lifestyle arm, women with bilateral oophorectomy had a lower adjusted hazard for diabetes (hazard ratio [HR], 0.19; 95% CI, 0.04-0.94), although observations were too few to determine if this was independent of hormone therapy use. No significant differences were seen in the metformin (HR, 1.29; 95% CI, 0.63-2.64) or placebo arms (HR, 1.37; 95% CI, 0.74-2.55). CONCLUSIONS: Among women at high risk for diabetes, natural menopause was not associated with diabetes risk and did not affect response to diabetes prevention interventions. In the lifestyle intervention, bilateral oophorectomy was associated with a decreased diabetes risk.

Evaluating the safety of new vaccines: summary of a workshop.

Public concerns about the safety of vaccines arise on a regular basis. In November 2000, a workshop titled "Evaluation of New Vaccines: How Much Safety Data?" was convened by US Public Health Service agencies, including the Food and Drug Administration, the National Institutes of Health, the Centers for Disease Control and Prevention, and the Health Resources and Services Administration, to discuss appropriate methods for evaluating the safety of new vaccines. Workshop presentations addressed the current standards and approaches for new vaccine evaluation and postlicensure surveillance, as well as public views about vaccine safety and alternative approaches that could be considered. The advantages and disadvantages of conducting large controlled trials before licensure or widespread use of a new vaccine were discussed. We summarize these presentations and discussions.

Potential use of the scan statistic for quality control in blood product manufacturing.

There are minimal standards for the processing of whole blood components, and to apply those standards requires a system of quality assurances. Excessive indications of failures in compliance trigger inspections and other remedial actions, but the demarcation of what is excessive is a critical issue. Issues of low volume in some production facilities, low expected frequency of nonconformance, multiple nonindependent statistical tests, and controlling both the false-positive and false-negative rates all complicate quality assurance procedures. The scan statistic is a statistic that computes the number of events in a moving window throughout the period of risk. Monitoring plans based on scan statistics are developed to estimate the probability that a process that is under control.

Independence of the statistician who analyses unblinded data.

This discussion considers arguments for and against separating responsibility for the unblinded interim analysis of a clinical trial from responsibility for trial management and modifications to the ongoing trial. The degree to which one or different statisticians carry out these responsibilities and thus the degree of statistician independence for the two activities can vary, but a sponsor should recognize that giving a single statistician both responsibilities might limit flexibility in managing the trial, particularly with respect to modifying an ongoing trial.