A survey of experts to identify methods to detect problematic studies: Stage 1 of the INSPECT-SR Project.

Background: Randomised controlled trials (RCTs) inform healthcare decisions. Unfortunately, some published RCTs contain false data, and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs which have been conducted on a given topic. This means that any of these 'problematic studies' are likely to be included, but there are no agreed methods for identifying them. The INSPECT-SR project is developing a tool to identify problematic RCTs in systematic reviews of healthcare-related interventions. The tool will guide the user through a series of 'checks' to determine a study's authenticity. The first objective in the development process is to assemble a comprehensive list of checks to consider for inclusion. Methods: We assembled an initial list of checks for assessing the authenticity of research studies, with no restriction to RCTs, and categorised these into five domains: Inspecting results in the paper; Inspecting the research team; Inspecting conduct, governance, and transparency; Inspecting text and publication details; Inspecting the individual participant data. We implemented this list as an online survey, and invited people with expertise and experience of assessing potentially problematic studies to participate through professional networks and online forums. Participants were invited to provide feedback on the checks on the list, and were asked to describe any additional checks they knew of, which were not featured in the list. Results: Extensive feedback on an initial list of 102 checks was provided by 71 participants based in 16 countries across five continents. Fourteen new checks were proposed across the five domains, and suggestions were made to reword checks on the initial list. An updated list of checks was constructed, comprising 116 checks. Many participants expressed a lack of familiarity with statistical checks, and emphasized the importance of feasibility of the tool. Conclusions: A comprehensive list of trustworthiness checks has been produced. The checks will be evaluated to determine which should be included in the INSPECT-SR tool.

Protocol for the development of a tool (INSPECT-SR) to identify problematic randomised controlled trials in systematic reviews of health interventions.

INTRODUCTION: Randomised controlled trials (RCTs) inform healthcare decisions. It is now apparent that some published RCTs contain false data and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs that have been conducted on a given topic. While it is usual to assess methodological features of the RCTs in the process of undertaking a systematic review, it is not usual to consider whether the RCTs contain false data. Studies containing false data therefore go unnoticed and contribute to systematic review conclusions. The INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project will develop a tool to assess the trustworthiness of RCTs in systematic reviews of healthcare-related interventions. METHODS AND ANALYSIS: The INSPECT-SR tool will be developed using expert consensus in combination with empirical evidence, over five stages: (1) a survey of experts to assemble a comprehensive list of checks for detecting problematic RCTs, (2) an evaluation of the feasibility and impact of applying the checks to systematic reviews, (3) a Delphi survey to determine which of the checks are supported by expert consensus, culminating in, (4) a consensus meeting to select checks to be included in a draft tool and to determine its format and (5) prospective testing of the draft tool in the production of new health systematic reviews, to allow refinement based on user feedback. We anticipate that the INSPECT-SR tool will help researchers to identify problematic studies and will help patients by protecting them from the influence of false data on their healthcare. ETHICS AND DISSEMINATION: The University of Manchester ethics decision tool was used, and this returned the result that ethical approval was not required for this project (30 September 2022), which incorporates secondary research and surveys of professionals about subjects relating to their expertise. Informed consent will be obtained from all survey participants. All results will be published as open-access articles. The final tool will be made freely available.

Imaging predictors of progression of lumbar spondylolysis to spondylolisthesis: a systematic review.

BACKGROUND CONTEXT: Isthmic spondylolisthesis (IS) is defined as the anterior translation of one lumbar vertebra relative to the next caudal segment as a result of a unilateral or bilateral fracture of the pars interarticularis. These fractures are interchangeably known as "pars defects" or "spondylolysis." Many risk factors have been proposed to explain the progression of a spondylolytic defect to IS, however, none are validated. PURPOSE: This systematic review provides an overview of various radiological and imaging parameters that can help predict the risk of progression of a spondylolytic defect into IS. STUDY DESIGN: Systematic review. METHODS: Medline, Embase and Cochrane online database were searched. The various correlations between imaging features with observed spondylolisthesis prevalence or severity or spondylolysis rates of spondylolisthesis were evaluated to provide a list of imaging risk factors to predict IS. Significance of the correlations in the original article was recorded to enable comparison of the collected evidence of separate image features. RESULTS: All searches combined generated a total of 431 results of which 26 articles were included into this study. Of the 22 potential risk factors identified, 5 were found to be statistically insignificant, 8 were found to be significant and 9 had mixed results. The following features were found to be significant risk factors in at least on study: disc degeneration, transverse process width, pelvic incidence, pelvic tilt, sacral slope, lumbar lordosis, lumbar index, thoracic kyphosis, facet joint angle above the level of defect, facet joint degeneration, facet tropism, multifidus size, lateral erector spinae size, mesenteric fat thickness, subcutaneous fat thickness and soft tissue calcification. CONCLUSION: Our research suggests that only disc degeneration had moderately strong evidence with consistent significant associations with development of IS in patients with spondylolysis. Transverse process width, pelvic incidence, pelvic tilt, sacral slope, lumbar lordosis, lumbar index, thoracic kyphosis, facet joint angle above the level of defect, facet joint degeneration, facet tropism, multifidus size, lateral erector spinae size, mesenteric fat thickness, subcutaneous fat thickness and soft tissue calcification had some evidence. All other radiological factors had weak evidence. The results of this study can be used to improve early clinical decision making for patients with spondylolysis.

Reconsidering high intensity zones: its role in intervertebral disk degeneration and low back pain.

PURPOSE: High intensity zones (HIZ) in the lumbar intervertebral disk (IVD) can be associated with degenerative changes which may ultimately manifest as low back pain (LBP). However, the relationship between the prevalence of HIZ and lumbar degenerative parameters is still unclear. The purpose of this study was to determine the prevalence of HIZ in the lumbar spine, analyze the independent relationship between HIZ and lumbar degenerative parameters measured on MRI and X-ray and determine the association between HIZ and the presence of LBP. METHODS: A retrospective review of MRI data, X-ray data, and radiology reports for 136 consecutively recruited patients, above 18-years-age and with both lumbar MRI and X-ray scans was conducted. 57 patients with HIZ were identified. Patients without HIZ (n = 79) made up the control group. RESULTS: HIZ was prevalent in 41.9% of patients and in 11.0% of all lumbar IVDs. The odds of developing HIZ were 6.4 (Exp(B) 6.4, 95%CI [3.157-12.988]) and 3.0 (Exp(B) 3.0, 95%CI [1.603, 5.674]) times higher in IVDs with disk bulge/protrusion and nucleus degeneration, respectively. Odds of HIZ was also increased in disks with larger IVD angle (Exp(B) 1.1, 95%CI [1.034, 1.169]). The odds of patients presenting to imaging with LBP was 3.0 (OR 3.0, 95%CI [1.478-6.338]) times higher in the HIZ compared to the control group. CONCLUSIONS: HIZ was prevalent in 41.9% of participants that were recruited in this study. Nucleus degeneration, disk bulge/protrusion and increased IVD angle were found to be independently associated with HIZ and since there is an increased likelihood of LBP, we posit that HIZ is likely a symptomatic and clinically meaningful diagnostic tool in the assessment of LBP.

Protocol for the development of a tool (INSPECT-SR) to identify problematic randomised controlled trials in systematic reviews of health interventions.

Introduction: Randomised controlled trials (RCTs) inform healthcare decisions. It is now apparent that some published RCTs contain false data and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs that have been conducted on a given topic. While it is usual to assess methodological features of the RCTs in the process of undertaking a systematic review, it is not usual to consider whether the RCTs contain false data. Studies containing false data therefore go unnoticed and contribute to systematic review conclusions. The INSPECT-SR project will develop a tool to assess the trustworthiness of RCTs in systematic reviews of healthcare related interventions. Methods and analysis: The INSPECT-SR tool will be developed using expert consensus in combination with empirical evidence, over five stages: 1) a survey of experts to assemble a comprehensive list of checks for detecting problematic RCTs, 2) an evaluation of the feasibility and impact of applying the checks to systematic reviews, 3) a Delphi survey to determine which of the checks are supported by expert consensus, culminating in 4) a consensus meeting to select checks to be included in a draft tool and to determine its format, 5) prospective testing of the draft tool in the production of new health systematic reviews, to allow refinement based on user feedback. We anticipate that the INSPECT-SR tool will help researchers to identify problematic studies, and will help patients by protecting them from the influence of false data on their healthcare.

Characteristics of baseline frequency data in spinal RCTs do not suggest widespread non-random allocation.

BACKGROUND: Recent signs of fraudulent behaviour in spine RCTs have queried the integrity of trials in the field. RCTs are particularly important due to the weight they are accorded in guiding treatment decisions, and thus, ensuring RCTs' reliability is crucial. This study investigates the presence of non-random baseline frequency data in purported RCTs published in spine journals. METHODS: A PubMed search was performed to obtain all RCTs published in four spine journals (Spine, The Spine Journal, the Journal of Neurosurgery Spine, and European Spine Journal) between Jan-2016 and Dec-2020. Baseline frequency data were extracted, and variable-wise p values were calculated using the Pearson Chi-squared test. These p values were combined for each study into study-wise p values using the Stouffer method. Studies with p values below 0.01 and 0.05 and those above 0.95 and 0.99 were reviewed. Results were compared to Carlisle's 2017 survey of anaesthesia and critical care medicine RCTs. RESULTS: One hundred sixty-seven of the 228 studies identified were included. Study-wise p values were largely consistent with expected genuine randomized experiments. Slightly more study-wise p values above 0.99 were observed than expected, but a number of these had good explanations to account for that excess. The distribution of observed study-wise p values was more closely matched to the expected distribution than those in a similar survey of the anaesthesia and critical care medicine literature. CONCLUSION: The data surveyed do not show evidence of systemic fraudulent behaviour. Spine RCTs in major spine journals were found to be consistent with genuine random allocation and experimentally derived data.

Age-based exclusion is common and multifactorial in spinal RCTs: a systematic review and quantitative analysis.

Most diseases of the spine disproportionately impact older persons, with the modal (i.e., commonest) patient a female in their 8th decade of life. We examined the corpus of spinal RCTs to determine how many included "average" spine patients. We searched PubMed for randomized clinical trials published in the top 7 spine journals over a period of 5 years from 2016 to 2020 and extracted nominal upper age cut-offs and the distribution of ages actually recruited. We identified 186 trials of 26,238 patients. We found that only 4.8% of trials could be applied to an "average" 75-year-old patient. This age-based exclusion was not dependent on funding source. Age-based exclusion was exacerbated by explicit upper age cut-offs, however, the age-based exclusion went beyond explicit age cut-offs. Only few trials were applicable to older patients even amongst trials with no age cut-off specified. Age-based exclusion from clinical trials starts at late middle age. The mismatch between spinal patient's age seen in clinical practice and spinal patient's age in trials was so severe that over the 5 years (2016-2020) almost no RCT evidence was produced applicable to the "average" aged-patient across the body of literature available. In conclusion, age-based exclusion is ubiquitous, multifactorial, and happens on a supratrial level. Eliminating age-based exclusion involves more than an arbitrary lifting of explicitly stated upper age cut-offs. Instead, recommendations include increasing input from geriatricians and ethics committees, establishing updated or new models of cares, and creating new protocols to facilitate further research.

Clinical and Research MRI Techniques for Assessing Spinal Cord Integrity in Degenerative Cervical Myelopathy-A Scoping Review.

BACKGROUND: Degenerative cervical myelopathy (DCM) manifests as the primary cause of spinal cord dysfunction and is non-traumatic, chronic and progressive in nature. Decompressive surgery is typically utilised to halt further disability and neurological dysfunction. The limitations of current diagnostic options surrounding assessment and prognostic potential render DCM still largely a clinical diagnosis. AIMS: To outline the limitations of current diagnostic techniques, present evidence behind novel quantitative MRI (qMRI) techniques for assessing spinal cord integrity in DCM and suggest future directions. METHOD: Articles published up to November 2021 were retrieved from Medline, EMBASE and EBM using key search terms: spinal cord, spine, neck, MRI, magnetic resonance imaging, qMRI, T1, T2, T2*, R2*, DTI, diffusion tensor imaging, MT, magnetisation transfer, SWI, susceptibility weighted imaging, BOLD, blood oxygen level dependent, fMRI, functional magnetic resonance imaging, functional MRI, MRS, magnetic resonance spectroscopy. RESULTS: A total of 2057 articles were retrieved with 68 articles included for analysis. The search yielded 2 articles on Quantitative T1 mapping which suggested higher T1 values in spinal cord of moderate-severe DCM; 43 articles on DTI which indicated a strong correlation of fractional anisotropy and modified Japanese Orthopaedic Association scores; 15 articles on fMRI (BOLD) which demonstrated positive correlation of functional connectivity and volume of activation of various connections in the brain with post-surgical recovery; 6 articles on MRS which suggested that Choline/N-acetylaspartate (Cho/NAA) ratio presents the best correlation with DCM severity; and 4 articles on MT which revealed a preliminary negative correlation of magnetisation transfer ratio with DCM severity. Notably, most studies were of low sample size with short timeframes within 6 months. CONCLUSIONS: Further longitudinal studies with higher sample sizes and longer time horizons are necessary to determine the full prognostic capacity of qMRI in DCM.

Plausibility of Claimed Covid-19 Vaccine Efficacies by Age: A Simulation Study.

BACKGROUND: Multiple vaccines against Covid-19 have passed through phase-3 trials; however, concerns have been raised about alleged excessive similarity of efficacy across age groups for the Sputnik V vaccine. STUDY QUESTION: How likely are the observed efficacies for all age subgroups to fall within the range of by-age efficacies claimed for the AstraZeneca, Janssen, Moderna, Pfizer, and Sputnik V vaccines, assuming that there is no effect of age on efficacy? STUDY DESIGN: We performed a simulation study using R of 1000 and then 50,000 simulated trials for each vaccine, with random allocation to each arm but fixed enrollment numbers by age group. We used study-wide efficacy and infection rate for all age groups. We recorded the observed vaccine efficacies in each age group and summated how many simulations had all observed efficacies fall within the range of efficacies described in the relevant article. RESULTS: In the 1000-trial simulation for the AstraZeneca vaccine, in 23.8% of simulated trials, the observed efficacies of all age subgroups fell within the efficacy bounds for age subgroups in the published article. The J + J simulation showed 44.7%, Moderna 51.1%, Pfizer 30.5%, and 0.0% of the Sputnik simulated trials had all age subgroups fall within the limits of the efficacy estimates described by the published article. In 50,000 simulated trials of the Sputnik vaccine, 0.026% had all age subgroups fall within the limits of the efficacy estimates described by the published article, whereas 99.974% did not. CONCLUSIONS: The distribution of alleged vaccine efficacies of the Sputnik vaccine by age in the phase-III trial is very unlikely to occur in genuine experimental data, even if the number of patients recruited, vaccine efficacy, and overall infection rate are true and there is no underlying difference in vaccine efficacy by age.

Making Statistical Sense of the Molnupiravir MOVe-OUT Clinical Trial.

Oral therapies for the early treatment of COVID-19 may prevent disease progression and health system overcrowding. A new oral therapeutic named molnupiravir has been promoted as providing an approximately 50% reduction in death or the need for hospitalization. The clinical trial evaluating this drug was stopped early at the recommendation of the Data Safety and Monitoring Board after approximately 50% of the sample had been recruited. At the point of discontinuing the trial, approximately 90% of the planned sample had been recruited and had available follow-up data accessible. We discuss issues about the study conduct, analysis, and interpretation, including 1) the authors and sponsors presented the interim analysis as the primary analysis; 2) communication between sponsors and the Data Safety and Monitoring Board was insufficient; 3) the treatment effects reverse when examining only the post-interim analysis population, and are substantially attenuated when examining the full data; 4) the choice of primary analysis is incorrect; 5) analysis of lost-to-follow-up patients favors the study drug; and 6) other known molnupiravir trials were not presented in the primary study findings. As a result of methodological and statistical concerns, it seems that external trials, separate from those supported by the sponsoring company, are required to determine the utility of this drug.

A novel magnetic resonance imaging postprocessing technique for the assessment of intervertebral disc degeneration-Correlation with histological grading in a rabbit disc degeneration model.

INTRODUCTION: Estimation of intervertebral disc degeneration on magnetic resonance imaging (MRI) is challenging. Qualitative schemes used in clinical practice correlate poorly with pain and quantitative techniques have not entered widespread clinical use. METHODS: As part of a prior study, 25 New Zealand white rabbits underwent annular puncture to induce disc degeneration in 50 noncontiguous lumbar discs. At 16 weeks, the animals underwent multi-echo T2 MRI scanning and were euthanized. The discs were stained and examined histologically. Quantitative T2 relaxation maps were prepared using the nonlinear least squares method. Decay Variance maps were created using a novel technique of aggregating the deviation in the intensity of each echo signal from the expected intensity based on the previous rate of decay. RESULTS: Decay Variance maps showed a clear and well demarcated nucleus pulposus with a consistent rate of decay (low Decay Variance) in healthy discs that showed progressively more variable decay (higher Decay Variance) with increasing degeneration. Decay Variance maps required significantly less time to generate (1.0 ± 0.0 second) compared with traditional T2 relaxometry maps (5 (±0.9) to 1788.9 (±116) seconds). Histology scores correlated strongly with Decay Variance scores (r = 0.82, P < .01) and weakly with T2 signal intensity (r = 0.32, P < .01) and quantitative T2 relaxometry (r = 0.39, P < .01). Decay Variance had superior sensitivity and specificity for the detection of degenerate discs when compared to T2 signal intensity or Quantitative T2 mapping. CONCLUSION: Our results show that using a multi-echo T2 MRI sequence, Decay Variance can quantitatively assess disc degeneration more accurately and with less image-processing time than quantitative T2 relaxometry in a rabbit disc puncture model. The technique is a viable candidate for quantitative assessment of disc degeneration on MRI scans. Further validation on human subjects is needed.

Bony stress in the lumbar spine is associated with intervertebral disc degeneration and low back pain: a retrospective case-control MRI study of patients under 25 years of age.

PURPOSE: Abnormal stress in the lumbar vertebra, also known as bony stress, can be a precursor to degenerative changes which may manifest as low back pain (LBP). However, the prevalence of bony stress in the lumbar spine and its relationship with degenerative changes and LBP is unclear. The purpose of this study was to evaluate the prevalence of bony stress in the lumbar spine and its relationship with intervertebral disc (IVD) degeneration, facet osteoarthritis and LBP in patients under 25 years of age. METHODS: A retrospective case-control study of 130 patients under 25 years of age was conducted from a population of 493 patients who had lumbar MRI across three imaging centres over three years. A cohort of 55 consecutive patients with bony stress was identified. A control group of consecutive patients (n = 75) without bony stress was also selected from the population. RESULTS: Bony stress was prevalent in 11% (95% CI [8.4-14.5%]) of patients and was not diagnosed in 36% (95% CI [22-55%]) of these cases. Patients with bony stress had over twofold (OR 2.3, 95% CI [1.1-4.8]) and fivefold (OR 5.3, 95% CI [2.11-13.3]) higher likelihood of having IVD degeneration and LBP, respectively, when compared with the control group. Bony stress was not found to be associated with facet osteoarthritis. CONCLUSION: Bony stress in the lumbar spine was prevalent in 11% of patients under 25 years of age. It was commonly undiagnosed in radiology reports (not reported in 36% of the cases). Being significantly associated and with an increased likelihood of IVD degeneration and LBP, we posit that bony stress is likely a symptomatic and clinically meaningful diagnostic entity in the assessment of LBP. These slides can be retrieved under Electronic Supplementary Material.

Burden of paediatric pyoderma and scabies in North West Queensland.

AIM: The study aims to assess the health burden of children admitted with 'scabies' to Mt Isa Hospital, the referral centre for North West Queensland, from 2006 to 2010. METHODS: This is a retrospective chart audit of admissions of children with 'scabies' including age, sex, date, residence, Indigenous status, result of skin swabs and length of stay, and the number of admissions with acute rheumatic fever (ARF) and acute post-streptococcal glomerulo-nephritis (APSGN) in that period. Financial burden was estimated from daily bed costs and transportation. RESULTS: There were 113 admissions with mean age of 23/12: 11% were <2/12 and mean stay was 4.5 days. 19 were admitted twice, 5 thrice and 2 four times. 7 individuals accounted for 25% of admissions. 'Scabies' accounted for 10.1% of medical admissions <5 years of age. Admissions increased from 10 in 2005 to 39 in 2010. The minimum cost per admission was $9584.07. Seventy-one per cent of swabs grew Group A streptococcus, all sensitive to penicillin. Sixty-three per cent of these were accompanied by Staphylococcus aureus, which was the sole organism in 18%. Sixty-four per cent of S. aureus were methicillin resistant. There were 29 admissions for ARF and 23 with APSGN. All children with 'scabies' and ARF and all but three with APSGN were Indigenous. CONCLUSION: Pyoderma and scabies are major health burdens in North West Queensland, requiring organised community-based prevention. The number of repeat admissions emphasises the futility of individual treatment.

Hallucinations in severe, repeated Sydenham's chorea in an Indigenous girl in North-West Queensland.

Sydenham's chorea is a cardinal feature of rheumatic fever. It is known by its dyskinesia and susceptibility to carditis, but associated psychiatric disorder is being recognised. This has included tics and obsessive compulsive disorder, but we report hallucinations in an indigenous girl, suffering her third bout of chorea.