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A P value, or the magnitude or direction of results can influence decisions about whether, when, and how research findings are disseminated. Regardless of whether an entire study or a particular study result is unavailable because investigators considered the results to be unfavorable, bias in a meta‐analysis may occur when available results differ systematically from missing results. In this article, we summarize the empirical evidence for various reporting biases that lead to study results being unavailable for inclusion in systematic reviews, with a focus on health research. These biases include publication bias and selective nonreporting bias. We describe processes that systematic reviewers can use to minimize the risk of bias due to missing results in meta‐analyses of health research, such as comprehensive searches and prospective approaches to meta‐analysis. We also outline methods that have been designed for assessing risk of bias due to missing results in meta‐analyses of health research, including using tools to assess selective nonreporting of results, ascertaining qualitative signals that suggest not all studies were identified, and generating funnel plots to identify small‐study effects, one cause of which is reporting bias. Highlights: Bias in a meta‐analysis may occur when available results differ systematically from missing results.Several different tools, plots, and statistical methods have been designed for assessing risk of bias due to missing results in meta‐analyses. These include comparison of prespecified analysis plans with completed reports to detect selective nonreporting of results, consideration of qualitative signals that suggest not all studies were identified, and the use of funnel plots to identify small‐study effects, for which reporting bias is one of several causes.Information from approaches such as funnel plots and selection models is more difficult to interpret than from less subjective approaches such as detection of incompletely reported results in studies for which prespecified analysis plans were available. [ABSTRACT FROM AUTHOR]

Importance: Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support.Objective: To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality.Design, Setting, and Participants: Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance-weighted fixed-effect analysis using risk ratios.Exposures: Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients).Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events.Results: A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as "low" for 6 of the 7 mortality results and as "some concerns" in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82]; P < .001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (I2 = 15.6%; P = .31 for heterogeneity) and the summary OR was 0.70 (95% CI, 0.48-1.01; P = .053) based on the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo.Conclusions and Relevance: In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. [ABSTRACT FROM AUTHOR]

Background: Previous trials suggest lower long-term risk of mortality after invasive rather than non-invasive management of patients with non-ST elevation myocardial infarction (NSTEMI), but the trials excluded very elderly patients. We aimed to estimate the effect of invasive versus non-invasive management within 3 days of peak troponin concentration on the survival of patients aged 80 years or older with NSTEMI.Methods: Routine clinical data for this study were obtained from five collaborating hospitals hosting NIHR Biomedical Research Centres in the UK (all tertiary centres with emergency departments). Eligible patients were 80 years old or older when they underwent troponin measurements and were diagnosed with NSTEMI between 2010 (2008 for University College Hospital) and 2017. Propensity scores (patients' estimated probability of receiving invasive management) based on pretreatment variables were derived using logistic regression; patients with high probabilities of non-invasive or invasive management were excluded. Patients who died within 3 days of peak troponin concentration without receiving invasive management were assigned to the invasive or non-invasive management groups based on their propensity scores, to mitigate immortal time bias. We estimated mortality hazard ratios comparing invasive with non-invasive management, and compared the rate of hospital admissions for heart failure.Findings: Of the 1976 patients with NSTEMI, 101 died within 3 days of their peak troponin concentration and 375 were excluded because of extreme propensity scores. The remaining 1500 patients had a median age of 86 (IQR 82-89) years of whom (845 [56%] received non-invasive management. During median follow-up of 3·0 (IQR 1·2-4·8) years, 613 (41%) patients died. The adjusted cumulative 5-year mortality was 36% in the invasive management group and 55% in the non-invasive management group (adjusted hazard ratio 0·68, 95% CI 0·55-0·84). Invasive management was associated with lower incidence of hospital admissions for heart failure (adjusted rate ratio compared with non-invasive management 0·67, 95% CI 0·48-0·93).Interpretation: The survival advantage of invasive compared with non-invasive management appears to extend to patients with NSTEMI who are aged 80 years or older.Funding: NIHR Imperial Biomedical Research Centre, as part of the NIHR Health Informatics Collaborative. [ABSTRACT FROM AUTHOR]

Background: Many studies have examined 'non-specific' vaccine effects on infant mortality: attention has been particularly drawn to diphtheria-tetanus-pertussis (DTP) vaccine, which has been proposed to be associated with an increased mortality risk. Both right and left censoring are common in such studies.Methods: We conducted simulation studies examining right censoring (at measles vaccination) and left censoring (by excluding early follow-up) in a variety of scenarios in which confounding was and was not present. We estimated both unadjusted and adjusted hazard ratios (HRs), averaged across simulations.Results: We identified scenarios in which right-censoring at measles vaccination was informative and so introduced bias in the direction of a detrimental effect of DTP vaccine. In some, but not all, situations, adjusting for confounding by health status removed the bias caused by censoring. However, such adjustment will not always remove bias due to informative censoring: inverse probability weighting was required in one scenario. Bias due to left censoring arose when both health status and DTP vaccination were associated with mortality during the censored early follow-up and was in the direction of attenuating a beneficial effect of DTP on mortality. Such bias was more severe when the effect of DTP changed over time.Conclusions: Estimates of non-specific effects of vaccines may be biased by informative right or left censoring. Authors of studies estimating such effects should consider the potential for such bias and use appropriate statistical approaches to control for it. Such approaches require measurement of prognostic factors that predict censoring. [ABSTRACT FROM AUTHOR]

Purpose: Up to 50% of urinary tract infections (UTIs) in young children are missed in primary care. Urine culture is essential for diagnosis, but urine collection is often difficult. Our aim was to derive and internally validate a 2-step clinical rule using (1) symptoms and signs to select children for urine collection; and (2) symptoms, signs, and dipstick testing to guide antibiotic treatment.Methods: We recruited acutely unwell children aged under 5 years from 233 primary care sites across England and Wales. Index tests were parent-reported symptoms, clinician-reported signs, urine dipstick results, and clinician opinion of UTI likelihood (clinical diagnosis before dipstick and culture). The reference standard was microbiologically confirmed UTI cultured from a clean-catch urine sample. We calculated sensitivity, specificity, and area under the receiver operator characteristic (AUROC) curve of coefficient-based (graded severity) and points-based (dichotomized) symptom/sign logistic regression models, and we then internally validated the AUROC using bootstrapping.Results: Three thousand thirty-six children provided urine samples, and culture results were available for 2,740 (90%). Of these results, 60 (2.2%) were positive: the clinical diagnosis was 46.6% sensitive, with an AUROC of 0.77. Previous UTI, increasing pain/crying on passing urine, increasingly smelly urine, absence of severe cough, increasing clinician impression of severe illness, abdominal tenderness on examination, and normal findings on ear examination were associated with UTI. The validated coefficient- and points-based model AUROCs were 0.87 and 0.86, respectively, increasing to 0.90 and 0.90, respectively, by adding dipstick nitrites, leukocytes, and blood.Conclusions: A clinical rule based on symptoms and signs is superior to clinician diagnosis and performs well for identifying young children for noninvasive urine sampling. Dipstick results add further diagnostic value for empiric antibiotic treatment. [ABSTRACT FROM AUTHOR]

In this article, we demonstrate how to fit fixed- and random-effects meta-analysis, meta-regression, and multivariate outcome meta-analysis models under the structural equation modeling framework using the sem and gsem commands. While all of these models can be fit using existing user-written commands, formulating the models in the structural equation modeling framework provides deeper insight into how they work. Further, the heterogeneity test for metaregression and multivariate meta-analysis is readily available from this output. [ABSTRACT FROM AUTHOR]

Rationale: Asthma is a complex heterogeneous disease that has increased in prevalence in many industrialised countries. However, the causes of asthma inception remain elusive. Consideration of sub-phenotypes of wheezing may reveal important clues to aetiological risk factors. Methods: Longitudinal phenotypes capturing population heterogeneity in wheezing reports from birth to 7 years were derived using latent class analysis in the Avon Longitudinal Study of Parents and Children (ALSPAC). Probability of class membership was used to examine the association between five wheezing phenotypes (transient early, prolonged early, intermediate-onset, late-onset, persistent) and early life risk factors for asthma. Results: Phenotypes had similar patterns and strengths of associations with early environmental factors. Comparing transient early with prolonged early wheezing showed a similar pattern of association with most exposure variables considered in terms of the direction of the effect estimates but with prolonged early wheezing tending to have stronger associations than transient early wheezing except for parity and day care attendance. Conclusions: Associations with early life risk factors suggested that prolonged early wheeze might be a severe form of transient early wheezing. Although differences were found in the associations of early life risk factors with individual phenotypes, these did not point to novel aetiological pathways. Persistent wheezing phenotype has features suggesting overlap of early and late-onset phenotypes. [ABSTRACT FROM AUTHOR]

Funnel plots, and tests for funnel plot symmetry, have been widely used to examine bias in the results of meta-analyses. Funnel plot asymmetry should not be equated with publication bias, because it has a number of other possible causes. This article describes how to interpret funnel plot asymmetry, recommends appropriate tests, and explains the implications for choice of meta-analysis model [ABSTRACT FROM AUTHOR]

In this paper, the authors describe different instrumental variable (IV) estimators of causal risk ratios and odds ratios with particular attention to methods that can handle continuously measured exposures. The authors present this discussion in the context of a Mendelian randomization analysis of the effect of body mass index (BMI; weight (kg)/height (m)2) on the risk of asthma at age 7 years (Avon Longitudinal Study of Parents and Children, 1991–1992). The authors show that the multiplicative structural mean model (MSMM) and the multiplicative generalized method of moments (MGMM) estimator produce identical estimates of the causal risk ratio. In the example, MSMM and MGMM estimates suggested an inverse relation between BMI and asthma but other IV estimates suggested a positive relation, although all estimates had wide confidence intervals. An interaction between the associations of BMI and fat mass and obesity-associated (FTO) genotype with asthma explained the different directions of the different estimates, and a simulation study supported the observation that MSMM/MGMM estimators are negatively correlated with the other estimators when such an interaction is present. The authors conclude that point estimates from various IV methods can differ in practical applications. Based on the theoretical properties of the estimators, structural mean models make weaker assumptions than other IV estimators and can therefore be expected to be consistent in a wider range of situations. [ABSTRACT FROM PUBLISHER]

To identify cause-of-death categories in which suicides might be misclassified in Taiwan. We plotted secular trends (1971–2007) in sex- and method-specific rates of deaths classified as suicide, undetermined intent and accident for the Taiwanese population aged 15+ and compared the sex, age and marital status profiles of deaths in these three categories by method of death. The demographic profiles of registered suicides generally resembled those for deaths of undetermined intent and accidents by pesticide poisoning/suffocation but differed from those for accidents from non-pesticide poisoning/drowning/falling/poisoning by non-domestic gas. For the period 1990–2007, suicide rates based on suicides alone (14.8 per 100,000) would increase by 23, 7 and 1%, respectively, when including deaths of undetermined intent, accidental pesticide poisonings and accidental suffocations. Suicide rates may be underestimated by more than 30% in Taiwan because some suicides are ‘hidden’ amongst deaths certified as due to other causes. [ABSTRACT FROM AUTHOR]

The article examines the reasons why multiple imputation of missing data may lead to bias and loss of information in epidemiological and clinical research. The circumstances in which multiple imputation of missing data may help in reducing bias or increasing pitfalls in its application are discussed, as well as the classification of the reasons for missing data. The statistical methods in handling missing data are explored, including the use of a missing category indicator and replacement of the missing values with the last measured value. The recent use and reporting of analyses using multiple imputation in general medical journals are described, as well as the suggested guidelines for the conduct and reporting of such analyses.

Background: Graphical displays of results allow researchers to summarise and communicate the key findings of their study. Diagnostic information should be presented in an easily interpretable way, which conveys both test characteristics (diagnostic accuracy) and the potential for use in clinical practice (predictive value). Methods: We discuss the types of graphical display commonly encountered in primary diagnostic accuracy studies and systematic reviews of such studies, and systematically review the use of graphical displays in recent diagnostic primary studies and systematic reviews. Results: We identified 57 primary studies and 49 systematic reviews. Fifty-six percent of primary studies and 53% of systematic reviews used graphical displays to present results. Dot-plot or box-and-whisker plots were the most commonly used graph in primary studies and were included in 22 (39%) studies. ROC plots were the most common type of plot included in systematic reviews and were included in 22 (45%) reviews. One primary study and five systematic reviews included a probability-modifying plot. Conclusion: Graphical displays are currently underused in primary diagnostic accuracy studies and systematic reviews of such studies. Diagnostic accuracy studies need to include multiple types of graphic in order to provide both a detailed overview of the results (diagnostic accuracy) and to communicate information that can be used to inform clinical practice (predictive value). Work is required to improve graphical displays, to better communicate the utility of a test in clinical practice and the implications of test results for individual patients. [ABSTRACT FROM AUTHOR]

The article presents medical research that examines the extent to which the prognosis for AIDS and the death of HIV-positive patients initiating highly active antiretroviral therapy (HAART) is affected by their characteristics at the time of initiation. Results indicate that injection drug abusers and people with advanced immunodeficiency at HAART initiation experience increased rates of AIDS and death.

Objective: To investigate the spatial patterning and possible contributors to the geographical distribution of suicide among 15-44-year-old men. Design: Small-area analysis and mapping of geo-coded 1988-94 suicide mortality data and 1991 census data using random-effects smoothing. Setting: 9265 electoral wards in England and Wales (mean population of men aged 15-44-years: about 1220). Main results: Two main patterns emerged: (a) in all of the 10 most densely populated cities studied, suicide showed a ‘bull's-eye’ pattern with rates highest in the inner-city areas and, in some cases, low rates in the peripheries, and (b) suicide rates were high in coastal areas, particularly those in more remote regions. Possible indicators of social fragmentation, such as the proportion of single-person households in an area, were most strongly and consistently associated with rates of suicide in both urban and rural areas. Levels of unemployment and long-term illness accounted for some of the coastal patterning. Although characteristics of areas accounted for more than half of the observed variability, substantial between-area variability in rates remained unexplained. Conclusions: The area characteristics investigated here did not fully account for the higher suicide rates observed in the most rural or remote areas. Alongside social and economic aspects, rural life itself may have an independent effect on the risk of suicide. A greater understanding of local geographies of suicide, and particularly the possible interactions between characteristics of people and their environments, might assist the design of prevention strategies that target those areas (and their characteristics) where risk is concentrated. [ABSTRACT FROM AUTHOR]

The rates of ureteric obstruction and complications for use of externally draining uretero-vesico-cutaneous (external) stents (Group 1: n=39) and the use of internal uretero-vesical (double-J) stents (Group 2: n=16), in 55 of 64 consecutive paediatric renal-transplant recipients, performed at our institution between January 1996 and December 2003, have been compared. Serum creatinine levels pre and post-operatively and pre and post-stent removal were recorded. The diagnosis of ureteric obstruction was based on an increase in serum creatinine of ≥20%, in conjunction with ultrasound evidence of hydronephrosis or hydroureter, where other causes of renal dysfunction were excluded. Ureteric obstruction occurred in 13 of the 39 patients (33.3%) in Group 1, compared with only one case of ureteric obstruction in the 16 patients (6.25%) in Group 2 (OR=7.5, 95% CI=0.8–70, P=0.038). There was no evidence of a difference in the number of urinary tract infections (9/39 in Group 1, 6/16 in Group 2, OR=0.5, 95% CI=0.14 to 1.8, P=0.275) or the mean length of hospital stay (10.9 days in Group 1, 10.1 days in Group 2, 95% CI=−2.3 to 4 days, P=0.565) between the two groups. Glomerular filtration rate (GFR) improved in the week after stent removal in Group 2, but deteriorated in Group 1 ( P=0.07). This non-randomised comparison of stent types supports the use of prophylactic double-J stents in paediatric renal transplantation- in terms of decreased ureteric complications and improved renal function post-stent removal. [ABSTRACT FROM AUTHOR]

Background Evidence on the effectiveness of highly active antiretroviral therapy (HAART) for HIV-infected individuals is limited. Most clinical trials examined surrogate endpoints over short periods of follow-up and there has been no placebo-controlled randomized trial of HAART. Estimation of treatment effects in observational studies is problematic, because of confounding by indication. We aimed to use novel methodology to overcome this problem in the Swiss HIV Cohort Study. Methods Patients were included if they had been examined after January 1996, when HAART became available in Switzerland, were not on HAART, and were free of AIDS at baseline. Cox regression models were weighted to create a statistical population in which the probability of being treated at each time point was unrelated to prognostic factors. Results Low CD4 counts and increasing HIV-1 viral load were associated with increased probability of starting HAART. Overall hazard ratios were 0·14 (95% CI 0·07-0·29) for HAART compared with no treatment, and 0·49 (0·31-0·79) compared with dual therapy. Compared with no treatment, HAART became more beneficial with increasing time since initiation but was less beneficial for patients whose presumed mode of transmission was via intravenous drug use (hazard ratio 0·27, 0·12-0·61) than for other patients (0·08, 0·03-0·19). Interpretation Our results, which are appropriately controlled for confounding by indication, are consistent with reported declines in rates of AIDS and death in developed countries, and provide a context in which to consider adverse effects of HAART. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the national distribution of prolonged waiting for elective day case and inpatient surgery, and to examine associations of prolonged waiting with markers of NHS capacity, activity in the independent sector, and need. Setting: NHS hospital trusts in England. Population: People waiting for elective treatment in the specialties of general surgery; ear, nose and throat surgery; ophthalmic surgery; and trauma and orthopaedic surgery. Main outcome measure: Numbers of people waiting six months or longer (prolonged waiting). Characteristics of trusts with large numbers waiting six months or longer were examined by using logistic regression. Results: The distribution of numbers of people waiting for day case or elective surgery in all the specialties examined was highly positively skewed. Between 52% and 83% of patients waiting longer than six months in the specialties studied were found in one quarter of trusts, which in turn contributed 23-45% of the national throughput specific to the specialty. In general, there was little evidence to show that capacity (measured by numbers of operating theatres, dedicated day case theatres, available beds, and bed occupancy rate) or independent sector activity were associated with prolonged waiting, although exceptions were noted for individual specialties. There was consistent evidence showing an increase in prolonged waiting, with increased numbers of anaesthetists across all specialties and with increased bed occupancy rates for ear, nose, and throat surgery. Markers of greater need for health care, such as deprivation score and rate of limiting long term illness, were inversely associated with prolonged waiting. Conclusion: In most instances, substantial numbers of patients waiting unacceptably long periods for elective surgery were limited to a small number of hospitals. Little and inconsistent support was found for associations of prolonged waiting with markers of capacity, independent sector... [ABSTRACT FROM AUTHOR]

Deals with the emergence of significance testing in medical research. Brief history of P values and significance testing; Analysis of the misrepresentations of P values and significance tests; Discussion on ways of reducing the degree from which one is misled by the practice of significance testing.

Discusses biases in medical research. How studies that show a significant effect of treatment are more likely to be published and cited in other studies; Funnel chart method of detecting bias in small and large studies; Statistical methods for detecting and correcting for bias; Recommendations for reducing bias in clinical studies, including easier access to data from published and unpublished studies.

Objectives: To examine differences in population based rates of gonorrhoea and chlamydia between black ethnic groups in Lambeth, Southwark and Lewisham Health Authority.Methods: Episodes of gonorrhoea or chlamydia recorded among attenders at 11 genitourinary clinics in south and central London from 1 January 1994 to 31 December 1995 were retrieved. Complete data on chlamydia were only available for women. Ethnic group was assigned according to census categories--white, black Caribbean, black African, black other, Asian, or other. We calculated yearly incidence rates for episodes of gonorrhoea and chlamydia in residents of Lambeth, Southwark and Lewisham Health Authority. Random effects Poisson regression models were used to examine associations between infection rates and age, ethnic group, and material deprivation.Results: During the study period there were 1996 episodes of gonorrhoea in men and women and 1376 episodes of chlamydia in women with complete data. For both infections rates among individuals from black Caribbean and black other ethnic groups were markedly higher than among black Africans. In men, the gonorrhoea rate among black Caribbean 20-24 year olds was 2348 (95% CI 1965 to 2831) episodes per 100,000 compared with 931 (95% CI 690 to 1288) in black African men and 111 (95% CI 100 to 124) per 100,000 in white men of the same age. Among women gonorrhoea rates were highest in black Caribbean 15-19 year olds (2612, 95% CI 2161 to 3190 per 100,000). In contrast, rates in black African women of the same age (331, 95% CI 154 to 846 per 100,000) were similar to those of white women (222, 95% CI 163 to 312). Chlamydia rates were also highest in black Caribbean 15-19 year old women (4579, 95% CI 3966 to 5314 per 100,000), compared with 1286 (95% CI 907 to 1888) in black African and 433 (95% CI 349 to 544) per 100,000 white women. Controlling for material deprivation and age only attenuated differences in rates between ethnic groups slightly.Conclusions: There are marked differences in rates of gonorrhoea and chlamydia between different black ethnic groups, with higher rates in black Caribbeans than black Africans. This study supports the hypothesis that assortative sexual mixing patterns can restrict epidemics of sexually transmitted infections within ethnic groups. Differences in disease occurrence between black ethnic groups should be explored before combining data, even when numbers of episodes are small. [ABSTRACT FROM AUTHOR]

Focuses on the skepticism that is often associated with medical research and significance tests. How P values, or significance levels, measure the strength of the evidence against the null hypothesis; Division of results, into significant or non-significant categories, based according to P value; Need for more powerful studies, in order to provide credibility to medical research.

Objectives: Primary objective: To estimate the effect of corticosteroids compared with usual care or placebo on mortality up to 28 days after randomization. Secondary objectives: To examine whether the effect of corticosteroids compared with usual care or placebo on mortality up to 28 days after randomization varies between subgroups related to treatment characteristics, disease severity at the time of randomization, patient characteristics, or risk of bias. To examine the effect of corticosteroids compared with usual care or placebo on serious adverse events.Study Design: Prospective meta-analysis of randomized controlled trials. Both placebo-controlled and open-label trials are eligible.Participants: Hospitalised, critically ill patients with suspected or confirmed COVID-19.Intervention and Comparator: Intervention groups will have received therapeutic doses of a steroid (dexamethasone, hydrocortisone or methylprednisolone) with IV or oral administration immediately after randomization. The comparator groups will have received standard of care or usual care or placebo.Main Outcome: All-cause mortality up to 28 days after randomization.Search Methods: Systematic searching of clinicaltrials.gov , EudraCT, the WHO ISRCTN registry, and the Chinese clinical trials registry. Additionally, research and WHO networks will be asked for relevant trials.Risk Of Bias Assessments: These will be based on the Cochrane RoB 2 tool, and will use structured information provided by the trial investigators on a form designed for this prospective meta-analysis. We will use GRADE to assess the certainty of the evidence.Statistical Analyses: Trial investigators will provide data on the numbers of participants who did and did not experience each outcome according to intervention group, overall and in specified subgroups. We will conduct fixed-effect (primary analysis) and random-effects (Paule-Mandel estimate of heterogeneity and Hartung-Knapp adjustment) meta-analyses. We will quantify inconsistency in effects between trials using I2 statistics. Evidence for subgroup effects will be quantified by ratios of odds ratios comparing effects in the subgroups, and corresponding interaction p-values. Comparisons between subgroups defined by trial characteristics will be made using random-effects meta-regression. Comparisons between subgroups defined by patient characteristics will be made by estimating trial-specific ratios of odds ratios comparing intervention effects between subgroups then combining these using random-effects meta-analysis. Steroid interventions will be classified as high or low dose according to whether the dose is greater or less than or equal to 400 mg hydrocortisone per day or equivalent. We will use network meta-analysis methods to make comparisons between the effects of high and low dose steroid interventions (because one trial randomized participants to both low and high dose steroid arms).Prospero Registration Number: CRD42020197242 FULL PROTOCOL: The full protocol for this prospective meta-analysis is attached as an additional file, accessible from the Trials website (Additional file 1). To expedite dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol for the systematic review. [ABSTRACT FROM AUTHOR]

This secondary analysis of a randomized clinical trial assesses whether screening for prostate-specific antigen reduces prostate cancer mortality at 15-year follow-up. Key Points: Question: In men aged 50 to 69 years, does a single invitation for a prostate-specific antigen (PSA) screening test reduce prostate cancer mortality at 15-year follow-up compared with no invitation for testing? Findings: In this secondary analysis of a randomized clinical trial of 415 357 men aged 50 to 69 years randomized to a single invitation for PSA screening (n = 195 912) or a control group without PSA screening (n = 219 445) and followed up for a median of 15 years, risk of death from prostate cancer was lower in the group invited to screening (0.69% vs 0.78%; mean difference, 0.09%) compared with the control group. Meaning: Compared with no invitation for routine PSA testing, a single invitation for a PSA screening test reduced prostate cancer mortality at a median follow-up of 15 years, but the absolute mortality benefit was small. Importance: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear. Objective: To evaluate the effect of a single invitation for PSA screening on prostate cancer–specific mortality at a median 15-year follow-up compared with no invitation for screening. Design, Setting, and Participants: This secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021. Intervention: Men received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation). Main Outcomes and Measures: The primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer–specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis. Results: Of 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P =.03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P <.001) and localized (T1/T2: 3.6% vs 3.1%; P <.001) disease but not intermediate (GS of 7), high-grade (GS ≥8), locally advanced (T3), or distally advanced (T4/N1/M1) tumors. There were 45 084 all-cause deaths in the intervention group (23.2% [95% CI, 23.0%-23.4%]) and 50 336 deaths in the control group (23.3% [95% CI, 23.1%-23.5%]) (RR, 0.97 [95% CI, 0.94-1.01]; P =.11). Eight of the prostate cancer deaths in the intervention group (0.7%) and 7 deaths in the control group (0.5%) were related to a diagnostic biopsy or prostate cancer treatment. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, a single invitation for PSA screening compared with standard practice without routine screening reduced prostate cancer deaths at a median follow-up of 15 years. However, the absolute reduction in deaths was small. Trial Registration: isrctn.org Identifier: ISRCTN92187251 [ABSTRACT FROM AUTHOR]

The article discusses a study which examined the effectiveness of two doses of coronavirus disease 2019 (COVID-19) vaccine beyond six months in England. Topics include increase in the cumulative incidence of receiving a third dose of vaccine during the eight weeks following eligibility, basis of the effectiveness of two doses during later comparison periods, and important factors in interpreting estimated vaccine effectiveness (VE).

Background: Missing data are unavoidable in epidemiological research, potentially leading to bias and loss of precision. Multiple imputation (MI) is widely advocated as an improvement over complete case analysis (CCA). However, contrary to widespread belief, CCA is preferable to MI in some situations.Methods: We provide guidance on choice of analysis when data are incomplete. Using causal diagrams to depict missingness mechanisms, we describe when CCA will not be biased by missing data and compare MI and CCA, with respect to bias and efficiency, in a range of missing data situations. We illustrate selection of an appropriate method in practice.Results: For most regression models, CCA gives unbiased results when the chance of being a complete case does not depend on the outcome after taking the covariates into consideration, which includes situations where data are missing not at random. Consequently, there are situations in which CCA analyses are unbiased while MI analyses, assuming missing at random (MAR), are biased. By contrast MI, unlike CCA, is valid for all MAR situations and has the potential to use information contained in the incomplete cases and auxiliary variables to reduce bias and/or improve precision. For this reason, MI was preferred over CCA in our real data example.Conclusions: Choice of method for dealing with missing data is crucial for validity of conclusions, and should be based on careful consideration of the reasons for the missing data, missing data patterns and the availability of auxiliary information. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Thigh Circumference and Risk of Heart Disease and Premature Death: Prospective Cohort Study," by B. L. Heitmann and P. Frederiksen in the September 3, 2009 issue.

Purpose: We conducted a systematic review and individual patient data (IPD) meta-analysis to examine the utility of cystatin C for evaluation of glomerular function in children with cancer.Methods: Eligible studies evaluated the accuracy of cystatin C for detecting poor renal function in children undergoing chemotherapy. Study quality was assessed using QUADAS-2. Authors of four studies shared IPD. We calculated the correlation between log cystatin C and GFR stratified by study and measure of cystatin C. We dichotomized the reference standard at GFR 80 ml/min/1.73m2 and stratified cystatin C at 1 mg/l, to calculate sensitivity and specificity in each study and according to age group (0-4, 5-12, and ≥ 13 years). In sensitivity analyses, we investigated different GFR and cystatin C cut points. We used logistic regression to estimate the association of impaired renal function with log cystatin C and quantified diagnostic accuracy using the area under the ROC curve (AUC).Results: Six studies, which used different test and reference standard thresholds, suggested that cystatin C has the potential to monitor renal function in children undergoing chemotherapy for malignancy. IPD data (504 samples, 209 children) showed that cystatin C has poor sensitivity (63%) and moderate specificity (89%), although use of a GFR cut point of < 60 ml/min/1.73m2 (data only available from two of the studies) estimated sensitivity to be 92% and specificity 81.3%. The AUC for the combined data set was 0.890 (95% CI 0.826, 0.951). Diagnostic accuracy appeared to decrease with age.Conclusions: Cystatin C has better diagnostic accuracy than creatinine as a test for glomerular dysfunction in young people undergoing treatment for cancer. Diagnostic accuracy is not sufficient for it to replace current reference standards for predicting clinically relevant impairments that may alter dosing of important nephrotoxic agents. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor in response to an editorial about tuberculosis.

Linear mixed-effects models are commonly used to model trajectories of repeated measures of biomarkers of disease. Taylor, Cumberland, and Sy (1994, Journal of the American Statistical Association 89: 727-736) proposed a linear mixed-effects model with an added integrated Ornstein-Uhlenbeck (IOU) process (linear mixed-effects IOU model). This allows for autocorrelation, changing within-subject variance, and the incorporation of derivative tracking (that is, how much a subject tends to maintain the same trajectory for extended periods of time). They argued that the covariance structure induced by the stochastic process in this model was interpretable and more biologically plausible than the standard linear mixed-effects model. However, their model is rarely used, partly because of the lack of available software. In this article, we present the new command xtmixediou, which fits the linear mixed-effects IOU model and its special case, the linear mixed-effects Brownian motion model. The model is fit to balanced and unbalanced data using restricted maximum-likelihood estimation, where the optimization algorithm is the Newton-Raphson, Fisher scoring, or average information algorithm, or any combination of these. To aid convergence, xtmixediou allows the user to change the method for deriving the starting values for optimization, the optimization algorithm, and the parameterization of the IOU process. We also provide a predict command to generate predictions under the model. We illustrate xtmixediou and predict with a simulated example of repeated biomarker measurements from HIV-positive patients. [ABSTRACT FROM AUTHOR]

The linear mixed model with an added integrated Ornstein–Uhlenbeck (IOU) process (linear mixed IOU model) allows for serial correlation and estimation of the degree of derivative tracking. It is rarely used, partly due to the lack of available software. We implemented the linear mixed IOU model in Stata and using simulations we assessed the feasibility of fitting the model by restricted maximum likelihood when applied to balanced and unbalanced data. We compared different (1) optimization algorithms, (2) parameterizations of the IOU process, (3) data structures and (4) random-effects structures. Fitting the model was practical and feasible when applied to large and moderately sized balanced datasets (20,000 and 500 observations), and large unbalanced datasets with (non-informative) dropout and intermittent missingness. Analysis of a real dataset showed that the linear mixed IOU model was a better fit to the data than the standard linear mixed model (i.e. independent within-subject errors with constant variance). [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated the association between body mass index (BMI) and mortality using the BMI of an offspring as an indicator of one's BMI in an intergenerational mortality study. The study involved 1,018,012 mother-son pairs and 1,004,617 father-son pairs that cover the general population of Sweden. The article also discusses main results and the role of chance, bias and other reasons for caution, generalisability to other populations, and potential competing interests.

Ribavirin has been used widely to treat Lassa fever in West Africa since the 1980s. However, few studies have systematically appraised the evidence for its use. We conducted a systematic review of published and unpublished literature retrieved from electronic databases and gray literature from inception to March 8, 2022. We identified 13 studies of the comparative effectiveness of ribavirin versus no ribavirin treatment on mortality outcomes, including unpublished data from a study in Sierra Leone provided through a US Freedom of Information Act request. Although ribavirin was associated with decreased mortality rates, results of these studies were at critical or serious risk for bias when appraised using the ROBINS-I tool. Important risks for bias related to lack of control for confounders, immortal time bias, and missing outcome data. Robust evidence supporting the use of ribavirin in Lassa fever is lacking. Well-conducted clinical trials to elucidate the effectiveness of ribavirin for Lassa fever are needed. [ABSTRACT FROM AUTHOR]

Background: A recent prospective meta-analysis demonstrated that interleukin-6 antagonists are associated with lower all-cause mortality in hospitalised patients with COVID-19, compared with usual care or placebo. However, emerging evidence suggests that clinicians are favouring the use of tocilizumab over sarilumab. A new randomised comparison of these agents from the REMAP-CAP trial shows similar effects on in-hospital mortality. Therefore, we initiated a network meta-analysis, to estimate pairwise associations between tocilizumab, sarilumab and usual care or placebo with 28-day mortality, in COVID-19 patients receiving concomitant corticosteroids and ventilation, based on all available direct and indirect evidence. Methods: Eligible trials randomised hospitalised patients with COVID-19 that compared tocilizumab or sarilumab with usual care or placebo in the prospective meta-analysis or that directly compared tocilizumab with sarilumab. Data were restricted to patients receiving corticosteroids and either non-invasive or invasive ventilation at randomisation. Pairwise associations between tocilizumab, sarilumab and usual care or placebo for all-cause mortality 28 days after randomisation were estimated using a frequentist contrast-based network meta-analysis of odds ratios (ORs), implementing multivariate fixed-effects models that assume consistency between the direct and indirect evidence. Findings: One trial (REMAP-CAP) was identified that directly compared tocilizumab with sarilumab and supplied results on all-cause mortality at 28-days. This network meta-analysis was based on 898 eligible patients (278 deaths) from REMAP-CAP and 3710 eligible patients from 18 trials (1278 deaths) from the prospective meta-analysis. Summary ORs were similar for tocilizumab [0·82 [0·71–0·95, p = 0·008]] and sarilumab [0·80 [0·61–1·04, p = 0·09]] compared with usual care or placebo. The summary OR for 28-day mortality comparing tocilizumab with sarilumab was 1·03 [95%CI 0·81–1·32, p = 0·80]. The p-value for the global test of inconsistency was 0·28. Conclusions: Administration of either tocilizumab or sarilumab was associated with lower 28-day all-cause mortality compared with usual care or placebo. The association is not dependent on the choice of interleukin-6 receptor antagonist. [ABSTRACT FROM AUTHOR]

Background: Thromboses in unusual locations after the Coronavirus Disease 2019 (COVID-19) vaccine ChAdOx1-S have been reported, although their frequency with vaccines of different types is uncertain at a population level. The aim of this study was to estimate the population-level risks of hospitalised thrombocytopenia and major arterial and venous thromboses after COVID-19 vaccination. Methods and findings: In this whole-population cohort study, we analysed linked electronic health records from adults living in England, from 8 December 2020 to 18 March 2021. We estimated incidence rates and hazard ratios (HRs) for major arterial, venous, and thrombocytopenic outcomes 1 to 28 and >28 days after first vaccination dose for ChAdOx1-S and BNT162b2 vaccines. Analyses were performed separately for ages <70 and ≥70 years and adjusted for age, age2, sex, ethnicity, and deprivation. We also prespecified adjustment for anticoagulant medication, combined oral contraceptive medication, hormone replacement therapy medication, history of pulmonary embolism or deep vein thrombosis, and history of coronavirus infection in analyses of venous thrombosis; and diabetes, hypertension, smoking, antiplatelet medication, blood pressure lowering medication, lipid lowering medication, anticoagulant medication, history of stroke, and history of myocardial infarction in analyses of arterial thromboses. We selected further covariates with backward selection. Of 46 million adults, 23 million (51%) were women; 39 million (84%) were <70; and 3.7 million (8.1%) Asian or Asian British, 1.6 million (3.5%) Black or Black British, 36 million (79%) White, 0.7 million (1.5%) mixed ethnicity, and 1.5 million (3.2%) were of another ethnicity. Approximately 21 million (46%) adults had their first vaccination between 8 December 2020 and 18 March 2021. The crude incidence rates (per 100,000 person-years) of all venous events were as follows: prevaccination, 140 [95% confidence interval (CI): 138 to 142]; ≤28 days post-ChAdOx1-S, 294 (281 to 307); >28 days post-ChAdOx1-S, 359 (338 to 382), ≤28 days post-BNT162b2-S, 241 (229 to 253); >28 days post-BNT162b2-S 277 (263 to 291). The crude incidence rates (per 100,000 person-years) of all arterial events were as follows: prevaccination, 546 (95% CI: 541 to 555); ≤28 days post-ChAdOx1-S, 1,211 (1,185 to 1,237); >28 days post-ChAdOx1-S, 1678 (1,630 to 1,726), ≤28 days post-BNT162b2-S, 1,242 (1,214 to 1,269); >28 days post-BNT162b2-S, 1,539 (1,507 to 1,572). Adjusted HRs (aHRs) 1 to 28 days after ChAdOx1-S, compared with unvaccinated rates, at ages <70 and ≥70 years, respectively, were 0.97 (95% CI: 0.90 to 1.05) and 0.58 (0.53 to 0.63) for venous thromboses, and 0.90 (0.86 to 0.95) and 0.76 (0.73 to 0.79) for arterial thromboses. Corresponding aHRs for BNT162b2 were 0.81 (0.74 to 0.88) and 0.57 (0.53 to 0.62) for venous thromboses, and 0.94 (0.90 to 0.99) and 0.72 (0.70 to 0.75) for arterial thromboses. aHRs for thrombotic events were higher at younger ages for venous thromboses after ChAdOx1-S, and for arterial thromboses after both vaccines. Rates of intracranial venous thrombosis (ICVT) and of thrombocytopenia in adults aged <70 years were higher 1 to 28 days after ChAdOx1-S (aHRs 2.27, 95% CI: 1.33 to 3.88 and 1.71, 1.35 to 2.16, respectively), but not after BNT162b2 (0.59, 0.24 to 1.45 and 1.00, 0.75 to 1.34) compared with unvaccinated. The corresponding absolute excess risks of ICVT 1 to 28 days after ChAdOx1-S were 0.9 to 3 per million, varying by age and sex. The main limitations of the study are as follows: (i) it relies on the accuracy of coded healthcare data to identify exposures, covariates, and outcomes; (ii) the use of primary reason for hospital admission to measure outcome, which improves the positive predictive value but may lead to an underestimation of incidence; and (iii) potential unmeasured confounding. Conclusions: In this study, we observed increases in rates of ICVT and thrombocytopenia after ChAdOx1-S vaccination in adults aged <70 years that were small compared with its effect in reducing COVID-19 morbidity and mortality, although more precise estimates for adults aged <40 years are needed. For people aged ≥70 years, rates of arterial or venous thrombotic events were generally lower after either vaccine compared with unvaccinated, suggesting that either vaccine is suitable in this age group. In a population-based cohort study, William Whiteley and colleagues investigate the association of COVID-19 vaccines ChAdOx1 and BNT162b2 with major venous, arterial, or thrombocytopenic events in England. Author summary: Why was this study done: Cases of venous and arterial thromboses in unusual locations, such as the cerebral veins, and with low platelet levels, have been reported after vaccination with ChAdOx1-S COVID-19 vaccine. Case finding efforts in vaccinated people may lead to overestimation of risk associated with vaccines, if diagnostic thresholds vary between vaccinated and unvaccinated people. Effects of vaccination on rates of common venous and arterial events—such as stroke, myocardial infarction (MI), deep vein thrombosis (DVT), and pulmonary embolism (PE)—are difficult to measure based on case reports. Population-level data may give better estimates. What did the researchers do and find: We used nationally collated data from electronic health records on 46 million adults, of whom 21 million were vaccinated during the study, and compared the incidence of venous and arterial events before and after the first vaccination with ChAdOx1-S and BNT162b2 COVID-19 vaccines. Overall rates of major arterial and venous events were lower after vaccination with both ChAdOx1-S and BNT162b2, after adjusting for potential confounding factors. In people <70 years, rates of hospitalisation due to intracranial venous thrombosis (ICVT) or due to thrombocytopenia were higher after vaccination with ChAdOx1-S but not BNT162b2, although the absolute increase in the risk of these events was very small. What do these findings mean: In adults ≥70 years, a first vaccination with either ChAdOx1-S and BNT162b2 was not associated with an increase in rates major arterial or venous thrombotic events. In adults <70 years, the small increased risks of ICVT and hospitalisation with thrombocytopenia after first vaccination with ChAdOx1-S are likely to be outweighed by the vaccines' effect in reducing COVID-19 mortality and morbidity. The main limitations of the study were its reliance on the accuracy of coded electronic health records, and the potential for residual confounding. [ABSTRACT FROM AUTHOR]

Background. Diagnostic and prognostic algorithms can help reduce clinical uncertainty. The selection of candidate symptoms and signs to be measured in Case Report Forms (CRFs) for potential inclusion in diagnostic algorithms needs to be comprehensive, clearly formulated and relevant for end users. Objective. To investigate whether qualitative methods could assist in designing CRFs in research developing diagnostic algorithms. Specifically, the study sought to establish whether qualitative methods could have assisted in designing the CRF for the Health Technology Association funded Diagnosis of Urinary Tract infection in Young children (DUTY) study, which will develop a diagnostic algorithm to improve recognition of urinary tract infection (UTI) in children aged <5 years presenting acutely unwell to primary care. Methods. Qualitative methods were applied using semi-structured interviews of 30 UK doctors and nurses working with young children in primary care and a Children’s Emergency Department. We elicited features that clinicians believed useful in diagnosing UTI and compared these for presence or absence and terminology with the DUTY CRF. Results. Despite much agreement between clinicians’ accounts and the DUTY CRFs, we identified a small number of potentially important symptoms and signs not included in the CRF and some included items that could have been reworded to improve understanding and final data analysis. Conclusions. This study uniquely demonstrates the role of qualitative methods in the design and content of CRFs used for developing diagnostic (and prognostic) algorithms. Research groups developing such algorithms should consider using qualitative methods to inform the selection and wording of candidate symptoms and signs. [ABSTRACT FROM PUBLISHER]

Multiple imputation is increasingly recommended in epidemiology to adjust for the bias and loss of information that may occur in analyses restricted to study participants with complete data (“complete-case analyses”). However, little guidance is available on applying the method, including which variables to include in the imputation model and the number of imputations needed. Here, the authors used multiple imputation to analyze the prevalence of wheeze among 81-month-old children in the Avon Longitudinal Study of Parents and Children (Avon, United Kingdom; 1991–1999) and the association of wheeze with gender, maternal asthma, and maternal smoking. The authors examined how inclusion of different types of variables in the imputation model affected point estimates and precision, and assessed the impact of number of imputations on Monte Carlo variability. Inclusion of variables associated with the outcome in the imputation model increased odds ratios and reduced standard errors. When only 5 or 10 imputations were used, variability due to the imputation procedure was substantial enough to affect conclusions. Careful preliminary analysis identified the scope for multiple imputation to reduce bias and improve efficiency and provided guidance for building the imputation model. When data are missing, such preliminary analyses should be routinely undertaken and reported, regardless of whether multiple imputation is used in the final analysis. [ABSTRACT FROM PUBLISHER]

Background: Early recognition and treatment of rheumatoid arthritis is important to prevent irreversible joint damage. Anti-citrullinated peptide antibodies (ACPA) have been suggested for early diagnosis. Purpose: To compare the accuracy of ACPA and rheumatoid factor in diagnosing rheumatoid arthritis in patients with early symptoms of the disease. Data Sources: 10 medical databases from inception to September 2009, with no language or publication restrictions, and references of included studies. Study Selection: Two independent reviewers screened searches. Full articles were assessed by one reviewer and checked by a second reviewer to identify studies that reported 2 × 2 data on ACPA for the diagnosis of rheumatoid arthritis (by 1987 American College of Rheumatology criteria). Data Extraction: One reviewer abstracted data on patient characteristics, ACPA details, and 2 × 2 data and assessed study quality by using the QUADAS tool. A second reviewer checked extractions. Data Synthesis: 151 studies were included, with considerable heterogeneity in sensitivity (range, 12% to 93%) and specificity (range, 63% to 100%). In cohort studies that investigated secondgeneration anti-cyclic citrullinated peptide antibodies (anti-CCP2) in patients with early rheumatoid arthritis (<2 years), summary sensitivity and specificity were 57% (95% CI, 51% to 63%) and 96% (CI, 93% to 97%), respectively. Case-control and cross-sectional studies and studies of patients with established rheumatoid arthritis all overestimated sensitivity. Anti-CCP2 had greater specificity than rheumatoid factor (96% vs. 86%), with similar sensitivity. Evidence was insufficient to ascertain whether the combination of anti-CCP2 and rheumatoid factor provides additional benefit over anti-CCP2 alone. Limitations: Most studies used a diagnostic case-control design, which overestimated sensitivity. Items relating to study quality were rarely reported. Publication bias could not be assessed. Conclusion: Anti-CCP2 should be included in the work-up of patients with early symptoms of rheumatoid arthritis. Primary Funding Source: United Kingdom Medical Research Council. [ABSTRACT FROM AUTHOR]

Observational epidemiological studies suffer from many potential biases, from confounding and from reverse causation, and this limits their ability to robustly identify causal associations. Several high-profile situations exist in which randomized controlled trials of precisely the same intervention that has been examined in observational studies have produced markedly different findings. In other observational sciences, the use of instrumental variable (IV) approaches has been one approach to strengthening causal inferences in non-experimental situations. The use of germline genetic variants that proxy for environmentally modifiable exposures as instruments for these exposures is one form of IV analysis that can be implemented within observational epidemiological studies. The method has been referred to as 'Mendelian randomization', and can be considered as analogous to randomized controlled trials. This paper outlines Mendelian randomization, draws parallels with IV methods, provides examples of implementation of the approach and discusses limitations of the approach and some methods for dealing with these. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Publication bias and related bias in meta-analysis is often examined by visually checking for asymmetry in funnel plots of treatment effect against its standard error. Formal statistical tests of funnel plot asymmetry have been proposed, but when applied to binary outcome data these can give false-positive rates that are higher than the nominal level in some situations (large treatment effects, or few events per trial, or all trials of similar sizes). We develop a modified linear regression test for funnel plot asymmetry based on the efficient score and its variance, Fisher's information. The performance of this test is compared to the other proposed tests in simulation analyses based on the characteristics of published controlled trials. When there is little or no between-trial heterogeneity, this modified test has a false-positive rate close to the nominal level while maintaining similar power to the original linear regression test ('Egger' test). When the degree of between-trial heterogeneity is large, none of the tests that have been proposed has uniformly good properties. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In the regression analysis of clustered data it is important to allow for the possibility of distinct between- and within-cluster exposure effects on the outcome measure, represented, respectively, by regression coefficients for the cluster mean and the deviation of the individual-level exposure value from this mean. In twin data, the within-pair regression effect represents association conditional on exposures shared within pairs, including any common genetic or environmental influences on the outcome measure. It has therefore been proposed that a comparison of the within-pair regression effects between monozygous (MZ) and dizygous (DZ) twins can be used to examine whether the association between exposure and outcome has a genetic origin. We address this issue by proposing a bivariate model for exposure and outcome measurements in twin-pair data. The between- and within-pair regression coefficients are shown to be weighted averages of ratios of the exposure and outcome variances and covariances, from which it is straightforward to determine the conditions under which the within-pair regression effect in MZ pairs will be different from that in DZ pairs. In particular, we show that a correlation structure in twin pairs for exposure and outcome that appears to be due to genetic factors will not necessarily be reflected in distinct MZ and DZ values for the within-pair regression coefficients. We illustrate these results in a study of female twin pairs from Australia and North America relating mammographic breast density to weight and body mass index. [ABSTRACT FROM AUTHOR]

Background: Highly active antiretroviral therapy (HAART) for the treatment of HIV infection was introduced a decade ago. We aimed to examine trends in the characteristics of patients starting HAART in Europe and North America, and their treatment response and short-term prognosis.Methods: We analysed data from 22,217 treatment-naive HIV-1-infected adults who had started HAART and were followed up in one of 12 cohort studies. The probability of reaching 500 or less HIV-1 RNA copies per mL by 6 months, and the change in CD4 cell counts, were analysed for patients starting HAART in 1995-96, 1997, 1998, 1999, 2000, 2001, and 2002-03. The primary endpoints were the hazard ratios for AIDS and for death from all causes in the first year of HAART, which were estimated using Cox regression.Results: The proportion of heterosexually infected patients increased from 20% in 1995-96 to 47% in 2002-03, and the proportion of women from 16% to 32%. The median CD4 cell count when starting HAART increased from 170 cells per muL in 1995-96 to 269 cells per muL in 1998 but then decreased to around 200 cells per muL. In 1995-96, 58% achieved HIV-1 RNA of 500 copies per mL or less by 6 months compared with 83% in 2002-03. Compared with 1998, adjusted hazard ratios for AIDS were 1.07 (95% CI 0.84-1.36) in 1995-96 and 1.35 (1.06-1.71) in 2002-03. Corresponding figures for death were 0.87 (0.56-1.36) and 0.96 (0.61-1.51).Interpretation: Virological response after starting HAART improved over calendar years, but such improvement has not translated into a decrease in mortality. [ABSTRACT FROM AUTHOR]

The article evaluates the efficacy and tolerability of oxycodone drug in the relief of pains in cancer. In the course of the research, it made to analyze the efficacy between the drugs of choice, the analgesic, oxycodone and morphine use. The data revealed that many favored the essence of oxycodone, with the adverse effects of mouth drying and drowsiness, than the use of analgesic and morphine which are administered intramuscularly due to its faster results and the extent of the relief.

The outcome of transplantation from grandparent donors in comparison with parental donors in paediatric renal transplantation was evaluated in 53 living related donor (LRD) transplantations performed between January 1996 and August 2003. The donor in 13 cases (25%) was a grandparent (Gpar group), and the remaining donors formed the parent group (Par group). The median age of recipients in the Gpar group was 2.75 (1.7–10.6) years and in the Par group was 12.75 (2.4–22) years ( P<0.0001). There was no evidence of a difference in patient and graft survival, glomerular filtration rate (GFR) after transplantation, or the number of biopsy proven episodes of rejection between the groups. Doses of prednisolone in the first year following transplantation were greater in recipients from Gpar donors, but the other immunosuppression doses were similar. The median age of donors in the Gpar group was 56 (50–67) years and in the Par group was 41 (27–58) years ( P<0.0001). There was no evidence of a difference between the two donor groups in mean creatinine clearance at last follow-up. There were two major donor complications in the Gpar group and one in the Par group. There was no evidence that the length of stay differed between the two groups in either the donors or recipients. These results support the use of carefully selected healthy grandparents as LRDs in children. This option potentially allows for the use of parent donors for a subsequent transplantation. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to investigate the association of childhood and adulthood social class with the occurrence of specific diseases, including those not associated with a high mortality rate, and to investigate daily stress as the mechanism for that part of any association which cannot be accounted for by established risk factors. Methods: This was a prospective cohort study with 25 years of follow-up for cause-specific morbidity and mortality. A total of 5577 Scottish men were recruited from 27 workplaces in the West of Scotland. Childhood social class was determined from the occupation held by the individual's father, and adulthood social class from the individual's occupation at enrolment. Daily stress was measured at enrolment using the Reeder Stress Inventory. Results: Health differentials were found for cardiovascular diseases, lung cancer, peptic ulcer, asthma, accidents and violence, alcohol-related diseases, and perhaps psychiatric illness. Adulthood circumstances were associated with the incidence of most diseases in adulthood, the exception being stroke, which was strongly associated with less privileged circumstances in childhood. Both childhood and adulthood circumstances contributed to the incidence of coronary heart disease. Daily stress did not underlie any of these associations once the influence of established risk factors had been taken into account. Conclusions: Socioeconomic circumstances in childhood and adulthood both contribute to health differentials in adulthood, the relative contributions depending upon the particular disease. Where known risk factors explained only part of the excess of a disease among individuals raised or living in less-privileged circumstances, there was no evidence to suggest that daily stress was the reason for the unexplained excess. [ABSTRACT FROM AUTHOR]

Background: Unhealthy alcohol use among persons living with HIV (PLWH) is linked to significant morbidity, and use of alcohol services may differ by HIV status. Our objective was to compare unhealthy alcohol use screening and treatment by HIV status in primary care. Methods: Cohort study of adult (≥18 years) PLWH and HIV‐uninfected participants frequency matched 20:1 to PLWH by age, sex, and race/ethnicity who were enrolled in a large integrated healthcare system in the United States, with information ascertained from an electronic health record. Outcomes included unhealthy alcohol screening, prevalence, provider‐delivered brief interventions, and addiction specialty care visits. Other predictors included age, sex, race/ethnicity, neighborhood deprivation index, depression, smoking, substance use disorders, Charlson comorbidity index, prior outpatient visits, insurance type, and medical facility. Cox proportional hazards models were used to compute hazard ratios (HR) for the outcomes of time to unhealthy alcohol use screening and time to first addiction specialty visit. Poisson regression with robust standard errors was used to compute prevalence ratios (PR) for other outcomes. Results: 11,235 PLWH and 227,320 HIV‐uninfected participants were included. By 4.5 years after baseline, most participants were screened for unhealthy alcohol use (85% of PLWH and 93% of HIV‐uninfected), but with a lower rate among PLWH (adjusted HR 0.84, 95% CI 0.82 to 0.85). PLWH were less likely, compared with HIV‐uninfected participants, to report unhealthy drinking among those screened (adjusted PR 0.74, 95% CI 0.69 to 0.79), and among those who screened positive, less likely to receive brief interventions (adjusted PR 0.82, 95% CI 0.75 to 0.90), but more likely (adjusted HR 1.7, 95% CI 1.2 to 2.4) to have an addiction specialty visit within 1 year. Conclusions: Unhealthy alcohol use was lower in PLWH, but the treatment approach by HIV status differed. PLWH reporting unhealthy alcohol use received less brief interventions and more addiction specialty care than HIV‐uninfected participants. [ABSTRACT FROM AUTHOR]

The article reports on the potential of double clustering to explain the negative results of some cluster randomised trials. Among the advantages of cluster randomised trials is their feasibility based on the fact that group dynamics can make it easier to change practices or behaviours within an overall group. Their disadvantages include reduced statistical power due to within cluster correlation of outcomes. The author also presents a review of an experience with the Promotion of Breastfeeding Intervention Trial to evaluate the effect of measurement error and clustering.