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Thorlund K.,McMaster University | Awad T.,McMaster University | Thabane L.,McMaster University | Thabane L.,Biostatistics Unit
BMC Infectious Diseases | Year: 2011

Background: Antivirals play a critical role in the prevention and the management of influenza. One class of antivirals, neuraminidase inhibitors (NAIs), is effective against all human influenza viruses. Currently there are two NAI drugs which are licensed worldwide: oseltamivir (Tamiflu®) and zanamivir (Relenza®); and two drugs which have received recent approval in Japan: peramivir and laninamivir. Until recently, the prevalence of antiviral resistance has been relatively low. However, almost all seasonal H1N1 strains that circulated in 2008-09 were resistant to oseltamivir whereas about 1% of tested 2009 pandemic H1N1 viruses were found to be resistant to oseltamivir. To date, no studies have demonstrated widespread resistance to zanamivir. It seems likely that the literature on antiviral resistance associated with oseltamivir as well as zanamivir is now sufficiently comprehensive to warrant a systematic review.The primary objectives were to systematically review the literature to determine the incidence of resistance to oseltamivir, zanamivir, and peramivir in different population groups as well as assess the clinical consequences of antiviral resistance.Methods: We searched MEDLINE and EMBASE without language restrictions in September 2010 to identify studies reporting incidence of resistance to oseltamivir, zanamivir, and peramivir. We used forest plots and meta-analysis of incidence of antiviral resistance associated with the three NAIs. Subgroup analyses were done across a number of population groups. Meta-analysis was also performed to evaluate associations between antiviral resistance and clinical complications and symptoms.Results: We identified 19 studies reporting incidence of antiviral resistance. Meta-analysis of 15 studies yielded a pooled incidence rate for oseltamivir resistance of 2.6% (95%CI 0.7% to 5.5%). The incidence rate for all zanamivir resistance studies was 0%. Only one study measured incidence of antiviral resistance among subjects given peramivir and was reported to be 0%. Subgroup analyses detected higher incidence rates among influenza A patients, especially for H1N1 subtype influenza. Considerable heterogeneity between studies precluded definite inferences about subgroup results for immunocompromised patients, in-patients, and children. A meta-analysis of 4 studies reporting association between oseltamivir-resistance and pneumonia yielded a statistically significant risk ratio of 4.2 (95% CI 1.3 to 13.1, p = 0.02). Oseltamivir-resistance was not statistically significantly associated with other clinical complications and symptoms.Conclusion: Our results demonstrate that that a substantial number of patients may become oseltamivir-resistant as a result of oseltamivir use, and that oseltamivir resistance may be significantly associated with pneumonia. In contrast, zanamivir resistance has been rarely reported to date. © 2011 Thorlund et al; licensee BioMed Central Ltd.

Hirano I.,Northwestern University | Moy N.,Northwestern University | Heckman M.G.,Biostatistics Unit | Thomas C.S.,Biostatistics Unit | Gonsalves N.,Northwestern University
Gut | Year: 2013

Objective: Abnormalities are commonly identified during endoscopy in eosinophilic oesophagitis (EoE). There is no standardised classification to describe these features. This study aimed to evaluate the interobserver agreement of a grading system for the oesophageal features of EoE. Method: The proposed system incorporated the grading of four major oesophageal features (rings, furrows, exudates, oedema) and the presence of additional features of narrow calibre oesophagus, feline oesophagus, stricture and crepe paper oesophagus. Endoscopic videos from 25 patients with EoE and controls were reviewed by 21 gastroenterologists. Interobserver agreement was assessed by estimating multi-rater κ and the proportion of pairwise agreement. Results: Using the original grading system, agreement for rings, furrows and exudates was moderate (κ=0.38-0.46, 56-65% agreement) but poor for oedema (κ=0.23, 51% agreement). Identification of narrow calibre oesophagus had fair agreement (κ=0.30, 74% agreement) while feline oesophagus had poor agreement (κ=0.15, 68% agreement). After collapsing the severity grading for oedema and furrows and eliminating poorly performing features of feline oesophagus and narrow calibre oesophagus, a modified grading system demonstrated good agreement for the four major features of EoE (κ=0.40-0.54, 71-81% agreement) and additional features of stricture and crepe paper oesophagus (κ=0.52 and 0.58, 79% and 92% agreement). Conclusions: The proposed system for endoscopicallyidentified oesophageal features of EoE defines common nomenclature and severity scores for the assessment of EoE disease activity. The system has good interobserver agreement among practising and academic gastroenterologists.

News Article | February 27, 2017

The combined results of two ovarian cancer screening trials suggest that a personalized strategy involving frequent screening of high-risk women could improve the chance that tumors are detected at early stages when they are easier to treat. As reported in a paper published in Clinical Cancer Research, these trials imply that a protocol involving quarterly blood test to identify significant increases above each patient's personal baseline in levels of the protein CA125, followed by ultrasound examination when such elevations are detected, could reduce the risk of diagnosis with advanced cancer in high-risk women who choose to delay recommended preventive surgery. "The standard advice for women at high risk of ovarian cancer, due to either family history or inherited gene mutations, is to have their ovaries and fallopian tubes removed once their families are complete. Some women choose to postpone this surgery," says Steven Skates, PhD, of the Massachusetts General Hospital (MGH) Cancer Center and the Biostatistics Unit, co-lead and corresponding author of the report. "Our screening protocol increased the proportion of tumors detected at early stages from 10 percent - which is typically seen in high-risk women who are not screened - to 50 percent." CA125 levels are known to be raised over the level of 35 in the blood of most women with ovarian cancer. While screening for raised CA125 and/or transvaginal ultrasound may be considered for high-risk women who postpone surgery, that approach has not been shown to improve patient outcomes. The two trials reported in the current paper utilize the Risk of Ovarian Cancer Algorithm (ROCA) - co-developed by Skates and Ian Jacobs, MD, FRCOG, of the University of New South Wales in Australia and University College London - which tracks CA125 levels over time to identify significant elevations above each patient's baseline levels, even those that do not exceed the traditional threshold of 35. One trial conducted through the National Cancer Institute's Cancer Genetics Network (CGN) - with additional patients from two ovarian Specialized Programs of Research Excellence (SPORE) and two Early Detection Research Network sites (EDRN) - was led by Skates. The other, conducted through the Gynecologic Oncology Group (GOG), was led by Mark H. Greene, MD, of the Clinical Genetics Branch at the National Cancer Institute (NCI). Both trials followed similar protocols, enrolling women at elevated risk for ovarian cancer - based on either a strong family history of ovarian and/or breast cancer or the presence in the patient or in close blood relatives of risk-associated mutations in the BRCA1 or BRCA2 genes - who had not yet had risk-reducing surgery. Participants had CA125 blood tests utilizing ROCA every three months, compared with screening for raised CA125 values every 6 or 12 months as in previous screening studies. The investigators calculated a patient's ROCA risk by analyzing the results of each new CA125 test, combined with previous results, and factors such as participant's age and menopausal status. Women at intermediate ROCA risk were referred for an ultrasound examination, while those at an elevated ROCA risk received both ultrasound and clinical evaluation by either a gynecologic oncologist or the site principal investigator. While the results of those examinations were used to guide decisions about surgical treatment, study participants were free to choose to have their ovaries and fallopian tubes removed at any time during the clinical trials, as is standard practice for women with a BRCA1/2 mutation. Between 2001 and 2011, the CGN trial enrolled 2,359 women at 25 U.S. sites. The GOG trial enrolled 1,459 women at 112 sites in the U.S. and Australia between 2003 and 2006 and screened them for five years. Among the more than 3,800 participants in both studies, 19 malignant tumors of the ovaries or fallopian tubes were identified during the study periods. Ten cases were diagnosed during screening, and nine were diagnosed by preventive surgery. Of the ten cases, there was evidence that four were present at the outset of the trial, while six tumors were likely to have developed during the trial period after a CA125 baseline had been measured. While the algorithm can calculate risk without a baseline, ROCA works best when a baseline has been established. The results in these six cases reflect the benefits of a long-term ROCA screening program; all but one were diagnosed by ROCA, giving a sensitivity of over 80 percent ,and 50 percent were detected at early stages. Another study - the UK Familial Ovarian Cancer Screening Study, led by ROCA co-developer Jacobs and published today in the Journal of Clinical Oncology - found that a similar protocol using ROCA-based testing every four months was also better than current practice at diagnosing early-stage tumors in high-risk women. Skates notes that a formal analysis of the data from all three trials could increase the statistical power of these studies and could lend stronger support to recommending frequent ROCA-based screening for high-risk women who choose to postpone surgery or while waiting for surgery. While the pattern of cancers detected in these studies supported the potential value of ROCA screening, these studies were not designed to assess whether screening reduced deaths due to ovarian cancer, the authors note. "It is important to note that removal of ovaries and fallopian tubes remains the standard of care when women at increased familial or genetic risk complete their families and reach an age when their risk exceeds that of the general population," stresses Skates, who is an associate professor of Medicine at Harvard Medical School. Adds Greene, who is a senior principal investigator at the NCI, "Surgery is the primary and best option for reducing the risk of ovarian cancer, and ROCA should only be considered as a promising but unproven option for patients who decide, against medical advice, to postpone their surgery." Both investigators note that further research to identify a greater range of ovarian cancer biomarkers and improved imaging technologies is needed to help detect even more tumors at even earlier stages. Skates is leading a program to discover new biomarkers for early detection of ovarian cancer as part of NCI's Early Detection Research Network. Skates and Greene are co-lead authors of the Clinical Cancer Research report; and Dianne Finkelstein, PhD, MGH Biostatistics, and Karen Lu, MD, M.D. Anderson Cancer Center, are co-senior authors. Support for the study includes multiple grants from the National Cancer Institute to the Cancer Genetics Network, the Specialized Programs of Research Excellence, and the Early Detection Research Network, and support from the NCI Intramural Research Program. Massachusetts General Hospital has co-licensed software implementing ROCA. Skates is on the scientific advisory board of SISCAPA Assay Technologies, a consultant for Abcodia, and has received a speaker honorarium from Astra-Zeneca. The NCI Division of Cancer Epidemiology and Genetics (DCEG), home to the Clinical Genetics Branch, is a global leader in cancer epidemiology and genetics research. With its cadre of renowned epidemiologists, geneticists and biostatisticians, DCEG conducts population and multidisciplinary research to discover the genetic and environmental determinants of cancer and new approaches to cancer prevention. The DCG research portfolio informs biological concepts, clinical practice and public health policy. Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."

Muturi E.J.,University of Illinois at Urbana - Champaign | Orindi B.O.,Biostatistics Unit | Kim C.-H.,University of Illinois at Urbana - Champaign
PLoS ONE | Year: 2013

Lentic freshwater systems including those inhabited by aquatic stages of mosquitoes derive most of their carbon inputs from terrestrial organic matter mainly leaf litter. The leaf litter is colonized by microbial communities that provide the resource base for mosquito larvae. While the microbial biomass associated with different leaf species in container aquatic habitats is well documented, the taxonomic composition of these microbes and their response to common environmental stressors is poorly understood. We used indoor aquatic microcosms to determine the abundances of major taxonomic groups of bacteria in leaf litters from seven plant species and their responses to low concentrations of four pesticides with different modes of action on the target organisms; permethrin, malathion, atrazine and glyphosate. We tested the hypotheses that leaf species support different quantities of major taxonomic groups of bacteria and that exposure to pesticides at environmentally relevant concentrations alters bacterial abundance and community structure in mosquito larval habitats. We found support for both hypotheses suggesting that leaf litter identity and chemical contamination may alter the quality and quantity of mosquito food base (microbial communities) in larval habitats. The effect of pesticides on microbial communities varied significantly among leaf types, suggesting that the impact of pesticides on natural microbial communities may be highly complex and difficult to predict. Collectively, these findings demonstrate the potential for detritus composition within mosquito larval habitats and exposure to pesticides to influence the quality of mosquito larval habitats. © 2013 Muturi et al.

Wang D.,Biostatistics Unit | Pocock S.,London School of Hygiene and Tropical Medicine
Pharmaceutical Statistics | Year: 2016

Clinical trials are often designed to compare continuous non-normal outcomes. The conventional statistical method for such a comparison is a non-parametric Mann-Whitney test, which provides a P-value for testing the hypothesis that the distributions of both treatment groups are identical, but does not provide a simple and straightforward estimate of treatment effect. For that, Hodges and Lehmann proposed estimating the shift parameter between two populations and its confidence interval (CI). However, such a shift parameter does not have a straightforward interpretation, and its CI contains zero in some cases when Mann-Whitney test produces a significant result. To overcome the aforementioned problems, we introduce the use of the win ratio for analysing such data. Patients in the new and control treatment are formed into all possible pairs. For each pair, the new treatment patient is labelled a 'winner' or a 'loser' if it is known who had the more favourable outcome. The win ratio is the total number of winners divided by the total numbers of losers. A 95% CI for the win ratio can be obtained using the bootstrap method. Statistical properties of the win ratio statistic are investigated using two real trial data sets and six simulation studies. Results show that the win ratio method has about the same power as the Mann-Whitney method. We recommend the use of the win ratio method for estimating the treatment effect (and CI) and the Mann-Whitney method for calculating the P-value for comparing continuous non-Normal outcomes when the amount of tied pairs is small. Copyright © 2016 John Wiley & Sons, Ltd.

News Article | December 8, 2016

Overweight and obesity in adolescents have increased substantially in recent decades, and today affect a third of the adolescent population in some developed countries. While the dangers posed by high adult BMI on cognitive function in later life have been documented, the association of adolescent BMI with cognitive function in midlife has not yet been reported. (BMI, or Body Mass Index, is a calculation of a person's weight in kilograms divided by the square of their height in meters.) To shed light on this issue, scientists at the Hebrew University-Hadassah Braun School of Public Health and Community Medicine set out to determine the association between cumulative life course burden of high-ranked body mass index (BMI), and cognitive function in midlife. The research, which will appear in the Journal of Alzheimer's Disease 55(3), was led by Prof. Jeremy Kark from the Braun School, in the Hebrew University of Jerusalem's Faculty of Medicine, working with colleagues in Israel and the United States. The researchers used weight and height data from 507 individuals tracked from over 33 years starting at age 17. The participants completed a computerized cognitive assessment at ages 48-52, and their socioeconomic position was assessed by multiple methods. Using mixed models the researchers calculated the life-course burden of BMI from age 17 to midlife, and used multiple regression to assess associations of BMI and height with global cognition and its ?ve component domains. "In this population-based study of a Jerusalem cohort, followed longitudinally from adolescence for over 33 years, we found that higher BMI in late adolescence and the long-term cumulative burden of BMI predicted poorer cognitive function later in life. Importantly, this study shows that an impact of obesity on cognitive function in midlife may already begin in adolescence, independently of changes in BMI over the adult life course," said the paper's senior author, Prof. Jeremy Kark of the Hebrew University-Hadassah Braun School of Public Health and Community Medicine. "Our results also show that taller stature was associated with better global cognitive function, independent of childhood and adult socioeconomic position, and that height increase in late adolescence, re?ecting late growth, conferred a protective effect, but among women only," added Irit Cohen-Manheim, doctoral candidate at the Braun School and lead author. The researchers point out that while socioeconomic position may have a particularly important role in the trajectory of a person's lifetime cognitive function, it has rarely been adequately taken into account: "To the best of our knowledge, the association between BMI and cognition as a function of childhood and adult socioeconomic position has not been previously reported. Childhood household socioeconomic position appears to strongly modify the association between adolescent BMI and poorer cognition in midlife, the inverse association being restricted to low childhood socioeconomic position," said Prof. Kark. "Our results are consistent with the hypothesis that childhood living conditions, as re?ected also by height, in?uence cognitive function later in life; however, our study is unique in showing that an adverse association of higher BMI with cognitive function appears to begin in adolescence and that it appears to be restricted to adults with lower childhood socioeconomic position," said Prof. Kark. "Evidence for the association between impaired cognitive function in midlife and subsequent dementia supports the clinical relevance of our results. Findings of the relation of BMI in adolescence with poorer midlife cognitive status, particularly in light of the ongoing epidemic of childhood obesity, require con?rmation," said Irit Cohen-Manheim. Scientists involved in this research are affiliated with the Hebrew University-Hadassah Braun School of Public Health and Community Medicine, Jerusalem, Israel; Department of Clinical Research, NeuroTrax Corporation, Modiin, Israel; Centre for Medical Decision Making, Ono Academic College, Kiryat Ono, Israel; Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA; Biostatistics Unit, Gertner Institute for Epidemiology and Health Policy Research, Tel-Hashomer, Israel. The Hebrew University of Jerusalem is Israel's leading academic and research institution, producing one-third of all civilian research in Israel. For more information, visit http://new. .

Tan S.-S.,Selayang Hospital | Bujang M.A.,Biostatistics Unit
Brazilian Journal of Infectious Diseases | Year: 2013

Objective: To describe the clinical manifestations and outcome of acute liver failure (ALF) associated with dengue viral infection, a rare but severe complication. Methods: One hundred and fifty five consecutive patients with ALF admitted to the national liver centre from 2001 to 2009 were reviewed retrospectively. Eight cases due to dengue infection were identified and their clinical characteristics are described. Results: All patients had severe dengue with one dengue shock syndrome. The median (minimum, maximum) age was 33.5 (17, 47) years with 50% female. The median (minimum, maximum) duration from the onset of fever to development of ALF was 7.5 (5, 13) days and the maximum hepatic encephalopathy (HE) grade were III in five patients and II in three patients. Three patients had systemic inflammatory responses (SIRS) on admission and were in grade III HE. The presence of SIRS on admission was associated with higher grade of HE and its development during the course of hospitalization was associated with worsening HE grade. The hepatitis was characterized by marked elevations in: alanine transaminase [median admission 1140.5. u/L (639, 4161); median peak 2487. u/L (998, 5181)], serum bilirubin [median admission 29. μmol/L (23, 291); median peak 127. μmol/L (72, 592)], and prothrombin time [median admission 16.8. s (15.3, 26.2); median peak 22. s (15.3, 40.7)]. The survival rate with standard medical therapy alone was 100%. Conclusions: Dengue associated ALF manifest about one week after the onset of fever with severe hepatitis and encephalopathy. In our experience, the outcome with standard medical therapy alone is excellent. © 2013 Elsevier Editora Ltda.

McGowan I.,University of Pittsburgh | Taylor D.J.,Biostatistics Unit
Sexually Transmitted Diseases | Year: 2010

BACKGROUND: Vaginal microbicides are topical products being studied for their potential to reduce the risk of penile-vaginal human immunodeficiency virus (HIV) transmission. Because the sexual acts that lead to infection in effectiveness trials are unobserved, identification of an effective vaginal product may be unwittingly circumvented if adherence to product is poor or if participants acquire infection through nonvaginal routes of exposure. PURPOSE: To model the impact of receptive anal intercourse (RAI) on the measured effectiveness of vaginal microbicides and the power of clinical trials. METHODS: A mathematical model is proposed for assessing effectiveness and power as a function of microbicide efficacy, the probability that the microbicide is used for vaginal acts of intercourse with exposure to HIV, the probability that an act of intercourse with exposure to HIV is rectal, and the ratio of transmission probabilities for rectal versus vaginal intercourse. RESULTS: The model demonstrated that a moderate frequency of RAI among vaginal microbicide trial participants is expected to substantially reduce study power; if 1 in 50 acts are rectal, and if the rectal transmission probability is 20-fold greater than that of vaginal intercourse, then power to detect an otherwise 40% effective product with a 160 endpoint trial is reduced from 90% to 56%. If 1 in 25 acts are rectal then power is only 34%. LIMITATIONS: Accurate reports of adherence and rates of RAI are difficult to obtain, and precise HIV transmission probabilities are unknown. Hence the true impact of unprotected RAI on vaginal microbicide trials cannot be quantified with certainty. CONCLUSIONS: Counseling against RAI should be provided to all vaginal microbicide trial participants irrespective of sexual history. Collection of accurate behavioral data on RAI during trials is essential to understand whether failure to demonstrate an effect might be attributed to RAI. Copyright © 2010 American Sexually Transmitted Diseases Association.

Pullenayegum E.M.,McMaster University | Pullenayegum E.M.,Biostatistics Unit
Statistics in Medicine | Year: 2011

It is well known that when a Bayesian meta-analysis includes a small number of studies, inference can be sensitive to the choice of prior for the between-study variance. Choosing a vague prior does not solve the problem, as inferences can be substantially different depending on the degree of vagueness. Moreover, because the data provide little information on between-study heterogeneity, posterior inferences for the between-study variance based on vague priors will tend to be unrealistic. It is thus preferable to adopt a reasonable, informed prior for the between-study variance. However, relatively little is known about what constitutes a realistic distribution. On the basis of data from the Cochrane Database of Systematic Reviews, this paper describes the distribution of between-study variance in published meta-analyses, and proposes some realistic, informed priors for use in meta-analyses of binary outcomes. It is hoped that these priors will improve the calibration of inferences from Bayesian meta-analyses. © 2011 John Wiley & Sons, Ltd.

For the purpose of comparing the efficacy and safety of a Similar Biotherapeutic Product (SBP) to a Reference Biotherapeutic Product (RBP), the " Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs)" issued by the World Health Organisation (WHO), states that equivalence or non-inferiority studies may be acceptable. While in principle, equivalence trials are preferred, non-inferiority trials may be considered if appropriately justified, such as for a medicinal product with a wide safety margin. However, the statistical issues involved in the design, conduct, analysis and interpretation of equivalence and non-inferiority trials are complex and subtle, and require that all aspects of these trials be given careful consideration. These issues are important in order to ensure that equivalence and non-inferiority trials provide valid data that are necessary to draw reliable conclusions regarding the clinical similarity of an SBP to an RBP. © 2011.

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