The Use of Routinely Collected Data in Clinical Trial Research

RCTs are the gold standard for assessing the effects of medical interventions, but they also pose many challenges, including the often-high costs in conducting them and a potential lack of generalizability of their findings. The recent increase in the availability of so called routinely collected data (RCD) sources has led to great interest in their application to support RCTs in an effort to increase the efficiency of conducting clinical trials. We define all RCTs augmented by RCD in any form as RCD-RCTs. A major subset of RCD-RCTs are performed at the point of care using electronic health records (EHRs) and are referred to as point-of-care research (POC-R). RCD-RCTs offer several advantages over traditional trials regarding patient recruitment and data collection, and beyond. Using highly standardized EHR and registry data allows to assess patient characteristics for trial eligibility and to examine treatment effects through routinely collected endpoints or by linkage to other data sources like mortality registries. Thus, RCD can be used to augment traditional RCTs by providing a sampling framework for patient recruitment and by directly measuring patient relevant outcomes. The result of these efforts is the generation of real-world evidence (RWE). Nevertheless, the utilization of RCD in clinical research brings novel methodological challenges, and issues related to data quality are frequently discussed, which need to be considered for RCD-RCTs. Some of the limitations surrounding RCD use in RCTs relate to data quality, data availability, ethical and informed consent challenges, and lack of endpoint adjudication which may all lead to uncertainties in the validity of their results. The purpose of this thesis is to help fill the aforementioned research gaps in RCD-RCTs, encompassing tasks such as assessing their current application in clinical research and evaluating the methodological and technical challenges in performing them. Furthermore, it aims to assess the reporting quality of published reports on RCD-RCTs

Machine learning clinical decision support systems for surveillance: a case study on pertussis and RSV in children

We tested the performance of a machine learning (ML) algorithm based on signs and symptoms for the diagnosis of RSV infection or pertussis in the first year of age to support clinical decisions and provide timely data for public health surveillance. We used data from a retrospective case series of children in the first year of life investigated for acute respiratory infections in the emergency room from 2015 to 2020. We collected data from PCR laboratory tests for confirming pertussis or RSV infection, clinical symptoms, and routine blood testing results, which were used for the algorithm development. We used a LightGBM model to develop 2 sets of models for predicting pertussis and RSV infection: for each type of infection, we developed one model trained with the combination of clinical symptoms and results from routine blood test (white blood cell count, lymphocyte fraction and C-reactive protein), and one with symptoms only. All analyses were performed using Python 3.7.4 with Shapley values (Shap values) visualization package for predictor visualization. The performance of the models was assessed through confusion matrices. The models were developed on a dataset of 599 children. The recall for the pertussis model combining symptoms and routine laboratory tests was 0.72, and 0.74 with clinical symptoms only. For RSV infection, recall was 0.68 with clinical symptoms and laboratory tests and 0.71 with clinical symptoms only. The F1 score for the pertussis model was 0.72 in both models, and, for RSV infection, it was 0.69 and 0.75. ML models can support the diagnosis and surveillance of infectious diseases such as pertussis or RSV infection in children based on common symptoms and laboratory tests. ML-based clinical decision support systems may be developed in the future in large networks to create accurate tools for clinical support and public health surveillance

Reporting transparency and completeness in trials : Paper 3 – trials conducted using administrative databases do not adequately report elements related to use of databases

Acknowledgments The development of CONSORT-ROUTINE and the present review were funded by grants from the Canadian Institutes of Health Research (PI Thombs, #PJT-156172; PIs Thombs and Kwakkenbos, #PCS-161863) and from the United Kingdom National Institute of Health Research (NIHR) Clinical Trials Unit Support Funding (PI Juszczak, Co-PI Gale, supported salary of SM). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Dr. Langan was supported by a Wellcome Senior Clinical Fellowship in Science (205039/Z/16/Z). Dr. Moher is supported by a University Research Chair (uOttawa). Dr. Gale was supported by the United Kingdom Medical Research Council through a Clinician Scientist Fellowship. Dr. Thombs was supported by a Tier 1 Canada Research Chair.Peer reviewedPublisher PD

Predictors of Intraspinal Pressure and Optimal Cord Perfusion Pressure After Traumatic Spinal Cord Injury.

BACKGROUND/OBJECTIVES: We recently developed techniques to monitor intraspinal pressure (ISP) and spinal cord perfusion pressure (SCPP) from the injury site to compute the optimum SCPP (SCPPopt) in patients with acute traumatic spinal cord injury (TSCI). We hypothesized that ISP and SCPPopt can be predicted using clinical factors instead of ISP monitoring. METHODS: Sixty-four TSCI patients, grades A-C (American spinal injuries association Impairment Scale, AIS), were analyzed. For 24 h after surgery, we monitored ISP and SCPP and computed SCPPopt (SCPP that optimizes pressure reactivity). We studied how well 28 factors correlate with mean ISP or SCPPopt including 7 patient-related, 3 injury-related, 6 management-related, and 12 preoperative MRI-related factors. RESULTS: All patients underwent surgery to restore normal spinal alignment within 72 h of injury. Fifty-one percentage had U-shaped sPRx versus SCPP curves, thus allowing SCPPopt to be computed. Thirteen percentage, all AIS grade A or B, had no U-shaped sPRx versus SCPP curves. Thirty-six percentage (22/64) had U-shaped sPRx versus SCPP curves, but the SCPP did not reach the minimum of the curve, and thus, an exact SCPPopt could not be calculated. In total 5/28 factors were associated with lower ISP: older age, excess alcohol consumption, nonconus medullaris injury, expansion duroplasty, and less intraoperative bleeding. In a multivariate logistic regression model, these 5 factors predicted ISP as normal or high with 73% accuracy. Only 2/28 factors correlated with lower SCPPopt: higher mean ISP and conus medullaris injury. In an ordinal multivariate logistic regression model, these 2 factors predicted SCPPopt as low, medium-low, medium-high, or high with only 42% accuracy. No MRI factors correlated with ISP or SCPPopt. CONCLUSIONS: Elevated ISP can be predicted by clinical factors. Modifiable factors that may lower ISP are: reducing surgical bleeding and performing expansion duroplasty. No factors accurately predict SCPPopt; thus, invasive monitoring remains the only way to estimate SCPPopt

Nonregistration, discontinuation, and nonpublication of randomized trials: A repeated metaresearch analysis

BACKGROUND We previously found that 25% of 1,017 randomized clinical trials (RCTs) approved between 2000 and 2003 were discontinued prematurely, and 44% remained unpublished at a median of 12 years follow-up. We aimed to assess a decade later (1) whether rates of completion and publication have increased; (2) the extent to which nonpublished RCTs can be identified in trial registries; and (3) the association between reporting quality of protocols and premature discontinuation or nonpublication of RCTs. METHODS AND FINDINGS We included 326 RCT protocols approved in 2012 by research ethics committees in Switzerland, the United Kingdom, Germany, and Canada in this metaresearch study. Pilot, feasibility, and phase 1 studies were excluded. We extracted trial characteristics from each study protocol and systematically searched for corresponding trial registration (if not reported in the protocol) and full text publications until February 2022. For trial registrations, we searched the (i) World Health Organization: International Clinical Trial Registry Platform (ICTRP); (ii) US National Library of Medicine (ClinicalTrials.gov); (iii) European Union Drug Regulating Authorities Clinical Trials Database (EUCTR); (iv) ISRCTN registry; and (v) Google. For full text publications, we searched PubMed, Google Scholar, and Scopus. We recorded whether RCTs were registered, discontinued (including reason for discontinuation), and published. The reporting quality of RCT protocols was assessed with the 33-item SPIRIT checklist. We used multivariable logistic regression to examine the association between the independent variables protocol reporting quality, planned sample size, type of control (placebo versus other), reporting of any recruitment projection, single-center versus multicenter trials, and industry versus investigator sponsoring, with the 2 dependent variables: (1) publication of RCT results; and (2) trial discontinuation due to poor recruitment. Of the 326 included trials, 19 (6%) were unregistered. Ninety-eight trials (30%) were discontinued prematurely, most often due to poor recruitment (37%; 36/98). One in 5 trials (21%; 70/326) remained unpublished at 10 years follow-up, and 21% of unpublished trials (15/70) were unregistered. Twenty-three of 147 investigator-sponsored trials (16%) reported their results in a trial registry in contrast to 150 of 179 industry-sponsored trials (84%). The median proportion of reported SPIRIT items in included RCT protocols was 69% (interquartile range 61% to 77%). We found no variables associated with trial discontinuation; however, lower reporting quality of trial protocols was associated with nonpublication (odds ratio, 0.71 for each 10% increment in the proportion of SPIRIT items met; 95% confidence interval, 0.55 to 0.92; p = 0.009). Study limitations include that the moderate sample size may have limited the ability of our regression models to identify significant associations. CONCLUSIONS We have observed that rates of premature trial discontinuation have not changed in the past decade. Nonpublication of RCTs has declined but remains common; 21% of unpublished trials could not be identified in registries. Only 16% of investigator-sponsored trials reported results in a trial registry. Higher reporting quality of RCT protocols was associated with publication of results. Further efforts from all stakeholders are needed to improve efficiency and transparency of clinical research

Routinely collected data for randomized trials: promises, barriers, and implications

This work was supported by Stiftung Institut für klinische Epidemiologie. The Meta-Research Innovation Center at Stanford University is funded by a grant from the Laura and John Arnold Foundation. The funders had no role in design and conduct of the study; the collection, management, analysis, or interpretation of the data; or the preparation, review, or approval of the manuscript or its submission for publication.Peer reviewedPublisher PD

SNCA Triplication Parkinson's Patient's iPSC-derived DA Neurons Accumulate α-Synuclein and Are Susceptible to Oxidative Stress

Parkinson's disease (PD) is an incurable age-related neurodegenerative disorder affecting both the central and peripheral nervous systems. Although common, the etiology of PD remains poorly understood. Genetic studies infer that the disease results from a complex interaction between genetics and environment and there is growing evidence that PD may represent a constellation of diseases with overlapping yet distinct underlying mechanisms. Novel clinical approaches will require a better understanding of the mechanisms at work within an individual as well as methods to identify the specific array of mechanisms that have contributed to the disease. Induced pluripotent stem cell (iPSC) strategies provide an opportunity to directly study the affected neuronal subtypes in a given patient. Here we report the generation of iPSC-derived midbrain dopaminergic neurons from a patient with a triplication in the α-synuclein gene (SNCA). We observed that the iPSCs readily differentiated into functional neurons. Importantly, the PD-affected line exhibited disease-related phenotypes in culture: accumulation of α-synuclein, inherent overexpression of markers of oxidative stress, and sensitivity to peroxide induced oxidative stress. These findings show that the dominantly-acting PD mutation is intrinsically capable of perturbing normal cell function in culture and confirm that these features reflect, at least in part, a cell autonomous disease process that is independent of exposure to the entire complexity of the diseased brain

Exploring the Role of Explicit and Implicit Self-Esteem and Self-Compassion in Anxious and Depressive Symptomatology Following Acquired Brain Injury

[EN] Objectives Acquired brain injury (ABI) can lead to the emergence of several disabilities and is commonly associated with high rates of anxiety and depression symptoms. Self-related constructs, such as self-esteem and self-compassion, might play a key role in this distressing symptomatology. Low explicit (i.e., deliberate) self-esteem is associated with anxiety and depression after ABI. However, implicit (i.e., automatic) self-esteem, explicit-implicit self-discrepancies, and self-compassion could also significantly contribute to this symptomatology. The purpose of the present study was to examine whether implicit self-esteem, explicit-implicit self-discrepancy (size and direction), and self-compassion are related to anxious and depressive symptoms after ABI in adults, beyond the contribution of explicit self-esteem. Methods The sample consisted 38 individuals with ABI who were enrolled in a long-term rehabilitation program. All participants completed the measures of explicit self-esteem, implicit self-esteem, self-compassion, anxiety, and depression. Pearson's correlations and hierarchical regression models were calculated. Results Findings showed that both self-compassion and implicit self-esteem negatively accounted for unique variance in anxiety and depression when controlling for explicit self-esteem. Neither the size nor direction of explicit-implicit self-discrepancy was significantly associated with anxious or depressive symptomatology. Conclusions The findings suggest that the consideration of self-compassion and implicit self-esteem, in addition to explicit self-esteem, contributes to understanding anxiety and depression following ABI.Lorena Desdentado is supported by a FPU doctoral scholarship (FPU18/01690) from the Spanish Ministry of Universities. 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Oksidacijski stres u lakirera izloženih niskim razinama olova

Lead toxicity is a public health problem particularly to the children and to occupationally exposed adults. Evidence is mounting successively regarding the adverse health effects of lead at low levels. This study was undertaken to assess the antioxidant status of lead-exposed residential and commercial painters of Lucknow city in Uttar Pradesh, India. Thirty-five painters aged 20 to 50 years who had blood lead levels ≤400 µg L-1 were selected for the study from a population of 56 male painters initially screened for blood lead. The control group included an equal number of subjects of the same age group without any occupational exposure to lead. We studied the association between low lead level exposure and antioxidant status and found that blood lead levels in painters were approximately seven times as high as in controls [(219.2 ± 61.9) µg L-1 vs. (30.6±10.1) µg L-1, respectively]. Among the biomarkers of lead toxicity a significant decrease in the level of delta-aminolevulinic acid dehydratase [(9.13±4.62) UL-1 vs. (39.38±5.05) UL-1] and an increase in the level of zinc protoporphyrin [(187.9±49.8) µg L-1 vs. (26.4±5.5) µg L-1] were observed in painters compared to controls. Among antioxidant enzymes, painters showed a significant decrease in catalase [(56.77±11.11) UL-1 vs. (230.30±42.55) UL-1] and superoxide dismutase [(0.64±0.19) UL-1 vs. (2.68±0.62) UL-1] compared to controls. Lipid peroxidation was monitored by measuring thiobarbituric acid reactive substances (TBARS) that were expressed in terms of malondialdehyde (MDA) equivalents. Concentration of MDA in plasma was higher in painters than in controls [(7.48±1.31) nmol mL-1 vs. (3.08±0.56) nmol mL-1]. Significant changes were also observed in reduced and oxidised glutathione levels. The strong association between blood lead levels and oxidative stress markers in this population suggests that oxidative stress should be considered in the pathogenesis of lead-related diseases among people with low level environmental exposure to lead.Toksičnost olova javnozdravstveni je problem, napose u djece i odraslih osoba koje su im izložene profesionalno. Sve je više dokaza o štetnom djelovanju olova pri niskim razinama. Svrha je ovog ispitivanja bila procijeniti antioksidacijski status u lakirera iz grada Lucknowa u indijskoj pokrajini Uttar Pradesh. Iz skupine od 56 muškaraca lakirera u dobi od 20 do 50 godina s pozitivnim početnim nalazima olova u krvi, za ispitivanje su izabrana 35-orica čije su razine iznosile ≤400 µg L-1. Izabran je i jednaki broj kontrolnih ispitanika iz iste dobne skupine, koji nisu bili profesionalno izloženi olovu. Ispitana je povezanost izme|u izloženosti niskim razinama olova i antioksidacijskoga stanja te je utvrđeno da su razine olova u krvi lakirera [(219,2±61,9) µg L-1] bile oko sedam puta više negoli u kontrolnih ispitanika [(30,6±10,1) µg L-1]. Od biopokazatelja toksičnosti olova u lakirera je zamijećen značajan pad razina delta- ALAD [(9,13±4,62) UL-1 prema (39,38±5,05) UL-1] te rast razina cinkova protoporfirina [(187,9±49,8) µg L-1 prema (26,4±5,5) µg L-1] u odnosu na kontrolne ispitanike. Od antioksidacijskih enzima u lakirera je značajno pala aktivnost katalaze [(56,77±11,11) UL-1 prema (230,30±42,55) UL-1] i superoksid dismutaze [(0,64±0.19) UL-1 prema (2,68±0,62) UL-1] u odnosu na kontrolu, dok je produkt lipidne peroksidacije u plazmi (izv. thiobarbituric acid reactive substances, TBARS) izražen kao koncentracija malondialdehida (MDA) porastao [(7,48±1,31) nmol mL-1 prema (3,08±0,56) nmol mL-1]. Značajne su promjene također zamijećene u smanjenim razinama glutationa i njihovoj oksidaciji. Snažna povezanost razina olova u krvi s pokazateljima oksidacijskoga stresa upućuje na to da u osoba s niskom razinom izloženosti olovu iz okoliša kod razmatranja patogeneze bolesti povezane s olovom u obzir valja uzeti oksidacijski stres