Clinical Focus

  • Pediatric Infectious Disease
  • Toxoplasmosis
  • General Pediatrics
  • Antibiotics and Weight Gain
  • Outcomes Research
  • Methodology of Pediatric Clinical Research

Academic Appointments

Administrative Appointments

  • Affiliated Faculty of METRICS, Meta-Research Innovation Center at Stanford (METRICS) (2014 - Present)
  • Clinical Associate Professor, Clinician Educator Line, Stanford University School of Medicine, Dept of Pediatrics-Division of Infectious Diseases, Stanford, CA (2011 - Present)
  • Clinical Associate Professor, Clinician Educator Line, Stanford University School of Medicine, Dept of Medicine-Division of Infectious Diseases and Geographic Medicine, Stanford, CA (2010 - 2011)

Professional Education

  • Certificate, American Board of Pediatrics-Subspecialty of Pediatric Infectious Diseases, Pediatric Infectious Diseases (2011)
  • Board Certification: Pediatric Infectious Disease, American Board of Pediatrics (1999)
  • Clinical and Research Fellowship, Children's National Medical Center and Center for Virology, Immunology and Infectious Disease, Children's Research Institute, George Washington Univ. Sch. of Med. and Health Sciences, Pediatric Infectious Diseases (1998)
  • Clinical and Research Fellowship, Boston City Hospital, Division of Pediatric Infectious Diseases, and Maxwell Finland Laboratory for Infectious Diseases, Boston University Sch of Med, Pediatric Infectious Diseases (1996)
  • Pediatric Residency (PGY2-PGY3), Boston City Hospital, Boston University School of Medicine, Boston, MA, Pediatrics (1995)
  • Pediatric Residency (PGY1), Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, Pediatrics (1993)
  • MD, University of Athens Medical School, Athens Greece, Medicine (1990)

Research & Scholarship

Current Research and Scholarly Interests

Evidence based medicine, systematic reviews and meta-analysis
Chronic Antibiotic Use and Weight Gain: a 10 year retrospective cohort study
Comparative effectiveness of medical interventions in adults vs children
Comparative appraisal of harms of medical interventions in adults vs children
Comparative effectiveness of medical interventions: evidence from RCTs from less developed countries vs. more developed countries
Comparative evidence on harms of medical interventions:evidence from RCTs from less developed countries vs. more developed countries
Family outbreaks of acute toxoplasmosis in the US
Seasonality patterns of acute toxoplasmosis in the US
Improving Laboratory Diagnosis of Congenital Toxoplasmosis
Trends in intussusception in the US (association with pediatric vaccines)
Empirical appraisal of CEA for pediatric vaccines (with and without inclusion of herd immunity assumptions)
Patient safety related empirical projects: evaluation of the drug “black box warning” labeling.
Empirical evaluation of the research agenda of meta-analyses.
Multidomain empirical evaluation of the proposed efficacy of systemic steroids over the last 35 years.
Appraisal of the use of quality of life instruments in randomized clinical trials
Empirical multidomain evaluation of the life cycle of translational research for medical interventions.


2015-16 Courses


All Publications

  • Agreement of treatment effects for mortality from routinely collected data and subsequent randomized trials: meta-epidemiological survey BMJ-BRITISH MEDICAL JOURNAL Hemkens, L. G., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2016; 352


     To assess differences in estimated treatment effects for mortality between observational studies with routinely collected health data (RCD; that are published before trials are available) and subsequent evidence from randomized controlled trials on the same clinical question. Meta-epidemiological survey. PubMed searched up to November 2014. Eligible RCD studies were published up to 2010 that used propensity scores to address confounding bias and reported comparative effects of interventions for mortality. The analysis included only RCD studies conducted before any trial was published on the same topic. The direction of treatment effects, confidence intervals, and effect sizes (odds ratios) were compared between RCD studies and randomized controlled trials. The relative odds ratio (that is, the summary odds ratio of trial(s) divided by the RCD study estimate) and the summary relative odds ratio were calculated across all pairs of RCD studies and trials. A summary relative odds ratio greater than one indicates that RCD studies gave more favorable mortality results. The evaluation included 16 eligible RCD studies, and 36 subsequent published randomized controlled trials investigating the same clinical questions (with 17 275 patients and 835 deaths). Trials were published a median of three years after the corresponding RCD study. For five (31%) of the 16 clinical questions, the direction of treatment effects differed between RCD studies and trials. Confidence intervals in nine (56%) RCD studies did not include the RCT effect estimate. Overall, RCD studies showed significantly more favorable mortality estimates by 31% than subsequent trials (summary relative odds ratio 1.31 (95% confidence interval 1.03 to 1.65; I(2)=0%)). Studies of routinely collected health data could give different answers from subsequent randomized controlled trials on the same clinical questions, and may substantially overestimate treatment effects. Caution is needed to prevent misguided clinical decision making.

    View details for DOI 10.1136/bmj.i493

    View details for Web of Science ID 000370380000002

    View details for PubMedID 26858277

  • Reply to letter by Ferrante di Ruffano et al.: Patient outcomes in randomized comparisons of diagnostic tests are still the ultimate judge JOURNAL OF CLINICAL EPIDEMIOLOGY Siontis, K. C., Siontis, G. C., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2016; 69: 267-268
  • Clustering of Toxoplasma gondii Infections Within Families of Congenitally Infected Infants CLINICAL INFECTIOUS DISEASES Contopoulos-Ioannidis, D., Wheeler, K. M., Ramirez, R., Press, C., Mui, E., Zhou, Y., Van Tubbergen, C., Prasad, S., Maldonado, Y., Withers, S., Boyer, K. M., Noble, A. G., Rabiah, P., Swisher, C. N., Heydemann, P., Wroblewski, K., Karrison, T., Grigg, M. E., Montoya, J. G., McLeod, R. 2015; 61 (12): 1815-1824

    View details for DOI 10.1093/cid/civ721

    View details for Web of Science ID 000366465100010

  • Seasonal variation of acute toxoplasmic lymphadenopathy in the United States EPIDEMIOLOGY AND INFECTION Contopoulos-Ioannidis, D., Talucod, J., Maldonado, Y., Montoya, J. G. 2015; 143 (9): 1893-1897


    SUMMARY We describe the seasonal variation of acute toxoplasmosis in the United States. Acute toxoplasmic lymphadenopathy (ATL) can be a surrogate of acute toxoplasmosis in patients in whom the date of onset of lymphadenopathy matches the window of acute infection predicted by serological tests performed at a reference laboratory. We used the electronic database of the Palo Alto Medical Foundation Toxoplasma Serology Laboratory (PAMF-TSL) (1997-2011) to identify cases of ATL. We tested the uniformity of distribution of ATL cases per month, across the 12 calendar months, using circular statistics uniformity tests. We identified 112 consecutive cases of ATL. The distribution of cases was not uniform across the 12 calendar months. We observed the highest peak of cases in December and a second highest peak in September. Similar months were identified in patients with acute toxoplasmosis in rural areas in France. The results were similar when we performed weighted analyses, weighting for the total number of Toxoplasma gondii IgG tests performed per month in the PAMF-TSL laboratory. This is the largest study to date of the seasonal variation of ATL in the United States. Physicians should advise high-risk individuals to avoid risk factors associated with T. gondii infections especially around those months.

    View details for DOI 10.1017/S0950268814002945

    View details for Web of Science ID 000355760600012

    View details for PubMedID 25410401

  • Trends in Hospitalizations for Intussusception in California in Relationship to the Introduction of New Rotavirus Vaccines, 1985-2010. Pediatric infectious disease journal Contopoulos-Ioannidis, D. G., Halpern, M. S., Maldonado, Y. 2015; 34 (7): 712-717


    The new rotavirus vaccines RV5 and RV1 have been associated with small increase in intussusception risk in active vaccine surveillance studies. It is unclear what the impact might be on the overall trends of intussusception hospitalizations at a large population basis.We conducted an ecological study of hospital discharges of infants with intussusception discharge diagnosis using the California Office of Statewide Health Planning and Development database (1985-2010). We measured incidence rates (IR) of intussusception hospitalizations per 100,000 births within 3 periods (1985-1997; 2000-2005; 2006-2010) related to past, pre-introduction and post-introduction of the new rotavirus vaccines. We estimated slopes of yearly IRs within each period, changes in slopes between periods and IR ratios (IRR) of the mean IRs between periods. We did subgroup analyses for 5 age-subgroups. We also analyzed intussusception hospitalizations of infants who also had a surgical repair and/or radiologic reduction procedure code (restricted cohort).We identified 6241 intussusception hospitalizations; 4696 also had pertinent procedure codes. There was an upward trend in yearly IRs during 2006-2010 (+2 excess cases per 100,000 births per year; P = 0.023); the change in slopes between 2006-2010 and 2000-2005 was +3.2 excess cases per 100,000 births per year (P = 0.052), and the IR in 2006-2010 was 10% higher than in 2000-2005 (IRR: 1.10; 95% confidence intervals: 1.01-1.19). The IRR in 2006-2010 versus 2000-2005 for the 6-14 weeks age-subgroup was 1.90 (95% confidence intervals: 1.33-2.74). In the restricted cohort, trends were similar, though not nominally significant.We documented at a population-level a small increased risk in intussusception hospitalizations post-introduction of the new rotavirus vaccines.

    View details for DOI 10.1097/INF.0000000000000653

    View details for PubMedID 26069946

  • Diagnostic tests often fail to lead to changes in patient outcomes. Journal of clinical epidemiology Siontis, K. C., Siontis, G. C., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2014; 67 (6): 612-621


    To evaluate the effects of diagnostic testing on patient outcomes in a large sample of diagnostic randomized controlled trials (D-RCTs) and to examine whether the effects for patient outcomes correlate with the effects on management and with diagnostic accuracy.We considered D-RCTs that evaluated diagnostic interventions for any condition and reported effectiveness data on one or more patient outcomes. We calculated odds ratios for patient outcomes and outcomes pertaining to the use of further diagnostic and therapeutic interventions and the diagnostic odds ratio (DOR) for the accuracy of experimental tests.One hundred forty trials (153 comparisons) were eligible. Patient outcomes were significantly improved in 28 comparisons (18%). There was no concordance in significance and direction of effects between the patient outcome and outcomes for use of further diagnostic or therapeutic interventions (weighted κ 0.02 and 0.09, respectively). The effect size for the patient outcome did not correlate with the effect sizes for use of further diagnostic (r = 0.05; P = 0.78) or therapeutic interventions (r = 0.18; P = 0.08) or the experimental intervention DOR in the same trial (r = -0.24; P = 0.51).Few tests have well-documented benefits on patient outcomes. Diagnostic performance or the effects on management decisions are not necessarily indicative of patient benefits.

    View details for DOI 10.1016/j.jclinepi.2013.12.008

    View details for PubMedID 24679598

  • Safety of medical interventions in children versus adults. Pediatrics Lathyris, D., Panagiotou, O. A., Baltogianni, M., Ioannidis, J. P., Contopoulos-Ioannidis, D. G. 2014; 133 (3): e666-73


    Compare the risk of harm from pharmacologic interventions in pediatric versus adult randomized controlled trials (RCTs).We used systematic reviews from the Cochrane Database of Systematic Reviews. We considered separately 7 categories of harms/harm-related end points: severe harms, withdrawals due to harms, any harm, organ system-level harms, specific harms, withdrawals for any reason, and mortality. Systematic reviews with quantitative synthesis from at least 1 adult and 1 pediatric RCT for any of those end points were eligible. We calculated the summary odds ratio (experimental versus control intervention) in adult and pediatric trials/meta-analysis; the relative odds ratio (ROR) in adults versus children per meta-analysis; and the summary ROR (sROR) across all meta-analyses for each end point. ROR <1 means that the experimental intervention fared worse in children than adults.We identified 176 meta-analyses for 52 types of harms/harm-related end points with 669 adult and 184 pediatric RCTs. Of those, 165 had sufficient data for ROR estimation. sRORs showed statistically significant discrepancy between adults and children only for headache (sROR 0.82; 95% confidence interval 0.70-0.96). Nominally significant discrepancies for specific harms were identified in 12 of 165 meta-analyses (RORs <1 in 7, ROR >1 in 5). In 36% of meta-analyses, the ROR estimates suggested twofold or greater differences between children and adults, and the 95% confidence intervals could exclude twofold differences only in 18% of meta-analyses.Available evidence on harms/harm-related end points from pharmacologic interventions has large uncertainty. Extrapolation of evidence from adults to children may be tenuous. Some clinically important discrepancies were identified.

    View details for DOI 10.1542/peds.2013-3128

    View details for PubMedID 24567023

  • Acute Toxoplasma gondii Infection among Family Members in the United States EMERGING INFECTIOUS DISEASES Contopoulos-Ioannidis, D. G., Maldonado, Y., Montoya, J. G. 2013; 19 (12): 1981-1984


    We investigated 32 families of persons with acute toxoplasmosis in which > or = 1 other family member was tested for Toxoplasma gondii infection; 18 (56%) families had > or = 1 additional family member with acute infection. Family members of persons with acute toxoplasmosis should be screened for infection, especially pregnant women and immunocompromised persons.

    View details for DOI 10.3201/eid1912.121892

    View details for Web of Science ID 000327826600012

  • Most meta-analyses of drug interventions have narrow scopes and many focus on specific agents JOURNAL OF CLINICAL EPIDEMIOLOGY Haidich, A., Pilalas, D., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2013; 66 (4): 371-378


    To assess the extent to which meta-analysis publications of drugs and biologics focus on specific named agents or even only a single agent, and identify characteristics associated with such focus.We evaluated 499 articles with meta-analyses published in 2010 and estimated how many did not cover all the available comparisons of tested interventions for a given condition (not all-inclusive); focused on specific named agent(s), or focused strictly on comparisons of only one specific active agent vs. placebo/no treatment or different doses/schedules.Of 499 eligible articles, 403 (80.8%) were not all-inclusive, 214 (42.9%) covered only specific named agent(s), and 74 (14.8%) examined only comparisons with one active agent vs. placebo/no treatment or different doses/schedules. Only 39 articles (7.8%) covered all possible indications for the examined agent(s). After adjusting for type of treatment/field, focus on specific named agent(s) was associated with publication in journal venues (odds ratio [OR]: 1.95; 95% confidence interval [CI]: 1.17-3.26) vs. Cochrane, industry sponsoring (OR: 3.94; 95% CI: 1.66-10.66), and individual patient data analyses (OR: 6.59; 95% CI: 2.24-19.39). Individual patient data analyses primarily (29/34) focused on specific named agent(s).The scope of meta-analysis publications frequently is narrow and shaped to serve particular agents.

    View details for DOI 10.1016/j.jclinepi.2012.10.014

    View details for Web of Science ID 000315935100006

  • Patient Safety Strategies Targeted at Diagnostic Errors A Systematic Review ANNALS OF INTERNAL MEDICINE McDonald, K. M., Matesic, B., Contopoulos-Ioannidis, D. G., Lonhart, J., Schmidt, E., Pineda, N., Ioannidis, J. P. 2013; 158 (5): 381-?
  • Comparative effect sizes in randomised trials from less developed and more developed countries: meta-epidemiological assessment BMJ-BRITISH MEDICAL JOURNAL Panagiotou, O. A., Contopoulos-Ioannidis, D. G., Ioannidis, J. P., Rehnborg, C. F. 2013; 346

    View details for DOI 10.1136/bmj.f707

    View details for Web of Science ID 000315087700003

  • Empirical Evaluation of Age Groups and Age-Subgroup Analyses in Pediatric Randomized Trials and Pediatric Meta-analyses PEDIATRICS Contopoulos-Ioannidis, D. G., Seto, I., Hamm, M. P., Thomson, D., Hartling, L., Ioannidis, J. P., Curtis, S., Constantin, E., Batmanabane, G., Klassen, T., Williams, K. 2012; 129: S161-S184


    An important step toward improvement of the conduct of pediatric clinical research is the standardization of the ages of children to be included in pediatric trials and the optimal age-subgroups to be analyzed.We set out to evaluate empirically the age ranges of children, and age-subgroup analyses thereof, reported in recent pediatric randomized clinical trials (RCTs) and meta-analyses. First, we screened 24 RCTs published in Pediatrics during the first 6 months of 2011; second, we screened 188 pediatric RCTs published in 2007 in the Cochrane Central Register of Controlled Trials; third, we screened 48 pediatric meta-analyses published in the Cochrane Database of Systematic Reviews in 2011. We extracted information on age ranges and age-subgroups considered and age-subgroup differences reported.The age range of children in RCTs published in Pediatrics varied from 0.1 to 17.5 years (median age: 5; interquartile range: 1.8-10.2) and only 25% of those presented age-subgroup analyses. Large variability was also detected for age ranges in 188 RCTs from the Cochrane Central Register of Controlled Trials, and only 28 of those analyzed age-subgroups. Moreover, only 11 of 48 meta-analyses had age-subgroup analyses, and in 6 of those, only different studies were included. Furthermore, most of these observed differences were not beyond chance.We observed large variability in the age ranges and age-subgroups of children included in recent pediatric trials and meta-analyses. Despite the limited available data, some age-subgroup differences were noted. The rationale for the selection of particular age-subgroups deserves further study.

    View details for DOI 10.1542/peds.2012-0055J

    View details for Web of Science ID 000307396800009

    View details for PubMedID 22661763

  • Standard 6: Age Groups for Pediatric Trials PEDIATRICS Williams, K., Thomson, D., Seto, I., Contopoulos-Ioannidis, D. G., Ioannidis, J. P., Curtis, S., Constantin, E., Batmanabane, G., Hartling, L., Klassen, T. 2012; 129: S153-S160

    View details for DOI 10.1542/peds.2012-0055I

    View details for Web of Science ID 000307396800008

    View details for PubMedID 22661762

  • Claims for improved survival from systemic corticosteroids in diverse conditions: an umbrella review EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2012; 42 (3): 233-244


    Systemic corticosteroids have been proposed for numerous indications and there are many claims that corticosteroids can reduce mortality in diverse conditions.We performed an umbrella, agenda-wide review of the evidence on systemic corticosteroids and mortality, focusing primarily on large trials (defined as those with > 100 deaths) and meta-analyses. Searches were performed in PubMed and Cochrane Central Register of Controlled Trials (last update February 2011). We also examined whether spurious subset analyses may be responsible for claims of survival benefits in indications where only small trials had been available.Among 257 identified randomized trials with mortality data in their abstract, we found 14 large trials pertaining to 10 different indications. Although 10 of these 14 trials have reported statistically significant survival differences in subset analyses, none shows a nominally statistically significant (P < 0·05) decrease in death risk for any of the tested conditions when all deaths on all randomized patients are analysed. Meta-analyses for these conditions show statistically significant reductions in mortality only with antenatal corticosteroids for preterm labour (relative risk 0·77, 95% CI, 0·67-0·89) and in tuberculous meningitis (relative risk 0·78, 95% CI, 0·67-0·91). For conditions without any large trials, statistically significant reductions in mortality in meta-analyses were noted for Pneumocystis pneumonia (relative risk 0·54, 95% CI, 0·38-0·79) and alcoholic hepatitis (relative risk 0·63, 95% CI, 0·50-0·80). Many small trials that claim significant benefits, even those for classic indications such as typhoid fever and tetanus, have shown these benefits only in subset analyses.Corticosteroids have been documented to decrease mortality in some indications, in particular, antenatal use for preterm labour, tuberculous meningitis, Pneumocystis pneumonia, and alcoholic hepatitis. Many postulated benefits of corticosteroids on mortality may reflect 'vibration of treatment effects' leading to false-positive claims from spurious subset analyses and even for standard indications, such biases may have inflated the treatment effect estimates. More large trials are needed for serious, common conditions where use of corticosteroids is proposed.

    View details for DOI 10.1111/j.1365-2362.2011.02584.x

    View details for Web of Science ID 000299832800002

    View details for PubMedID 21880039

  • Different Black Box Warning Labeling for Same-Class Drugs JOURNAL OF GENERAL INTERNAL MEDICINE Panagiotou, O. A., Contopoulos-Ioannidis, D. G., Papanikolaou, P. N., Ntzani, E. E., Ioannidis, J. P. 2011; 26 (6): 603-610


    Black box warnings (BBWs) are the strongest medication-related safety warnings in a drug's labeling information and highlight major risks. Absence of a BBW or asynchronous addition of a BBW among same-class drugs could have major implications.We identified the 20 top-selling drugs in 2008 (10 with BBWs and 10 without BBWs on their label) that belonged to different drug classes. We collected labeling information on all drugs belonging in these 20 classes, and recorded differences in the presence and timing of acquisition of BBWs for same-class drugs.Across the 20 evaluated drug classes, we identified 176 different agents, of which 7 had been withdrawn for safety reasons. The reasons for the withdrawals became BBWs in other same-class agents only in two of the seven cases. Differences were identified in 9 of the 20 classes corresponding to 15 BBWs that were not present in all drugs of the same class. The information for 10 of the 15 different BBWs were included in the labels of same-class drugs as simple warnings or text, while it was absent entirely in 5 BBWs. The median interval from the time the BBW had appeared in another drug of the same class was 66 months.Differences in BBW labeling in same-class drugs are common and shape impressions about the safety of similar agents. BBW labeling needs to become more systematic.

    View details for DOI 10.1007/s11606-011-1633-9

    View details for Web of Science ID 000290576600010

    View details for PubMedID 21286838

  • Comparative Effectiveness of Medical Interventions in Adults Versus Children JOURNAL OF PEDIATRICS Contopoulos-Ioannidis, D. G., Baltogianni, M. S., Ioannidis, J. P. 2010; 157 (2): 322-330


    To estimate the comparative effectiveness of medical interventions in adults versus children.We identified from the Cochrane Database of Systematic Reviews (Issue 1, 2007) meta-analyses with data on at least 1 adult and 1 pediatric randomized trial with binary primary efficacy outcome. For each meta-analysis, we calculated the summary odds ratio of the adult trials and the pediatric trials, respectively; the relative odds ratio (ROR) of the adult versus pediatric odds ratios per meta-analysis; and the summary ROR across all meta-analyses. ROR <1 means that the experimental intervention is more unfavorable in children than adults.Across 128 eligible meta-analyses (1051 adult and 343 pediatric trials), the summary ROR did not show a statistically significant difference between adults and children (0.96; 95% confidence intervals, 0.86 to 1.08). However, in all meta-analyses except for 1, the individual ROR's 95% confidence intervals could not exclude a relative difference in efficacy over 20%. In two-thirds, the relative difference in observed point estimates exceeded 50%. Nine statistically significant discrepancies were identified; 4 of them were also clinically important.Treatment effects are on average similar in adults and children, but available evidence leaves large uncertainty about their relative efficacy. Clinically important discrepancies may occur.

    View details for DOI 10.1016/j.jpeds.2010.02.011

    View details for Web of Science ID 000279871700031

    View details for PubMedID 20434730

  • Reporting and interpretation of SF-36 outcomes in randomised trials: systematic review BRITISH MEDICAL JOURNAL Contopoulos-Ioannidis, D. G., Karvouni, A., Kouri, I., Ioannidis, J. P. 2009; 338


    To determine how often health surveys and quality of life evaluations reach different conclusions from those of primary efficacy outcomes and whether discordant results make a difference in the interpretation of trial findings.Systematic review.PubMed, contact with authors for missing information, and author survey for unpublished SF-36 data.Randomised trials with SF-36 outcomes (the most extensively validated and used health survey instrument for appraising quality of life) that were published in 2005 in 22 journals with a high impact factor.Analyses on the two composite and eight subdomain SF-36 scores that corresponded to the time and mode of analysis of the primary efficacy outcome.Of 1057 screened trials, 52 were identified as randomised trials with SF-36 results (66 separate comparisons). Only eight trials reported all 10 SF-36 scores in the published articles. For 21 of the 66 comparisons, SF-36 results were discordant for statistical significance compared with the results for primary efficacy outcomes. Of 17 statistically significant SF-36 scores where primary outcomes were not also statistically significant in the same direction, the magnitude of effect was small in six, moderate in six, large in three, and not reported in two. Authors modified the interpretation of study findings based on SF-36 results in only two of the 21 discordant cases. Among 100 additional randomly selected trials not reporting any SF-36 information, at least five had collected SF-36 data but only one had analysed it.SF-36 measurements sometimes produce different results from those of the primary efficacy outcomes but rarely modify the overall interpretation of randomised trials. Quality of life and health related survey information should be utilised more systematically in randomised trials.

    View details for DOI 10.1136/bmj.a3006

    View details for Web of Science ID 000263192800001

    View details for PubMedID 19139138

  • Recurrent Rhabdomyolysis in a Patient With Oculocutaneous Albinism Type 1 and Platelet Storage-Pool Deficiency AMERICAN JOURNAL OF MEDICAL GENETICS PART A Contopoulos-Ioannidis, D., Evangeliou, A., ter Laak, H., de Vries, B., Pfundt, R., Schewer, H., Smeitink, J., Tzoufi, M., Makis, A., Marinos, E., Hess, R., Adams, D., Huizing, M., Morava, E. 2008; 146A (23): 3100-3103

    View details for DOI 10.1002/ajmg.a.32569

    View details for Web of Science ID 000261636100020

    View details for PubMedID 19006216

  • Medicine - Life cycle of translational research for medical interventions SCIENCE Contopoulos-Ioannidis, D. G., Alexiou, G. A., Gouvias, T. C., Ioannidis, J. P. 2008; 321 (5894): 1298-1299

    View details for DOI 10.1126/science.1160622

    View details for Web of Science ID 000258914300031

    View details for PubMedID 18772421

  • International ranking systems for universities and institutions: a critical appraisal BMC MEDICINE Ioannidis, J. P., Patsopoulos, N. A., Kavvoura, F. K., Tatsioni, A., Evangelou, E., Kouri, I., Contopoulos-Ioannidis, D. G., Liberopoulos, G. 2007; 5


    Ranking of universities and institutions has attracted wide attention recently. Several systems have been proposed that attempt to rank academic institutions worldwide.We review the two most publicly visible ranking systems, the Shanghai Jiao Tong University 'Academic Ranking of World Universities' and the Times Higher Education Supplement 'World University Rankings' and also briefly review other ranking systems that use different criteria. We assess the construct validity for educational and research excellence and the measurement validity of each of the proposed ranking criteria, and try to identify generic challenges in international ranking of universities and institutions.None of the reviewed criteria for international ranking seems to have very good construct validity for both educational and research excellence, and most don't have very good construct validity even for just one of these two aspects of excellence. Measurement error for many items is also considerable or is not possible to determine due to lack of publication of the relevant data and methodology details. The concordance between the 2006 rankings by Shanghai and Times is modest at best, with only 133 universities shared in their top 200 lists. The examination of the existing international ranking systems suggests that generic challenges include adjustment for institutional size, definition of institutions, implications of average measurements of excellence versus measurements of extremes, adjustments for scientific field, time frame of measurement and allocation of credit for excellence.Naïve lists of international institutional rankings that do not address these fundamental challenges with transparent methods are misleading and should be abandoned. We make some suggestions on how focused and standardized evaluations of excellence could be improved and placed in proper context.

    View details for DOI 10.1186/1741-7015-5-30

    View details for Web of Science ID 000252409300001

    View details for PubMedID 17961208

  • Pharmacogenetics of the response to beta 2 agonist drugs: a systematic overview of the field. Pharmacogenomics Contopoulos-Ioannidis, D. G., Kouri, I., Ioannidis, J. P. 2007; 8 (8): 933-958


    The response to beta2-agonist treatment shows large repeatability within individuals and may thus be determined by genetic influences. Here we present a systematic overview of the available genetic association and linkage data for beta2-agonist treatment response. Systematic searches identified 66 eligible articles, as of March 2007, pertaining either to B2AR gene polymorphisms and short-acting or long-acting beta2-agonists or to another 29 different genes. We systematize these study results according to gene, agent and type of outcomes addressed. The systematic review highlights major challenges in the field, including extreme multiplicity of analyses; lack of consensus for main phenotypes of interest; typically small sample sizes; and poor replicability of the proposed genetic variants. Future studies will benefit from standardization of analyses and outcomes, hypothesis-free genome-wide association testing platforms, potentially additional fine mapping around new discovered variants, and large-scale collaborative studies with prospective plans for replication among several teams, with transparent public recording of all data.

    View details for PubMedID 17716228

  • Genetic predisposition to asthma and atopy RESPIRATION Contopoulos-Ioannidis, D. G., Kouri, I. N., Ioannidis, J. P. 2007; 74 (1): 8-12


    A large number of studies have tried to identify heritable components in the susceptibility to asthma and atopy phenotypes. This review examines the evidence of multigenetic inheritance for these conditions. We identified in the literature at least 372 gene-disease association studies for asthma and 124 for atopy published in the last 6 years. Gene-environment analyses were performed in 41 and 14 articles, respectively, in the same time period. Many postulated associations have been probed with limited sample sizes and will require more extensive replication and large-scale evidence. Meta-analyses have been performed for polymorphisms in 5 genes and provide modest evidence for genetic association of asthma with ADAM33 and TNFA gene polymorphisms. Meta-analyses of linkage studies show that it is unlikely to detect strong linkage peaks for asthma susceptibility. However, linkage was claimed between loci on chromosomes 2, 4, 6, 9, 10, 11 and 15 and total serum IgE levels. Careful definitions and standardization of phenotypes across teams of investigators are important to endorse. New large-scale testing platforms may offer new opportunities for discovering susceptibility gene variants, but they need to be coupled with careful study design, international collaboration, and possibly also dissection of gene-environment interactions.

    View details for DOI 10.1159/000096833

    View details for Web of Science ID 000244565400003

    View details for PubMedID 17190999

  • An empirical evaluation of multifarious outcomes in pharmacogenetics: beta-2 adrenoceptor gene polymorphisms in asthma treatment PHARMACOGENETICS AND GENOMICS Contopoulos-Ioannidis, D. G., Alexiou, G. A., Gouvias, T. C., Ioannidis, J. P. 2006; 16 (10): 705-711


    Pharmacogenetics promises to individualize therapeutics. Concerns, however, exist about the lack of replication of discoveries. Selective use of different endpoints, times of assessment, types of interventions and genetic groups across studies may lead to spurious results. Here, we examined the variability of definitions of endpoints and analyses reported across studies addressing the association of the Arg16Gly and/or Gln27Glu polymorphisms of the beta2-adrenergic receptor gene with clinical response to beta2-agonist therapy in asthma.We systematically calculated the number and type of endpoints and analyses reported across studies and recorded the appraisal of their statistical significance.Across 21 studies, the total number of probed and reported associations was 487 when the multiple endpoints and types of comparisons presented by multiple comparisons were considered (337 for Arg16Gly, 98 for Gln27Glu and 52 for their haplotypes): 465 (95%) were probed only once; only six associations were probed twice and two associations were probed five times, for the same endpoint, time of assessment, type of interventions and genetic group. Most studies (17/21) claimed at least one significant association. Overall, however, 243/487 (49.9%) probed and reported associations were not statistically significant, 120 (24.6%) were of unspecified statistical significance, 86 (17.7%) were statistically significant only for specific selected genetic contrasts and only 38 (7.8%) were genuinely statistically significant for the comparison between all available genetic groups.The multifarious outcomes in this literature are inconsistent across studies and susceptible to selective reporting. The lack of standardization hinders the evaluation of replication validity for reported discoveries.

    View details for Web of Science ID 000203009100002

    View details for PubMedID 17001289

  • Hereditary hyperferritinemia cataract syndrome in three unrelated families of western Greek origin caused by the C39 > G mutation of L-ferritin IRE BLOOD CELLS MOLECULES AND DISEASES Papanikolaou, G., Chandrinou, H., Bouzas, E., Contopoulos-Ioannidis, D., Kalotychou, V., Prentzas, K., Lilakos, K., Asproudis, I., Palaiologou, D., Premetis, E., Papassotiriou, I., Sakellaropoulos, N. 2006; 36 (1): 33-40


    Hereditary hyperferritinemia-cataract syndrome (HHCS) is a well-characterized autosomal dominant disease caused by mutations in the iron responsive element (IRE) of ferritin L-chain (FTL) mRNA. Mutations in the IRE result in reduced binding of the trans-acting iron regulatory proteins (IRPs) and hence in upregulation of ferritin L-chain synthesis. The disease is characterized by increased L-ferritin in serum and tissues and early onset of bilateral cataracts. Iron metabolism is normal, and there is no tissue iron overload. At least 25 nucleotide substitutions and deletions in the L-ferritin IRE have been described in families with HHCS, originating from diverse European, Australian and North American populations. We studied the molecular pathogenesis of HHCS in three unrelated kinderships of western Greek origin, with 19 affected members. We identified a relatively rare C39G mutation located in the hexanucleotide loop of L-ferritin IRE. Computational analysis of mRNA folding of mutant FTL IRE predicted that the C39 > G mutation leads to a rearrangement of base pairing in this critical region, which is likely to modify the IRP binding affinity. All subjects with HHCS were heterozygotes for the same C39G mutation. Clinical and laboratory phenotypes were described. Moreover, there was evidence of an association between this FTL IRE stem-loop mutation and very high ferritin levels. Our findings broaden the list of populations where HHCS has been described.

    View details for DOI 10.1016/j.bcmd.2005.10.003

    View details for Web of Science ID 000234880000006

    View details for PubMedID 16406710

  • Meta-analysis of the association of beta 2-adrenergic receptor polymorphisms with asthma phenotypes JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Contopoulos-Ioannidis, D. G., Manoli, E. N., Ioannidis, J. P. 2005; 115 (5): 963-972


    Two common polymorphisms of the beta2-adrenergic receptor gene (Arg16Gly and Gln27Glu ) have been extensively studied for their possible association with asthma-related phenotypes, but the results of individual studies have been inconclusive.We aimed to integrate quantitatively the available evidence on the association of the Arg16Gly and the Gln27Glu polymorphisms with asthma, nocturnal asthma, asthma severity, and bronchial hyperresponsiveness.Meta-analysis of case-control and cohort studies using random effects models.A total of 28 studies were included in the meta-analysis. The summary estimates suggested that neither the Gly16 nor the Glu27 allele contributes to asthma susceptibility overall (odds ratio [OR], 1.01; 95% CI, 0.90-1.13; and OR, 0.95; 95% CI, 0.83-1.09, respectively) or to bronchial hyperresponsiveness (OR, 0.90; 95% CI, 0.77-1.05; and OR, 1.07; 95% CI, 0.94-1.22, respectively). There was a strong association of Gly16 with nocturnal asthma (OR, 2.20; 95% CI, 1.56-3.11) and a less strong association with severe or moderate rather than milder asthma (OR, 1.42; 95% CI, 1.04-1.94). No such effects were seen for the Glu27 allele (OR, 1.02; 95% CI, 0.74-1.40; and OR, 0.82; 95% CI, 0.59-1.14, respectively). Moreover, there was evidence that Gly16 homozygotes had a much higher risk for nocturnal asthma (OR, 5.15; 95% CI, 2.44-10.84) and asthma severity (OR, 2.84; 95% CI, 1.62-4.96) than the Arg16 homozygotes.The Gly16 allele of the beta2-adrenergic receptor gene predisposes to nocturnal asthma, and this may also explain the association with asthma severity. Neither polymorphism modulates the risk for bronchial hyperresponsiveness or mild asthma.

    View details for DOI 10.1016/j.jaci.2004.12.1119

    View details for Web of Science ID 000229055100011

    View details for PubMedID 15867853

  • Comparison of large versus smaller randomized trials for mental health-related interventions AMERICAN JOURNAL OF PSYCHIATRY Contopoulos-Ioannidis, D. G., Gilbody, S. M., Trikalinos, T. A., Churchill, R., Wahlbeck, K., Ioannidis, J. P. 2005; 162 (3): 578-584


    The extent of disagreement between large and smaller randomized, controlled trials on mental health issues is unknown. The authors aimed to compare the results of large versus smaller trials on mental health-related interventions.The authors screened 161 Cochrane and 254 Database of Abstracts of Reviews of Effectiveness systematic reviews on mental health-related interventions. They identified 16 meta-analyses with at least one "large" randomized trial with sample size >800 and at least one "smaller" trial. Effect sizes were calculated separately for large and smaller trials. Heterogeneity was assessed between all studies, within each group (large and smaller studies), and between large and smaller studies.Significant between-study heterogeneity was seen in five meta-analyses. By random-effects calculations, the results of large and smaller trials differed beyond chance in four meta-analyses (25%). In three of these disagreements (effect of day care on IQ, discontinuation of antidepressants, risperidone versus typical antipsychotics for schizophrenia), the smaller trials showed greater effect sizes than the large trials. The inverse was seen in one case (olanzapine versus typical antipsychotics for schizophrenia). With fixed-effects models, disagreements beyond chance occurred in five cases (31%). In four meta-analyses, the effect size differed over twofold between large and smaller trials. Various quality and design parameters were identified as potential explanations for some disagreements.Large trials are uncommon in mental health. Their results are usually comparable with the results of smaller studies, but major disagreements do occur. Both large and smaller trials should be scrutinized as they offer a continuum of randomized evidence.

    View details for Web of Science ID 000227523500022

    View details for PubMedID 15741476

  • Anticonvulsants for alcohol withdrawal COCHRANE DATABASE OF SYSTEMATIC REVIEWS Polycarpou, A., Papanikolau, P., Ioannidis, J. P., Contopoulos-Ioannidis, D. G. 2005


    Alcohol withdrawal syndrome is a cluster of symptoms that occurs in alcohol-dependent people after cessation or reduction in alcohol use. This systematic review focuses on the evidence of anticonvulsants' use in the treatment of alcohol withdrawal symptoms.To evaluate the effectiveness and safety of anticonvulsants in the treatment of alcohol withdrawal.We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2004); MEDLINE (1966 to October 2004); EMBASE (1988 to October 2004) and EU-PSI PSI-Tri database with no language and publication restrictions and references of articles.All randomized controlled trials examining the effectiveness, safety and overall risk-benefit of an anticonvulsant in comparison with a placebo or other pharmacological treatment or another anticonvulsant were considered.The authors independently assessed trial quality extracted data.Forty-eight studies, involving 3610 people were included. Despite the considerable number of randomized controlled trials, there was a variety of outcomes and of different rating scales that led to a limited quantitative synthesis of data. For the anticonvulsant versus placebo comparison, therapeutic success tended to be more common among the anticonvulsant-treated patients (relative risk (RR) 1.32; 95% confidence interval (CI) 0.92 to 1.91), and anticonvulsant tended to show a protective benefit against seizures (RR 0.57; 95% CI 0.27 to 1.19), but no effect reached formal statistical significance. For the anticonvulsant versus other drug comparison, CIWA-Ar score showed non-significant differences for the anticonvulsants compared to the other drugs at the end of treatment (weighted mean difference (WMD) -0.73; 95% CI -1.76 to 0.31). For the subgroup analysis of carbamazepine versus benzodiazepine, a statistically significant protective effect was found for the anticonvulsant (WMD -1.04; 95% CI -1.89 to -0.20), p = 0.02), but this was based on only 260 randomized participants. There was a non-significant decreased incidence of seizures (RR 0.50; 95% CI 0.18 to 1.34) favouring the patients that were treated with anticonvulsants than other drugs, and side-effects tended to be less common in the anticonvulsant-group (RR 0.56; 95% CI 0.31 to 1.02).It is not possible to draw definite conclusions about the effectiveness and safety of anticonvulsants in alcohol withdrawal, because of the heterogeneity of the trials both in interventions and the assessment of outcomes. The extremely small mortality rate in all these studies is reassuring, but data on other safety outcomes are sparse and fragmented.

    View details for DOI 10.1002/14651858.CD00564.pub2

    View details for Web of Science ID 000232202500072

    View details for PubMedID 16034965

  • Treatment options for acute sinusitis in children CURRENT ALLERGY AND ASTHMA REPORTS Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2004; 4 (6): 471-477


    Much controversy exists regarding the best diagnostic method for acute sinusitis, the efficacy of antibiotics, the best choice of antibiotics, the most appropriate duration of therapy, and the efficacy of ancillary measures and nasal corticosteroids. The therapeutic goal is to identify those children who are more likely to have bacterial sinusitis and unlikely to resolve spontaneously, who may require treatment with antibiotics. The inaccuracy of clinical signs and symptoms complicates further the management of these children. Acute sinusitis is expected to resolve spontaneously in most cases, including many cases of bacterial sinusitis. Antibiotics are needed only for a minority of non-self-resolving infections. Based on current resistance considerations, approximately 80% of bacterial infections are expected to respond to standard doses of amoxicillin. High-dose amoxicillin, amoxicillin/clavulanate, or other b-lactam antibiotics should be considered for children at high risk for carrying resistant organisms. Evidence for the effectiveness of ancillary measures is limited.

    View details for Web of Science ID 000230808900008

    View details for PubMedID 15462714

  • Establishment of genetic associations for complex diseases is independent of early study findings EUROPEAN JOURNAL OF HUMAN GENETICS Trikalinos, T. A., Ntzani, E. E., Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 2004; 12 (9): 762-769


    Numerous genetic association studies for complex diseases are performed. Investigators place emphasis on formal statistical significance (P-values < 0.05), but the predictive ability of early statistically significant ('positive') findings is unclear. We scrutinized 55 cumulative meta-analyses of genetic associations (579 studies), in order to assess whether having statistical significance in the earliest (first) published study or in at least half among several (> or =3) early-published studies, or high statistical significance in early studies had any predictive ability for establishing or refuting the presence of the genetic association in subsequent research. In 35 associations, a first study was 'positive' and in 15 associations more than half of the early-published reports were 'positive'. The average publication rate of subsequent studies increased 1.71-fold with a 'positive' first report. When compared against the summary results of subsequent research, sensitivity and specificity were 0.65 and 0.38 for the first reports, and 0.40 and 0.73, respectively, when at least three early studies were considered. First studies also had poor predictive ability, when we considered the estimated attributable fraction and coverage of the 95% confidence interval thereof or higher levels of statistical significance. We conclude that although 'positive' findings in the very first reports provide strong incentive for conducting more studies on a putative genetic epidemiological association, the statistical significance or even the magnitude of the effect of early studies cannot adequately predict eventual establishment of an association. Conversely, many genuine epidemiological associations would be missed, if research were abandoned after early underpowered 'negative' studies.

    View details for DOI 10.1038/sj.ejhg.5201227

    View details for Web of Science ID 000223403900011

    View details for PubMedID 15213707

  • Extended-interval aminoglycoside administration for children: A meta-analysis PEDIATRICS Contopoulos-Ioannidis, D. G., Giotis, N. D., Baliatsa, D. V., Ioannidis, J. P. 2004; 114 (1): E111-E118


    There has been a long-standing debate regarding whether aminoglycosides should be administered on a multiple daily dosing (MDD) or once-daily dosing (ODD) schedule. Several unique characteristics of the aminoglycosides make ODD an attractive and possibly superior alternative to MDD. These include concentration-dependent bactericidal activity; postantibiotic effect, which allows continued efficacy even when serum concentrations fall below expected minimum inhibitory concentrations; decreased risk of adaptive resistance; and diminished accumulation in renal tubules and inner ear.To assess the relative efficacy and toxicity of ODD, compared with MDD, of aminoglycosides among pediatric patients.Randomized, controlled trials among children, evaluating the relative efficacy and toxicity of ODD versus MDD of aminoglycosides, with similar total daily doses in the compared arms, were selected.PubMed (1966-2003) and Embase (1982-2003) databases, the Cochrane Controlled Trials Registry (2003), and references of eligible studies and pediatric review articles were searched.Study population characteristics and outcome data were extracted independently in duplicate, and consensus was reached on all items. The following outcome data were considered: (1) clinical or microbiologic failure, as defined in each study; (2) clinical failure; (3) microbiologic failure; (4) primary nephrotoxicity, ie, any rise in serum creatinine or decrease in creatinine clearance with thresholds as defined in each study; (5) secondary nephrotoxicity, ie, urinary excretion of proteins or phospholipids; and (6) ototoxicity based on pure tone audiometry, brainstem auditory evoked responses, or otoacoustic emissions for neonates and infants, vestibular testing, clinical impression, or any other method. All of the efficacy and toxicity outcomes were evaluated at the end of therapy.Identification of eligible studies and study characteristics: 24 eligible studies published between 1991 and 2003 were identified. Aminoglycosides were used in different clinical settings (neonatal intensive care unit: 6 studies; cystic fibrosis: 3 studies; cancer: 5 studies; urinary tract infections: 4 studies; diverse infectious indications: 5 studies; pediatric intensive care unit: 1 study). Aminoglycosides used included amikacin (9 studies), gentamicin (11 studies), tobramycin (2 studies), netilmicin (2 studies), and tobramycin or netilmicin (1 study).There was no significant difference between ODD and MDD in the clinical failure rate, microbiologic failure rate, and combined clinical or microbiologic failure rates, but trends favored ODD consistently. There was no between-study heterogeneity for any outcome. Efficacy analysis of all trials indicating either clinical or microbiologic failures demonstrated pooled failure rates of 4.6% (23 of 501 cases) in the ODD arms and 6.9% (34 of 494 cases) in the MDD arms. The fixed-effects risk ratio was 0.71 (95% confidence interval [CI]: 0.45-1.11). A statistically significant benefit was seen with ODD over MDD in trials using amikacin, whereas no statistical significance was seen in trials using other antibiotics. The pooled clinical failure rates were 6.7% (22 of 330 cases) in the ODD arms and 10.4% (34 of 327 cases) in the MDD arms. The fixed-effects risk ratio was 0.67 (95% CI: 0.42-1.07). The pooled microbiologic failure rates were 1.8% (5 of 283 cases) with ODD and 4.0% (11 of 275 cases) with MDD. The fixed-effects risk ratio was 0.51 (95% CI: 0.22-1.18). NEPHROTOXICITY: There was no significant difference between ODD and MDD in the primary nephrotoxicity outcomes. Secondary nephrotoxicity outcomes were significantly better with ODD. The pooled primary nephrotoxicity rates were 1.6% (15 of 955 cases) in the ODD arms and 1.6% (15 of 923 cases) in the MDD arms. The fixed-effects risk ratio was 0.97 (95% CI: 0.55-1.69). The pooled secondary nephrotoxicity rates were 4.4% (3 of 69 cases) in the ODD arms and 15.9% (11 of 69 cases) in the MDD arms, suggesting a statistically significant superiority of ODD. The fixed-effects risk ratio was 0.33 (95% CI: 0.12-0.89). Results were consistent across types of clinical settings and aminoglycosides. OTOTOXICITY: There was no significant difference between ODD and MDD in the primary ototoxicity outcomes. The pooled ototoxicity rates for studies that provided auditory testing results were 2.3% (10 of 436 cases) in the ODD arms and 2.0% (8 of 406 cases) in the MDD arms. The fixed-effects risk ratio was 1.06 (95% CI: 0.51-2.19). In studies that provided clinical vestibular function testing results, no toxicity was documented among 209 patients given ODD and 206 patients given MDD. Studies noting only the clinical impression of hearing impairment also failed to identify any toxicity (ODD: 114 cases; MDD: 114 cases). SUBGROUP AND BIAS ANALYSES: We detected no statistically significant differences between ODD and MDD in any of the examined subgroups (neonatal intensive care unit, cystic fibrosis, cancer, or urinary tract infection), with respect to combined clinical or microbiologic failure outcomes, primary nephrotoxicity outcomes, or ototoxicity (based on auditory testing), when sufficient data were available. Moreover, there was no significant relationship between the effect size (risk ratio) and the trial size for any of the outcomes. DATA INTERPRETATION: Clinical failures were uncommon in the pediatric trials, regardless of the regimen used. If anything, fewer clinical failures tended to occur with ODD. Moreover, we observed a trend toward decreased bacteriologic failures. One meta-analysis of adult data suggested that ODD might reduce nephrotoxicity, whereas other meta-analyses showed nonsignificant trends or no difference in nephrotoxicity outcomes. In our meta-analysis, we were not able to show any reduction in the risk of primary nephrotoxicity outcomes with ODD. However, the event rate was much lower among children, compared with adults, and the secondary nephrotoxicity outcomes favored ODD. Finally, although the 2 regimens seemed equivalent with respect to ototoxicity, reporting on ototoxicity outcomes was incomplete. Reassuringly, even in the trials that performed auditory testing, the rates of ototoxicity in the MDD arms were very low. These results were consistent with meta-analyses of adult data, which showed no difference in ototoxicity rates between ODD and MDD.Although single trials have been small, the available randomized evidence supports the general adoption of ODD of aminoglycosides in pediatric clinical practice. This approach minimizes cost, simplifies administration, and provides similar or even potentially improved efficacy and safety, compared with MDD of these drugs.

    View details for Web of Science ID 000222439200017

    View details for PubMedID 15231982

  • Effects of CCR5-Delta 32 and CCR2-64I alleles on disease progression of perinatally HIV-1-infected children: an international meta-analysis AIDS Ioannidis, J. P., Contopoulos-Ioannidis, D. G., Rosenberg, P. S., Goedert, J. J., De Rossi, A., Espanol, T., Frenkel, L., Mayaux, M. J., Newell, M. L., Pahwa, S. G., Rousseau, C., Scarlatti, G., Sei, S., Sen, L., O'Brien, T. R. 2003; 17 (11): 1631-1638


    Among perinatally infected children, the effects of certain alleles of the CCR5 and CCR2 genes on the rate of disease progression remain unclear. We addressed the effects of CCR5-delta32 and CCR2-64I in an international meta-analysis.Genotype data were contributed from 10 studies with 1317 HIV-1-infected children (7263 person-years of follow-up). Time-to-event analyses were performed stratified by study and racial group. Endpoints included progression to clinical AIDS, death, and death after the diagnosis of clinical AIDS. The time-dependence of the genetic effects was specifically investigated.There was large heterogeneity in the observed rates of disease progression between different cohorts. For progression to clinical AIDS, both CCR5-delta32 and CCR2-64I showed overall non-significant trends for protection [hazard ratios 0.84, 95% confidence interval (CI) 0.58-1.23; and 0.87, 95% CI 0.67-1.14, respectively]. However, analyses of survival showed statistically significant time-dependence. No deaths occurred among CCR5-delta32 carriers in the first 3 years of life, whereas there was no protective effect (hazard ratio 0.95; 95% CI 0.43-2.10) in later years (P=0.01 for the time-dependent model). For CCR2-64I, the hazard ratio for death was 0.69 (95% CI 0.39-1.21) in the first 6 years of life and 2.56 (95% CI 1.26-5.20) in subsequent years (P<0.01 for the time-dependent model). CCR5-delta32 and CCR2-64I offered no clear protection after clinical AIDS had developed.The CCR5-delta32 and CCR2-64I alleles are associated with a decreased risk of death among perinatally infected children, but only for the first years of life.

    View details for DOI 10.1097/01.aids.0000060411.18106.0f

    View details for Web of Science ID 000184661800007

    View details for PubMedID 12853745

  • Translation of highly promising basic science research into clinical applications AMERICAN JOURNAL OF MEDICINE Contopoulos-Ioannidis, D. G., Ntzani, E. E., Ioannidis, J. P. 2003; 114 (6): 477-484


    To evaluate the predictors of and time taken for the translation of highly promising basic research into clinical experimentation and use.We identified 101 articles, published between 1979 and 1983 in six major basic science journals, which clearly stated that the technology studied had novel therapeutic or preventive promises. Each case was evaluated for whether the promising finding resulted in relevant randomized controlled trials and clinical use. Main outcomes included the time to published trials, time to published trials with favorable results ("positive" trials), and licensed clinical use.By October 2002, 27 of the promising technologies had resulted in at least one published randomized trial, 19 of which had led to the publication of at least one positive randomized trial. Five basic science findings are currently licensed for clinical use, but only has been used extensively for the licensed indications. Promising technologies that did not lead to a published human study within 10 to 12 years were unlikely to be tested in humans subsequently. Some form of industry involvement in the basic science publication was the strongest predictor of clinical experimentation, accelerating the process by about eightfold (95% confidence interval: 3 to 19) when an author had industry affiliations.Even the most promising findings of basic research take a long time to translate into clinical experimentation, and adoption in clinical practice is rare.

    View details for DOI 10.1016/S0002-9343(03)00013-5

    View details for Web of Science ID 000182551900007

    View details for PubMedID 12731504

  • Genetic associations in large versus small studies: an empirical assessment LANCET Ioannidis, J. P., Trikalinos, T. A., Ntzani, E. E., Contopoulos-Ioannidis, D. G. 2003; 361 (9357): 567-571


    Advances in human genetics could help us to assess prognosis on an individual basis and to optimise the management of complex diseases. However, different studies on the same genetic association sometimes have discrepant results. Our aim was to assess how often large studies arrive at different conclusions than smaller studies, and whether this situation arises more frequently when findings of first published studies disagree with those of subsequent research.We examined the results of 55 meta-analyses (579 study comparisons) of genetic associations and tested whether the magnitude of the genetic effect differs in large versus smaller studies.We noted significant between-study heterogeneity in 26 (47%) meta-analyses. The magnitude of the genetic effect differed significantly in large versus smaller studies in ten (18%), 20 (36%), and 21 (38%) meta-analyses with tests of rank correlation, regression on SE, and regression on inverse of variance, respectively. The largest studies generally yielded more conservative results than the complete meta-analyses, which included all studies (p=0.005). In 14 (26%) meta-analyses the proposed association was significantly stronger in the first studies than in subsequent research. Only in nine (16%) meta-analyses was the genetic association significant and replicated without hints of heterogeneity or bias. There was little concordance in first versus subsequent discrepancies, and large versus small discrepancies.Genuine heterogeneity and bias could affect the results of genetic association studies. Genetic risk factors for complex diseases should be assessed cautiously and, if possible, using large scale evidence.

    View details for Web of Science ID 000181033400010

    View details for PubMedID 12598142

  • Acute sinusitis in children: current treatment strategies. Paediatric drugs Contopoulos-Ioannidis, D. G., Ioannidis, J. P., Lau, J. 2003; 5 (2): 71-80


    Acute sinusitis is a very common infection in childhood, but its management remains a controversial issue. Antibacterials may be effective in selected children, but direct evidence is limited. One randomized, placebo-controlled trial has shown that amoxicillin or amoxicillin/clavulanate are better than placebo for children with symptoms of nasal discharge and cough that are persistent (over 10 days) and not improving. However, another placebo-controlled trial of the same agents did not demonstrate any benefit from antibacterials in a patient population selected with a clinical diagnosis of sinusitis of moderate severity, based on a composite clinical symptom score. A systematic assessment of cure rates with various antibacterials shows no consistent differences between classes. Evidence on the use of ancillary measures and nasal corticosteroids is also limited. The only randomized, placebo-controlled trial of antihistamines and decongestants has shown no incremental benefit when given in addition to amoxicillin. Another placebo-controlled randomized trial showed some transient symptomatic improvement with the use of nasal corticosteroids. No randomized trials exist on the use of antral lavage in children with acute sinusitis. The current rates of antimicrobial resistance among commonly implicated pathogens should be considered in therapeutic decisions. However, there is no evidence from well-designed trials on specifically how to manage children at high risk of carrying resistant organisms. The inaccuracy of clinical signs and symptoms in documenting the diagnosis further complicates therapeutic decisions. Nevertheless, radiographic assessment does not meaningfully improve the accuracy of the diagnosis for uncomplicated cases, and it is not cost effective. In the absence of definitive evidence, treatment with amoxicillin 45 mg/kg/day in two divided doses may be used in selected patients with symptoms that are persistent and not improving. High doses (90 mg/kg in two divided doses) may also be considered, and amoxicillin/clavulanate may be a more appropriate choice when there is high risk of resistant pathogens, e.g. in a child attending a childcare center, or recent use of antibacterials. However, a considerable proportion of children, especially those with mild or improving symptoms, may not have to be treated at all.

    View details for PubMedID 12529160

  • Effect of CCR5-Delta 32 heterozygosity on the risk of perinatal HIV-1 infection: A meta-analysis JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Contopoulos-Ioannidis, D. G., O'Brien, T. R., Goedert, J. J., Rosenberg, P. S., Ioannidis, J. P. 2003; 32 (1): 70-76


    Several studies have investigated whether heterozygosity for a 32-basepair deletion in the CC chemokine receptor 5 gene (CCR5-Delta32 ) affects susceptibility to perinatal HIV-1 infection, but results have been inconclusive. We performed a meta-analysis of published data from 11 studies of HIV-1 perinatally exposed children who were genotyped for the CCR5-Delta32 polymorphism. The crude overall HIV-1 infection rates, by simple data pooling, were 20% (one of five) amongCCR5-Delta32 homozygote children, 39% (131 of 335) among CCR5-Delta32 heterozygote children, and 40% (1408 of 3526) among wild-type CCR5 homozygote children. Compared with wild-type homozygotes, the random effects risk ratio for heterozygotes was 1.04 (95% confidence interval [CI], 0.92-1.17) among all children (N = 3861) and 1.03 (95% CI, 0.90-1.17) among those of European descent (n = 2890). Results were similar when adjusted for the available data on the CCR2-641 polymorphism (n = 1542). The meta-analysis clarifies that perinatal infection is not significantly altered by heterozygosity for CCR5-Delta32 in the child.

    View details for Web of Science ID 000180407600010

    View details for PubMedID 12514416

  • Azithromycin is effective in patients with chronic bronchitis - Reply JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY Contopoulos-Ioannidis, D. G., Ioannidis, J. P., Lau, J. 2002; 50 (3): 434-434

    View details for DOI 10.1093/jac/dkf120

    View details for Web of Science ID 000177999000021

  • Citation of randomized evidence in support of guidelines of therapeutic and preventive interventions JOURNAL OF CLINICAL EPIDEMIOLOGY Giannakakis, I. A., Haidich, A. B., Contopoulos-Ioannidis, D. G., Papanikolaou, G. N., Baltogianni, M. S., Ioannidis, J. P. 2002; 55 (6): 545-555


    Guideline statements may be supported by evidence obtained from various study designs, but randomized trials are usually considered most important for making recommendations about therapeutic and preventive interventions. This study evaluated the extent to which randomized trials are cited in guidelines published in major journals. The references of 191 guidelines of therapeutic and/or preventive interventions published in Annals of Internal Medicine, BMJ, JAMA, Lancet, NEJM and Pediatrics in 1979, 1984, 1989, 1994, and 1999, were analyzed. The percentage of guidelines not citing any randomized controlled trials (RCTs) decreased gradually from 95% in 1979 to 53% in 1999. Among 4,853 references of the guidelines, there were 393 RCTs (8.1% of total), 19 systematic reviews (0.4%), and 23 meta-analyses of RCTs (0.5%). Among 19 guidelines published in 1999 or 1994 with <2 RCTs cited, in eight cases additional pertinent RCTs were identified that had not been cited by the guideline. There is a clear increase in the use of randomized evidence by guidelines over time. However, several guidelines in major journals still cite few or no RCTs.

    View details for Web of Science ID 000175958600002

    View details for PubMedID 12063096

  • Meta-analysis of randomized controlled trials on the comparative efficacy and safety of azithromycin against other antibiotics for upper respiratory tract infections JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY Ioannidis, J. P., Contopoulos-Ioannidis, D. G., Chew, P., Lau, J. 2001; 48 (5): 677-689


    We carried out a meta-analysis of randomized controlled trials comparing 3-5 days of azithromycin with other antibiotics that are typically given in longer courses for the treatment of upper respiratory tract infections. For acute otitis media (19 comparisons including 3421 patients), acute sinusitis (11 comparisons including 1742 patients) and acute pharyngitis (16 comparisons including 2447 patients), azithromycin had similar clinical failure rates to the other antibiotics [random effects odds ratios 1.12, 95% confidence interval (CI) 0.81-1.54; 0.91, 95% CI 0.60-1.39; and 1.07, 95% CI 0.59-1.94, respectively]. The difference in clinical failures was <0.5%, and no 95% CIs exceeded 2.0%. There was no heterogeneity between studies. Subtle differences between comparators could have been due to chance. There were no significant differences in bacteriological outcomes. Azithromycin was discontinued because of adverse events in only 37 of 4870 (0.8%) patients. Short courses of azithromycin are as effective as longer courses of other antibiotics for upper respiratory tract infections. Convenience of dosing should be balanced against the increased cost of this regimen for the treatment of these common infections, where often no antibiotic may be indicated at all.

    View details for Web of Science ID 000172342800011

    View details for PubMedID 11679557

  • Replication validity of genetic association studies NATURE GENETICS Ioannidis, J. P., Ntzani, E. E., Trikalinos, T. A., Contopoulos-Ioannidis, D. G. 2001; 29 (3): 306-309


    The rapid growth of human genetics creates countless opportunities for studies of disease association. Given the number of potentially identifiable genetic markers and the multitude of clinical outcomes to which these may be linked, the testing and validation of statistical hypotheses in genetic epidemiology is a task of unprecedented scale. Meta-analysis provides a quantitative approach for combining the results of various studies on the same topic, and for estimating and explaining their diversity. Here, we have evaluated by meta-analysis 370 studies addressing 36 genetic associations for various outcomes of disease. We show that significant between-study heterogeneity (diversity) is frequent, and that the results of the first study correlate only modestly with subsequent research on the same association. The first study often suggests a stronger genetic effect than is found by subsequent studies. Both bias and genuine population diversity might explain why early association studies tend to overestimate the disease protection or predisposition conferred by a genetic polymorphism. We conclude that a systematic meta-analytic approach may assist in estimating population-wide effects of genetic risk factors in human disease.

    View details for Web of Science ID 000171911000017

    View details for PubMedID 11600885

  • Comparison of evidence of treatment effects in randomized and nonrandomized studies JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ioannidis, J. P., Haidich, A. B., Pappa, M., Pantazis, N., Kokori, S. I., Tektonidou, M. G., Contopoulos-Ioannidis, D. G., Lau, J. 2001; 286 (7): 821-830


    There is substantial debate about whether the results of nonrandomized studies are consistent with the results of randomized controlled trials on the same topic.To compare results of randomized and nonrandomized studies that evaluated medical interventions and to examine characteristics that may explain discrepancies between randomized and nonrandomized studies.MEDLINE (1966-March 2000), the Cochrane Library (Issue 3, 2000), and major journals were searched.Forty-five diverse topics were identified for which both randomized trials (n = 240) and nonrandomized studies (n = 168) had been performed and had been considered in meta-analyses of binary outcomes.Data on events per patient in each study arm and design and characteristics of each study considered in each meta-analysis were extracted and synthesized separately for randomized and nonrandomized studies.Very good correlation was observed between the summary odds ratios of randomized and nonrandomized studies (r = 0.75; P<.001); however, nonrandomized studies tended to show larger treatment effects (28 vs 11; P =.009). Between-study heterogeneity was frequent among randomized trials alone (23%) and very frequent among nonrandomized studies alone (41%). The summary results of the 2 types of designs differed beyond chance in 7 cases (16%). Discrepancies beyond chance were less common when only prospective studies were considered (8%). Occasional differences in sample size and timing of publication were also noted between discrepant randomized and nonrandomized studies. In 28 cases (62%), the natural logarithm of the odds ratio differed by at least 50%, and in 15 cases (33%), the odds ratio varied at least 2-fold between nonrandomized studies and randomized trials.Despite good correlation between randomized trials and nonrandomized studies-in particular, prospective studies-discrepancies beyond chance do occur and differences in estimated magnitude of treatment effect are very common.

    View details for Web of Science ID 000170429600030

    View details for PubMedID 11497536

  • Pathways for inappropriate dispensing of antibiotics for rhinosinusitis: A randomized trial CLINICAL INFECTIOUS DISEASES Contopoulos-Ioannidis, D. G., Koliofoti, I. D., Koutroumpa, I. C., Giannakakis, I. A., Ioannidis, J. P. 2001; 33 (1): 76-82


    We evaluated the extent of and factors that determine the inappropriate use of antibiotics that are obtained without a physician's prescription. Ninety-eight Greek pharmacists were visited by actress-researchers who played clients requesting antibiotics without a physician's prescription. Pharmacists were randomly challenged in a scenario that involved simulated cases of acute uncomplicated rhinosinusitis with either low fever (38.5 degrees C) or high fever (40 degrees C). Antibiotics were offered by 34 (69%) of 49 pharmacists who were presented with the high-fever scenario and by 42 (86%) of 49 pharmacists who were presented with the low-fever scenario (risk difference, 16.3%; P = .05). Thirty-two (65%) and 35 (71%) pharmacists in the high- and low-fever study arms, respectively, agreed to sell the actress-researchers broad-spectrum antibiotics. Only 28 (57%) and 17 (35%) pharmacists, respectively, recommended that the patient visit a physician (P = .03). Inappropriate recommendations regarding antibiotic use were very common in the studied setting. Antibiotics were more likely to be offered to persons who did not have a prescription when they were less likely to be clinically indicated.

    View details for Web of Science ID 000169101500019

    View details for PubMedID 11389498

  • The carboxyl terminus of the human cytomegalovirus UL37 immediate-early glycoprotein is conserved in primary strains and is important for transactivation JOURNAL OF GENERAL VIROLOGY Hayajneh, W. A., Contopoulos-Ioannidis, D. G., Lesperance, M. M., Venegas, A. M., Colberg-Poley, A. M. 2001; 82: 1569-1579


    The human cytomegalovirus (HCMV) UL37 exon 3 (UL37x3) open reading frame (ORF) encodes the carboxyl termini of two immediate-early glycoproteins (gpUL37 and gpUL37(M)). UL37x3 homologous sequences are not required for mouse cytomegalovirus (MCMV) growth in vitro; yet, they are important for MCMV growth and pathogenesis in vivo. Similarly, UL37x3 sequences are dispensable for HCMV growth in culture, but their requirement for HCMV growth in vivo is not known. To determine this requirement, we directly sequenced the complete UL37x3 gene in multiple HCMV primary strains. A total of 63 of the 310 amino acids in the UL37x3 ORF differ non-conservatively in one or more HCMV primary strains. The HCMV UL37x3 genetic diversity is non-random: the N-glycosylation (46/186 aa) and basic (9/15 aa) domains have the highest proportion of non-conservative variant amino acids. Nonetheless, most (15/17 signals) of the N-glycosylation signals are retained in all HCMV primary strains. Moreover, new N-glycosylation signals are encoded by 5/20 primary strains. In sharp contrast, the UL37x3 transmembrane (TM) ORF completely lacks diversity in all 20 HCMV sequenced primary strains, and only 1 of 28 cytosolic tail residues differs non-conservatively. To test the functional significance of the conserved carboxyl terminus, gpUL37 mutants lacking the TM and/or cytosolic tail were tested for transactivating activity. The gpUL37 carboxyl-terminal mutants are partially defective in hsp70 promoter transactivation even though they trafficked similarly to the wild-type protein into the endoplasmic reticulum and to mitochondria. From these results, we conclude that N-glycosylated gpUL37, particularly its TM and cytosolic domains, is important for HCMV growth in humans.

    View details for Web of Science ID 000169435800005

    View details for PubMedID 11413367

  • The sequence and antiapoptotic functional domains of the human cytomegalovirus UL37 exon 1 immediate early protein are conserved in multiple primary strains VIROLOGY Hayajneh, W. A., Colberg-Poley, A. M., Skaletskaya, A., Bartle, L. M., Lesperance, M. M., Contopoulos-Ioannidis, D. G., Kedersha, N. L., Goldmacher, V. S. 2001; 279 (1): 233-240


    The human cytomegalovirus UL37 exon 1 gene encodes the immediate early protein pUL37x1 that has antiapoptotic and regulatory activities. Deletion mutagenesis analysis of the open reading frame of UL37x1 identified two domains that are necessary and sufficient for its antiapoptotic activity. These domains are confined within the segments between amino acids 5 to 34, and 118 to 147, respectively. The first domain provides the targeting of the protein to mitochondria. Direct PCR sequencing of UL37 exon 1 amplified from 26 primary strains of human cytomegalovirus demonstrated that the promoter, polyadenylation signal, and the two segments of pUL37x1 required for its antiapoptotic function were invariant in all sequenced strains and identical to those in AD169 pUL37x1. In total, UL37 exon 1 varies between 0.0 and 1.6% at the nucleotide level from strain AD169. Only 11 amino acids were found to vary in one or more viral strains, and these variations occurred only in the domains of pUL37x1 dispensable for its antiapoptotic function. We infer from this remarkable conservation of pUL37x1 in primary strains that this protein and, probably, its antiapoptotic function are required for productive replication of human cytomegalovirus in humans.

    View details for Web of Science ID 000166516300023

    View details for PubMedID 11145905

  • Reporting of conflicts of interest in guidelines of preventive and therapeutic interventions. BMC medical research methodology Papanikolaou, G. N., Baltogianni, M. S., Contopoulos-Ioannidis, D. G., Haidich, A. B., Giannakakis, I. A., Ioannidis, J. P. 2001; 1: 3-?


    Guidelines published in major medical journals are very influential in determining clinical practice. It would be essential to evaluate whether conflicts of interests are disclosed in these publications. We evaluated the reporting of conflicts of interest and the factors that may affect such disclosure in a sample of 191 guidelines on therapeutic and/or preventive measures published in 6 major clinical journals (Annals of Internal Medicine, BMJ, JAMA, Lancet, New England Journal of Medicine, Pediatrics) in 1979, 1984, 1989, 1994 and 1999.Only 7 guidelines (3.7%) mentioned conflicts of interest and all were published in 1999 (17.5% (7/40) of guidelines published in 1999 alone). Reporting of conflicts of interest differed significantly by journal (p=0.026), availability of disclosure policy by the journal (p=0.043), source of funding (p < 0.001) and number of authors (p=0.004). In the entire database of 191 guidelines, a mere 18 authors disclosed a total of 24 potential conflicts of interest and most pertained to minor issues.Despite some recent improvement, reporting of conflicts of interest in clinical guidelines published in influential journals is largely neglected.

    View details for PubMedID 11405896

  • Maternal viral load and the risk of perinatal transmission of HIV-1 NEW ENGLAND JOURNAL OF MEDICINE Ioannidis, J. P., Contopoulos-Ioannidis, D. G. 1999; 341 (22): 1698-1699

    View details for Web of Science ID 000083847500017

    View details for PubMedID 10610439

  • Predictors and impact of losses to follow-up in an HIV-1 perinatal transmission cohort in Malawi INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Ioannidis, J. P., Taha, T. E., Kumwenda, N., Broadhead, R., Mtimavalye, L., Miotti, P., Yellin, F., Contopoulos-Ioannidis, D. G., Biggar, R. J. 1999; 28 (4): 769-775


    Large simple trials which aim to study therapeutic interventions and epidemiological associations of human immunodeficiency virus (HIV) infection, including perinatal transmission, in Africa may have substantial rates of loss to follow-up. A better understanding of the characteristics and the impact of women and children lost to follow-up is needed.We studied predictors and the impact of losses to follow-up of infants born in a large cohort of delivering women in urban Malawi. The cohort was established as part of a trial of vaginal cleansing with chlorhexidine during delivery to prevent mother-to-infant transmission of HIV.The HIV infection status could not be determined for 797 (36.9%) of 2156 infants born to HIV-infected mothers; 144 (6.7%) with missing status because of various sample problems and 653 (30.3%) because they never returned to the clinic. Notably, the observed rates of perinatal transmission were significantly lower in infants who returned later for determination of their infection status (odds ratio = 0.94 per month, P = 0.03), even though these infants must have had an additional risk of infection from breastfeeding. In multivariate models, infants of lower birthweight (P = 0.003) and, marginally, singletons (P = 0.09) were less likely to return for follow-up. The parents of infants lost to follow-up tended to be less educated (P < 0.001) and more likely to be in farming occupations, although one educated group, teachers and students, were also significantly less likely to return. Of these variables, infant birthweight, twins versus singletons, and maternal education were also associated with significant variation in the observed risk of perinatal transmission among infants of known HIV status.Several predictors of loss to follow-up were identified in this large HIV perinatal cohort. Losses to follow-up can impact the observed transmission rate and the risk associations in different studies.

    View details for Web of Science ID 000082344000026

    View details for PubMedID 10480709

  • Recursive cumulative meta-analysis: A diagnostic for the evolution of total randomized evidence from group and individual patient data JOURNAL OF CLINICAL EPIDEMIOLOGY Ioannidis, J. P., Contopoulos-Ioannidis, D. G., Lau, J. 1999; 52 (4): 281-291


    Meta-analyses of randomized evidence may include published, unpublished, and updated data in an ongoing estimation process that continuously accommodates more data. Synthesis may be performed either with group data or with meta-analysis of individual patient data (MIPD). Although MIPD with updated data is considered the gold standard of evidence, there is a need for a careful study of the impact different sources of data have on a meta-analysis and of the change in the treatment effect estimates over sequential information steps. Unpublished data and late-appearing data may be different from early-appearing data. Updated information after the end of the main study follow-up may be affected by cross-overs, missing information, and unblinding. The estimated treatment effect may thus depend on the completeness and updating of the available evidence. To address these issues, we present recursive cumulative meta-analysis (RCM) as an extension of cumulative metaanalysis. Recursive cumulative meta-analysis is based on the principle of recalculating the results of a cumulative meta-analysis with each new or updated piece of information and focuses on the evolution of the treatment effect as a more complete and updated picture of the evidence becomes available. An examination of the perturbations of the cumulative treatment effect over sequential information steps may signal the presence of bias or heterogeneity in a meta-analysis. Recursive cumulative meta-analysis may suggest whether there is a true underlying treatment effect to which the meta-analysis is converging and how treatment effects are sequentially altered by new or modified evidence. The method is illustrated with an example from the conduct of an MIPD on acyclovir in human immunodeficiency virus infection. The relative strengths and limitations of both metaanalysis of group data and MIPD are discussed through the RCM perspective.

    View details for Web of Science ID 000080058300002

    View details for PubMedID 10235168

  • Reporting of safety data from randomised trials LANCET Ioannidis, J. P., Contopoulos-Ioannidis, D. G. 1998; 352 (9142): 1752-1753

    View details for Web of Science ID 000077246500014

    View details for PubMedID 9848355

  • Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: A meta-analysis of randomized individual patient data JOURNAL OF INFECTIOUS DISEASES Ioannidis, J. P., Collier, A. C., Cooper, D. A., Corey, L., FIDDIAN, A. P., Gazzard, B. G., Griffiths, P. D., Contopoulos-Ioannidis, D. G., Lau, J., Pavia, A. T., Saag, M. S., Spruance, S. L., Youle, M. S. 1998; 178 (2): 349-359


    A meta-analysis of 8 randomized trials (1792 patients, 2947 patient-years of follow-up) showed that acyclovir (> or = 3200 mg/day) offered a significant survival benefit (P = .006 by log-rank test) in human immunodeficiency virus (HIV) infection. The treatment effect did not vary significantly in patient subgroups of different CD4 cell counts, hemoglobin levels, age, race, and sex, and with or without AIDS diagnosis. Acyclovir treatment (hazard ratio, 0.78; 95% confidence interval [CI], 0.65-0.93), higher CD4 cell count (P < .001), higher hemoglobin level (P < .001), and younger age (P < .001) reduced the hazard of mortality. Acyclovir decreased herpes simplex virus infections (odds ratio [OR], 0.28; 95% CI, 0.21-0.37) and varicella-zoster virus infections (OR, 0.29; 95% CI, 0.13-0.63) but not cytomegalovirus disease or mortality from lymphoma or Kaposi's sarcoma. A survival advantage was seen specifically in studies with high incidence of clinical herpesvirus infections (> or = 25% per year). Given the wide confidence intervals, the small effect in low-risk patients, and recent changes in HIV therapeutics, the results should be interpreted cautiously, but the meta-analysis supports the importance of pathogenetic interactions between herpesviruses and HIV.

    View details for Web of Science ID 000075153000009

    View details for PubMedID 9697714

  • Maternal cell-free viremia in the natural history of perinatal HIV-1 transmission - A meta-analysis JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Contopoulos-Ioannidis, D. G., Ioannidis, J. P. 1998; 18 (2): 126-135


    We performed a meta-analysis of the predictive value of maternal cell-free viral load in vertical HIV-1 transmission, including 9 cohorts with 1115 mother-infant pairs (696 untreated and 419 treated women). The pooled rate of transmission in untreated women was 21.3% (95% confidence interval [CI], 18.3%-24.5%). The rates of transmission for untreated women in the <1000 copies/ml, 1000 to 9999 copies/ml, and > or = 10,000 copies/ml categories were 5% (95% CI, 2%-11%), 15% (95% CI, 11%-20%) and 37% (95% CI, 29%-46% by random effects), respectively. The area under the receiver operating characteristic (ROC) curve in individual studies ranged from 0.67 to 1.00. The predictive performance of RNA differed between cohorts in which different percentages of transmitters had RNA values >10,000 copies/ml. When 95% of transmitters have RNA values >1000 copies/ml, 77% of nontransmitters would also have values above this cutoff. Transmission rates for treated women in the 1000 to 9999 copies/ml category (7%; 95% CI, 4%-11%,) and > or = 10,000 copies/ml category (18%; 95% CI, 12%-27%) were probably lower than those for untreated women, whereas the transmission rate for treated women with <1000 copies/ml was 5% (95% CI, 2%-11 %). Thus, the risk gradient between RNA categories seems attenuated in treated women. Several aspects of the design, analysis, and reporting of research in this area may be improved in the future with attention to selection and observer biases, multivariate adjustment, and technical consistency. Maternal HIV-1 RNA is a modest predictor of transmission for individual mothers, but a strong predictor of the average risk in groups of untreated mothers. Its discriminatory power is better in untreated than in treated populations and is better in cohorts with a high prevalence of elevated viral load values than in cohorts with generally low levels of viremia.

    View details for Web of Science ID 000074168900004

    View details for PubMedID 9637577

  • Genetic effects on HIV disease progression NATURE MEDICINE Ioannidis, J. P., O'Brien, T. R., Rosenberg, P. S., Contopoulos-Ioannidis, D. G., Goedert, J. J. 1998; 4 (5): 536-536

    View details for Web of Science ID 000073399900002

    View details for PubMedID 9585207

  • PCR detection of human cytomegalovirus DNA in clinical specimens using novel UL37 exon 3 and US3 primers CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY Lesperance, M. M., Contopoulos-Ioannidis, D. G., Gutierrez, M. D., Colberg-Poley, A. M. 1998; 5 (2): 256-258


    The sensitivity and specificity of novel UL37 exon 3 (UL37x3) and US3 immediate-early (IE) gene PCR primers to detect human cytomegalovirus (HCMV) DNA in clinical specimens are comparable to those of HCMV DNA polymerase (UL54) primers. The use of these IE primers increases the diagnostic performance of HCMV PCR.

    View details for Web of Science ID 000072405600023

    View details for PubMedID 9521154