An approach to exploring patterns of imbalance and potential missingness in reports of the randomized baseline values for primary outcomes measurable at baseline in randomized controlled trials for meta-analyses

This study evaluated the adequacy of randomization in randomized controlled trials by investigating baseline differences in the primary outcome when a meta-analysis employed an outcome whose baseline level was measurable. We retrieved Cochrane reviews published during one year. We calculated the proportion of studies that reported randomized baseline values for the primary outcome. The standardized mean difference (SMD) was used to assess baseline imbalance and heterogeneity. We explored ranking-ordered forest plots using a normal cumulative probability curve as a guideline representing well-performed randomized trials. When skewness was suggested, a funnel plot was drawn to assess whether there was a significant linear trend. In 10 of 18 meta-analyses, more than 25% of trials did not report randomized baseline values of the primary outcomes. Three meta-analyses indicated baseline imbalance (P  60%). Four meta-analyses with forest plots suggesting a skewed SMD distribution also showed a linear trend on their standard errors on the funnel plot. If the primary outcome is measured at baseline, it is essential to explore the full scope of baseline imbalance among the trials. This could help understand patterns of bias, including missingness, for designing adjustment

Understanding noninferiority trials

Noninferiority trials test whether a new experimental treatment is not unacceptably less efficacious than an active control treatment already in use. With continuous improvements in health technologies, standard care, and clinical outcomes, the incremental benefits of newly developed treatments may be only marginal over existing treatments. Sometimes assigning patients to a placebo is unethical. In such circumstances, there has been increasing emphasis on the use of noninferiority trial designs. Noninferiority trials are more complex to design, conduct, and interpret than typical superiority trials. This paper reviews the concept of noninferiority trials and discusses some important issues related to them

Increase in mortality rate following coprescription of cisapride and contraindicated drugs

BACKGROUND: No epidemiologic study, as of this writing, has been published on the use of cisapride with contraindicated drugs and its relation to mortality rates in a population-based setting. OBJECTIVE: To estimate the prevalence of concomitant use of cisapride with contraindicated drugs and evaluate the association between this and the risk of mortality. METHODS: Claims data were obtained from the Health Insurance Review Agency of Korea. The study population consisted of patients younger than 85 years who visited clinics or hospitals in the city of Busan as new users of cisapride between November 1, 2000, and April 30, 2002. The coprescription of cisapride was defined as prescribing cisapride with one or more contraindicated drugs with the same prescription. Nationwide mortality data were also used. The prevalence of coprescribing cisapride was estimated and the association between this and the risk of mortality was assessed by rate ratios (RRs). The RRs were estimated using Cox's regression model with time-dependent covariate, adjusted for age, sex, and comorbidities. RESULTS: A total of 36,865 patients out of 56,012 claims were newly prescribed cisapride; of these, 1175 patients (3.2%) were concomitantly prescribed at least one contraindicated drug, which suggested adjusted mortality RRs of 14.08 (95% CI 7.41 to 26.76) for recent users and 1.33 (95% CI 0.92 to 1.93) for past users of cisapride. CONCLUSIONS: Despite the discontinuation of the drug's commercial marketing, cisapride was still in use in clinics and hospitals in Busan. In many cases, cisapride was co-prescribed with contraindicated drugs, which is associated with increased mortality rates

Immunogenicity of Haemophilus influenzae Type b Conjugate Vaccines in Korean Infants: A Meta-analysis

A meta-analysis was performed on the immunogenicity of Haemophilus influenzae type b (Hib) conjugate vaccines after 2 (2 and 4 months) and 3 doses (2, 4, and 6 months) in Korean infants. A database search of MEDLINE, KoreaMed, and Korean Medical Database was done. The primary outcome measure was the proportion of infants with anti-polyribosylribitol phosphate (PRP) concentrations >= 1.0 mu g/mL. Eight studies including eleven trials were retrieved. One trial reported on the diphtheria toxoid conjugate vaccine (PRP-D) and 2 trials each on the mutant diphtheria toxin (PRP-CRM) and Neisseria meningitidis outer-membrane protein (PRP-OMP) conjugate vaccine. Heterogeneity in study designs between trials on PRP-CRM was noted and one trial reported on a monovalent and another on a combination PRP-OMP vaccine. Thus, a meta-analysis was conducted only on the tetanus toxoid conjugate vaccine (PRP-T). After a primary series of 2 doses and 3 doses, 80.6% (95% confidence interval [CI]; 76.0-85.1%) and 95.7% (95% CI; 94.0-98.0%) of infants achieved an antibody level >= 1.0 mu g/mL, respectively. The immunogenic response to the PRP-T vaccine was acceptable after a primary series of 3 doses and also 2 doses. A reduced number of doses as a primary series could be carefully considered in Korean infants.Kim KH, 2008, J KOREAN MED SCI, V23, P929, DOI 10.3346/jkms.2008.23.6.929Rossi IA, 2007, VACCINE, V25, P7075, DOI 10.1016/j.vaccine.2007.07.058Obonyo CO, 2006, EUR J CLIN MICROBIOL, V25, P90, DOI 10.1007/s10096-006-0092-4*WHO, 2006, WKLY EPIDEMIOL REC, V81, P445CHUNG EH, 2006, KOREAN J PEDIAT INFE, V13, P163Kelly DF, 2004, IMMUNOLOGY, V113, P163, DOI 10.1111/j.1365-2567.2004.01971.xKim JS, 2004, VACCINE, V22, P3952, DOI 10.1016/j.vaccine.2004.04.003WENGER JD, 2004, VACCINES, P229Makela PH, 2003, VACCINE, V22, P287, DOI 10.1016/S0264-410X(03)00524-3CHUNG EH, 2003, KOREAN J PEDIAT INFE, V10, P71YANG PS, 2002, J KOREAN PEDIAT SOC, V45, P987*CDCP, 2002, MMWR-MORBID MORTAL W, V51, P234Granoff DM, 2001, CLIN INFECT DIS, V33, pS278Peltola H, 2000, CLIN MICROBIOL REV, V13, P302Moher D, 1999, LANCET, V354, P1896Peltola H, 1999, J INFECT DIS, V179, P223CHOI SY, 1999, J KOREAN PEDIAT SOC, V42, P771Heath PT, 1998, PEDIATR INFECT DIS J, V17, pS117Lagos R, 1998, LANCET, V351, P1472Mulholland K, 1997, LANCET, V349, P1191Kurikka S, 1996, J PEDIATR, V128, P524KIM JS, 1996, KOREAN J INFECT DIS, V28, P225YOO ES, 1995, J KOREAN PEDIAT SOC, V38, P1201DECKER MD, 1992, J PEDIATR, V120, P184SANTOSHAM M, 1991, NEW ENGL J MED, V324, P1767ESKOLA J, 1990, NEW ENGL J MED, V323, P1381LAIRD NM, 1990, INT J TECHNOL ASSESS, V6, P5DERSIMONIAN R, 1986, CONTROL CLIN TRIALS, V7, P177ANDERSON P, 1984, J INFECT DIS, V149, P1034KAYHTY H, 1983, J INFECT DIS, V147, P1100

Methodological bias in cluster randomised trials

Background: Cluster randomised trials can be susceptible to a range of methodological problems. These problems are not commonly recognised by many researchers. In this paper we discuss the issues that can lead to bias in cluster trials. Methods: We used a sample of cluster randomised trials from a recent review and from a systematic review of hip protectors. We compared the mean age of participants between intervention groups in a sample of 'good' cluster trials with a sample of potentially biased trials. We also compared the effect sizes, in a funnel plot, between hip protector trials that used individual randomisation compared with those that used cluster randomisation. Results: There is a tendency for cluster trials, with evidence methodological biases, to also show an age imbalance between treatment groups. In a funnel plot we show that all cluster trials show a large positive effect of hip protectors whilst individually randomised trials show a range of positive and negative effects, suggesting that cluster trials may be producing a biased estimate of effect. Conclusion: Methodological biases in the design and execution of cluster randomised trials is frequent. Some of these biases associated with the use of cluster designs can be avoided through careful attention to the design of cluster trials. Firstly, if possible, individual allocation should be used. Secondly, if cluster allocation is required, then ideally participants should be identified before random allocation of the clusters. Third, if prior identification is not possible, then an independent recruiter should be used to recruit participants

A time-dependent subdistribution hazard model for major dental treatment events in cancer patients: a nationwide cohort study

Abstract Background Dental care in cancer patients tends to be less prioritized. However, limited research has focused on major dental treatment events in cancer patients after the diagnosis. This study aimed to examine dental treatment delays in cancer patients compared to the general population using a national claims database in South Korea. Method The Korea National Health Insurance Service-National Sample Cohort version 2.0, collected from 2002 to 2015, was analyzed. Treatment events were considered for stomatitis, tooth loss, dental caries/pulp disease, and gingivitis/periodontal disease. For each considered event, time-dependent hazard ratios and associated 95% confidence intervals were calculated by applying a subdistribution hazard model with time-varying covariates. Mortality was treated as a competing event. Subgroup analyses were conducted by type of cancer. Results The time-dependent subdistribution hazard ratios (SHRs) of stomatitis treatment were greater than 1 in cancer patients in all time intervals, 2.04 within 30 days after cancer diagnosis, and gradually decreased to 1.15 after 5 years. The SHR for tooth loss was less than 0.70 within 3 months after cancer diagnosis and increased to 1 after 5 years. The trends in SHRs of treatment events for other dental diseases were similar to those observed for tooth loss. Subgroup analyses by cancer type suggested that probability of all dental treatment event occurrence was higher in head and neck cancer patients, particularly in the early phase after cancer diagnosis. Conclusion Apart from treatments that are associated with cancer therapy, dental treatments in cancer patients are generally delayed and cancer patients tend to refrain from dental treatments. Consideration should be given to seeking more active and effective means for oral health promotion in cancer patients

Geriatric Nutritional Risk Index as a prognostic marker in patients with extensive-stage disease small cell lung cancer: Results from a randomized controlled trial

Background Clinical impact of the Geriatric Nutritional Risk Index (GNRI) in patients with extensive-stage disease small cell lung cancer (ED-SCLC) have not previously been reported. Methods This study analyzed 352 patients enrolled in a previous randomized phase III trial comparing the efficacy of irinotecan plus cisplatin with that of etoposide plus cisplatin as the first-line therapy for ED-SCLC. GNRI values were calculated using serum albumin levels and actual and ideal bodyweights. Patients with a GNRI > 98, 92-98, and <92 were grouped into no, low, and moderate/major risk groups, respectively. Results The objective response rates were 63.2%, 52.6%, and 49.2% in the no, low, and moderate/major risk groups, respectively (P = 0.024). The median progression-free survival (PFS) was shorter in patients with a lower GNRI than in those with a higher GNRI (no vs. low vs. moderate/major risk group; 6.5 vs. 5.8 vs. 5.9 months, respectively; P = 0.028). There were significant differences in median overall survival (OS) according to GNRI (no vs. low vs. moderate/major risk group; 13.2 vs. 10.3 vs. 8.4 months, respectively; P < 0.001). Multivariate analysis revealed that being in the moderate/major risk group was an independent poor prognostic factor for PFS (hazard ratio [HR]: 1.300, 95% confidence interval [CI]: 1.012-1.670; P = 0.040) and OS (HR: 1.539; 95% CI: 1.069-2.216; P = 0.020). Conclusions This prospective study shows that a low GNRI value was associated with a poor prognosis, and it supports the relationship between systemic inflammation, nutritional status, and clinical outcomes in patients with ED-SCLC.Key points Significant findings of the study The lower GNRI group had a low response rate to chemotherapy for ED-SCLC. The HRs for PFS and OS were 1.300 and 1.539 in the patients with GNRI < 92. What this study adds Low GNRI is associated with poor prognosis in ED-SCLC.

Prognostic implication of aberrant promoter hypermethylation of CpG islands in adenocarcinoma of the lung

ObjectivesDNA hypermethylation in promoter regions has been studied for various types of cancer. However, there is no clear evidence that shows whether methylation status can predict long-term survival in patients with lung cancer.MethodsWe collected tissues from 72 patients with lung adenocarcinomas. The cancer and normal lung tissues were tested for DNA hypermethylation by using methylation-specific polymerase chain reaction. The genes investigated were p16INK4α(p16), retinoic acid receptor β-promoter (RARβP2), death-associated protein kinase (DAPK), O6-methylguanine-DNA-methyltransferase (MGMT), and glutathione-S-transferase P1 (GSTP1). The status of the DNA methylation was analyzed, and we focused on long-term outcomes, as well as other clinical variables.ResultsDNA hypermethylation was observed in 83% for p16, 63% for RARβP2, 32% for DAPK, 17% for MGMT, and 46% for GSTP1 from the cancer tissue. From normal lung tissue, the results of methylation were positive in 75% for p16, 24% for RARβP2, 10% for DAPK, 6% for MGMT, and 33% for GSTP1. During the mean follow-up period of 18 ± 11 months (1-40 months), 25 (35%) patients experienced recurrence, and 13 died. In multivariable analysis, old age (>60 years, P = .007), male sex (P = .004), unmethylation of DAPK from cancer tissue (P = .045), and hypermethylation of RARβP2 from normal tissue (P = .000) were risk factors for poor survival. Pathologic stage (P = .023), unmethylation of DAPK from normal tissue (P = .043), and hypermethylation of RARβP2 from normal tissue (P = .030) were risk factors for disease-free survival.ConclusionsDNA methylation status of CpG islands seems to be a useful predictor of long-term outcome for adenocarcinoma of the lung. However, because the predictive power is still low, further studies, including those with multiple genes, are necessary to increase its usefulness in the clinical setting

Treatment shortening of drug-sensitive pulmonary tuberculosis using high-dose rifampicin for 3 months after culture conversion (Hi-DoRi-3): a study protocol for an open-label randomized clinical trial

Background : The standard treatment regimen for drug-sensitive tuberculosis (TB), comprising four companion drugs, requires a minimum duration of 6 months, and this lengthy treatment leads to poor adherence and increased toxicity. To improve rates of adherence, reduce adverse events, and lower costs, a simplified and shortened treatment regimen is warranted. Methods : This study is a multicenter, open-label randomized clinical trial of non-inferiority design that compares a new regimen with the conventional regimen for drug-sensitive pulmonary TB. The investigational group will use a regimen of high-dose rifampicin (30 mg/kg/day) with isoniazid and pyrazinamide, and the treatment will be maintained for 12 weeks after the achievement of negative conversion of sputum culture. The control group will be treated for 6 months with a World Health Organization-endorsed regimen consisting of isoniazid, rifampicin (10 mg/kg/day), ethambutol, and pyrazinamide. The primary endpoint is the proportion of unfavorable outcomes at 18 months after randomization. Secondary outcomes include time to unfavorable treatment outcome, time to culture conversion on liquid medium, treatment success rate at the end of treatment, proportion of recurrence at 18 months after randomization, time to recurrence after treatment completion, and adverse events of grade 3 or higher during the treatment. We predict a 10% unfavorable outcome for the control group, and 0% difference from the investigational group. Based on 80% verification power and a 2.5% one-sided significance level for a non-inferiority margin of 6%, 393 participants per group are required. Considering the 15% dropout rate, a total of 926 participants (463 in each group) will be recruited. Discussion : This study will inform on the feasibility of the treatment regimen using high-dose rifampicin with a shortened and individualized treatment duration for pulmonary TB. Trial registration : ClinicalTrials.gov NCT04485156.Registered on July 24, 2020.This work was supported by a grant from the Korea National Institute of Health (2020-ER5201-01), Republic of Korea. High-dose rifampicin tablets and capsules were donated from Yuhan (Seoul, Republic of Korea) for this study. The funder and donor had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript