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bioRxiv2018

DataPackageR: Reproducible data preprocessing, standardization and sharing using R/Bioconductor for collaborative data analysis.

A central tenet of reproducible research is that scientific results are published along with the underlying data and software code necessary to reproduce and verify the findings. A host of tools and software have been released that facilitate such work-flows and scientific journals have increasingly demanded that code and primary data be made available with publications. There has been little practical advice on implementing reproducible research work-flows for large omics or systems biology data sets used by teams of analysts working in collaboration. In such instances it is important to ensure all analysts use the same version of a data set for their analyses. Yet, instantiating relational databases and standard operating procedures can be unwieldy, with high \"startup\" costs and poor adherence to procedures when they deviate substantially from an analysts usual work-flow. Ideally a reproducible research work-flow should fit naturally into an individuals existing work-flow, with minimal disruption. Here, we provide an overview of how we have leveraged popular open source tools, including Bioconductor, Rmarkdown, git version control, R, and specifically Rs package system combined with a new tool DataPackageR, to implement a lightweight reproducible research work-flow for preprocessing large data sets, suitable for sharing among small-to-medium sized teams of computational scientists. Our primary contribution is the DataPackageR tool, which decouples time-consuming data processing from data analysis while leaving a traceable record of how raw data is processed into analysis-ready data sets. The software ensures packaged data objects are properly documented and performs checksum verification of these along with basic package version management, and importantly, leaves a record of data processing code in the form of package vignettes. Our group has implemented this work-flow to manage, analyze and report on pre-clinical immunological trial data from multi-center, multi-assay studies for the past three years.

bioinformatics↗

bioRxiv2018

Impact of a ketogenic diet intervention during radiotherapy on body composition: III. An interim analysis of the KETOCOMP study

BackgroundKetogenic therapy (KT) in the form of ketogenic diets (KDs) and/or supplements that induce nutritional ketosis have gained interest as a complementary treatment for cancer patients. Besides putative anti-tumor effects, preclinical and preliminary clinical data indicate that KT could induce favorable changes in body composition of the tumor bearing host. Here we present first results of our ongoing KETOCOMP study (NCT02516501) study concerning body composition changes among rectal, breast and head & neck cancer (HNC) patients who underwent concurrent KT during standard-of-care radiotherapy (RT).\n\nMethodsEligible patients were assigned to one of three groups: (i) a standard diet group; (ii) a ketogenic breakfast group taking 50-250 ml of a medium-chain triglyceride (MCT) drink plus 10 g essential amino acids in the morning of RT days; (iii) a complete KD group supplemented with 10 g essential amino acids on RT days. Body composition was to be measured prior to and weekly during RT using 8-electrode bioimpedance analysis. Longitudinal data were analyzed using mixed effects linear regression.\n\nResultsA total of 17 patients underwent KT during RT thus far (rectal cancer: n=6; HNC: n=6; breast cancer: n=5). All patients consuming a KD (n=14) reached nutritional ketosis and finished the study protocol with only minor problems reported. Compared to control subjects, the ketogenic intervention in rectal and breast cancer patients was significantly associated with a decline in fat mass over time (-0.3 and -0.5 kg/week, respectively), with no significant changes in skeletal muscle mass. In HNC patients, concurrent chemotherapy was the strongest predictor of body weight, fat free and skeletal muscle mass decline during radiotherapy, while KT showed significant opposite associations. Rectal cancer patients who underwent KT during neoadjuvant RT had significantly better tumor response at the time of surgery as assessed by the Dworak regression grade (median 3 versus 2, p=0.04483).\n\nConclusionsWhile sample sizes are still small our results already indicate some significant favorable effects of KT on body composition. These as well as a putative radiosensitizing effect on rectal tumor cells need to be confirmed once the final analysis of our study becomes possible.

clinical trials↗

bioRxiv2018

Crohn’s disease patients effectively mobilize peripheral blood stem cells to perform autologous haematopoietic stem cell transplantation

BackgroundTreatment with high doses chemotherapy followed by autologous haematopoietic stem cell transplantation is promising for refractory Crohns disease patients with no therapeutic option and at imminent risk of further surgeries.\n\nObjectivesTo evaluate the feasibility and efficacy of haematopoietic progenitor cell mobilization in a group of Crohns disease patients preparing for autologous unselected haematopoietic stem cell transplantation in a single institution. This is the first study to evaluate mobilization for Crohns disease.\n\nMethodsPatients were selected according to criteria of the European Bone Marrow Transplant Society.\n\nResultsAll patients mobilized with the mean number of haematopoietic progenitor cells obtained and infused being 16.17 x 106/CD34+/kg. Most patients required only one leukapheresis session to reach the ideal number of cells. Grafting occurred around ten days after cells infusion. Complications and adverse events during the mobilization period were rare with only one patient presenting sepsis as a relevant event in the period.\n\nMost patients 20 (70%) had anaemia from the beginning of the mobilization but only 11 (37.9%) received packed red blood cell transfusions.\n\nConclusionMobilization in patients with Crohns disease is effective and it seems they are good mobilizers.

clinical trials↗

bioRxiv2018

Improvement in Patient-Reported Sleep in Type 2 Diabetes and Prediabetes Participants Receiving a Continuous Care Intervention with Nutritional Ketosis

ObjectiveSleep disruption is frequently associated with type 2 diabetes (T2D) and hyperglycemia. We recently reported the effectiveness of a continuous care intervention (CCI) emphasizing nutritional ketosis for improving HbA1c, body weight and cardiovascular risk factors in T2D patients. The present study assessed the effect of this CCI approach on sleep quality using a subjective patient-reported sleep questionnaire. MethodsA non-randomized, controlled longitudinal study; 262 T2D and 116 prediabetes patientsenrolled in the CCI and 87 separately recruited T2D patients continued usual care (UC) treatment. Patients completed the Pittsburgh Sleep Quality Index (PSQI) questionnaire. A PSQI score of >5 (scale 0 to 21) was used to identify poor sleepers. ResultsGlobal sleep quality improved in the CCI T2D (p<0.001) and prediabetes (p<0.001) patients after one year of intervention. Subjective sleep quality (component 1), sleep disturbance (component 5) and daytime dysfunction (component 7), also showed improvements in the CCI T2D (p<0.01 for sleep quality and sleep disturbance; and p<0.001 for daytime dysfunction) and prediabetes patients (p<0.001 for all three components); compared to the UC T2D group after one year. The proportion of patients with poor sleep quality was significantly reduced after one year of CCI (T2D; from 68.3% at baseline to 56.5% at one year, p=0.001 and prediabetes; from 77.9% at baseline to 48.7% at one year, p<0.001). ConclusionThis study demonstrates improved sleep quality as assessed by PSQI in patients with T2D and prediabetes undergoing CCI including nutritional ketosis but not in T2D patients receiving UC. The dietary intervention benefited both sleep quality and the severity of T2D symptoms suggesting that nutritional ketosis improves overall health via multiple mechanisms.

clinical trials↗

bioRxiv2018

Derivation of a simple postoperative delirium incidence and severity prediction model

BackgroundDelirium is an important postoperative complication, yet a simple and effective delirium prediction model remains elusive. We hypothesized that the combination of the National Surgical Quality Improvement Program (NSQIP) risk calculator for serious complications (NSQIP-SC) or risk of death (NSQIP-D), and cognitive tests of executive function (Trail Making Test A and B [TMTA, TMTB]), could provide a parsimonious model to predict postoperative delirium incidence or severity.\n\nMethodsData were collected from 100 adults ([≥]65yo) undergoing major non-cardiac surgery. In addition to NSQIP-SC, NSQIP-D, TMTA and TMTB, we collected participant age, sex, ASA score, tobacco use, type of surgery, depression, Framingham risk score, and preoperative blood pressure. Delirium was diagnosed with the Confusion Assessment Method (CAM), and the Delirium Rating Scale-R-98 (DRS) was used to assess symptom severity. LASSO and Best Subsets logistic and linear regression were employed in line with TRIPOD guidelines.\n\nResultsThree participants were excluded due to intraoperative deaths (2) and alcohol withdrawal (1). Ninety-seven participants with a mean age of 71.68{+/-}4.55, 55% male (31/97 CAM+, 32%) and a mean Peak DRS of 21.5{+/-}6.40 were analyzed. Of the variables included, only NSQIP-SC and TMTB were identified to be predictors of postoperative delirium incidence (p<0.001, AUROC 0.81, 95% CI: 0.72, 0.90) and severity (p<0.001, Adj. R2: 0.30).\n\nConclusionsIn this cohort, preoperative NSQIP-SC and TMTB were identified as predictors of postoperative delirium incidence and severity. Future studies should verify whether this two-factor model could be used for accurate delirium prediction.

clinical trials↗

bioRxiv2018

Bacterial strain displacement in inflammatory bowel diseases after fecal microbiota transplantation

Fecal microbiota transplantation (FMT), which is thought to have the potential to correct dysbiosis of gut microbiota, has recently been used to treat inflammatory bowel disease (IBD). To elucidate the extent and principles of microbiota engraftment in IBD patients after FMT treatment, we conducted an interventional prospective cohort study. The cohort included two categories of patients: (1) patients with moderate to severe Crohns disease (CD) (Harvey-Bradshaw Index [≥] 7, n = 11, and (2) patients with ulcerative colitis (UC) (Montreal classification, S2 and S3, n = 4). All patients were treated with a single FMT (via mid-gut, from healthy donors) and follow-up visits were performed at baseline, 3 days, one week, and one month after FMT (missing time points included). At each follow-up time point, fecal samples of the participants were collected along with their clinical metadata. For comparative analysis, 10 fecal samples from 10 healthy people were included to represent the diversity level of normal gut microbiota. Additionally, the metagenomic data of 25 fecal samples from 5 individuals with metabolic syndrome who underwent autologous FMT treatment were downloaded from a previous published paper to represent natural microbiota shifts during FMT. All fecal samples underwent shotgun metagenomic sequencing. We found that 3 days after FMT, 11 out of 15 recipients were in remission (3 out of 4 UC recipients; 8 out of 11 CD recipients). Generally, bacterial colonization was observed to be lower in CD recipients than in UC recipients at both species and strain levels. Furthermore, across species, different strains displayed disease-specific displacement advantages under two-disease status. Finally, most post-FMT species (> 80%) could be properly predicted (AUC > 85%) using a random forest classification model, with the gut microbiota composition and clinical parameters of pre-FMT recipients acting as the most contributive factors for prediction accuracy.

clinical trials↗

bioRxiv2018

Multi-Center Study of Resectable Lung Lesions by Ultra-Deep Sequencing of Targeted Genes in Plasma Cell-Free DNA to Assess Nodule Malignancy and Detect Lung Cancers

BACKGROUNDEarly detection of lung cancer to allow curative treatment remains challenging. Cell-free circulating tumor DNA (ctDNA) analysis may aid in malignancy assessment and early cancer diagnosis of lung nodules found in screening imagery.\n\nMETHODSThe multi-center clinical study enrolled 192 patients with operable occupying lung diseases. Plasma ctDNA, white blood cell genomic DNA (gDNA) and tumor tissue gDNA of each patient were analyzed by ultra-deep sequencing to an average of 35,000X of the coding regions of 65 lung cancer-related genes.\n\nRESULTSThe cohort consists of a quarter of benign lung diseases and three quarters of cancer patients with all histopathology subtypes. 64% of the cancer patients is at Stage I. Gene mutations detection in tissue gDNA and plasma ctDNA results in a sensitivity of 91% and specificity of 88%. When ctDNA assay was used as the test, the sensitivity was 69% and specificity 96%. As for the lung cancer patients, the assay detected 63%, 83%, 94% and 100%, for Stage I, II, III and IV, respectively. In a linear discriminant analysis, combination of ctDNA, patient age and a panel of serum biomarkers boosted the overall sensitivity to 80% at a specificity of 99%. 29 out of the 65 genes harbored mutations in the lung cancer patients with the largest number found in TP53 (30% plasma and 62% tumor tissue samples) and EGFR (20% and 40%, respectively).\n\nCONCLUSIONPlasma ctDNA was analyzed in lung nodule assessment and early cancer detection while an algorithm combining clinical information enhanced the test performance.

clinical trials↗

bioRxiv2017

A multicenter, randomized study of decitabine as epigenetic priming with induction chemotherapy in children with AML

BackgroundDecitabine is a deoxycytidine nucleoside derivative inhibitor of DNA-methyltransferases, which has been studied extensively and is approved for myelodysplastic syndrome in adults but with less focus in children. Accordingly, we conducted a phase 1 multicenter, randomized, open-label study to evaluate decitabine pre-treatment before standard induction therapy in children with newly diagnosed AML to assess safety and tolerability and explore a number of biologic endpoints.\n\nResultsTwenty-four patients were fully assessable for all study objectives per protocol (10 in Arm A, 14 in Arm B). All patients experienced neutropenia and thrombocytopenia. The most common grade 3 and 4 non-hematologic adverse events observed were gastrointestinal toxicities and hypophosphatemia. Plasma decitabine PK were similar to previously reported adult data. Overall CR/CRi was similar for the two arms. MRD negativity at end-induction was 85% in Arm A versus 67% in Arm B patients. DNA methylation measured in peripheral blood over the course of treatment tracked with blast clearance and matched marrow aspirates at day 0 and day 21. Unlike end-point marrow analyses, promoter methylation in blood identified an apparent reversal of response in the lone treatment failure, one week prior to the patients marrow aspirate confirming non-response. Decitabine-induced effects of end-induction marrows in Arm A were reflected by changes in DNA methylation and gene expression comparison with matched paired marrow diagnostic aspirates.\n\nConclusionsThis first-in-pediatrics trial demonstrates that decitabine prior to standard combination chemotherapy is feasible and well tolerated in children with newly diagnosed AML. Pre-treatment with decitabine may represent a newer therapeutic option for pediatric AML, especially as it appears to induce important epigenetic alterations. The novel biological correlates studied in this trial offer a clinically relevant window into disease progression and remission. Additional studies are needed to definitively assess whether decitabine can enhance durability responses in children with AML. This trial was registered at www.clinicaltrials.gov as NCT01177540.

clinical trials↗

bioRxiv2017

A Pilot Randomized Trial of Oral Magnesium Supplementation on Supraventricular Arrhythmias

BackgroundMagnesium is believed to have a physiologic role in cardiac contractility, and evidence from epidemiologic and clinical studies has suggested that low serum concentrations of magnesium may be associated with increased risk of atrial fibrillation (AF).\n\nObjectiveAs part of the planning effort for a large randomized trial to prevent AF with magnesium supplementation, we conducted a 12-week pilot study to assess adherence to oral magnesium supplementation and matching placebo, estimate the effect on circulating magnesium concentrations, and evaluate the feasibility of using an ambulatory monitoring device (ZioPatch) for assessing premature atrial contractions (PACs), a predictor of AF.\n\nDesignDouble-blind randomized pilot clinical trial comparing supplementation with 400 mg magnesium oxide daily (versus placebo) over 12 weeks of follow-up. The ZioPatch was applied for 14 days at baseline and the end of follow-up. Adherence to the assigned treatment, and changes in PACs, serum magnesium concentration, glucose and blood pressure were assessed.\n\nResultsA total of 59 participants, 73% women and average age 62 years, were randomized. 98% of participants completed follow-up. Those assigned to the magnesium supplement took 75% of tablets as compared to 83% for those in the placebo group. Change in magnesium concentrations was significantly greater for those given magnesium supplement compared to placebo (0.07; 95% confidence interval (CI): 0.03, 0.12 mEq/L; p = 0.002). ZioPatch was worn for an average of 13.0 of the requested 14 days at baseline; at the end of follow-up, the average number of days of monitoring was 13.0 days for the magnesium supplement group and 12.7 days for the placebo group. For log PAC burden (episodes per hour), the average change from baseline was -0.05 (95% CI: -0.31, 0.20) for those randomized to magnesium supplement and 0.04 (95% CI: -0.24, 0.31) for those randomized to placebo (p=0.79 for difference). Gastrointestinal problems were reported by 50% of participants in the magnesium supplement group and 7% in the placebo group. Only one person in the magnesium supplement group and none in the placebo group experienced adverse events which led to treatment discontinuation.\n\nConclusionsIn this pilot randomized clinic trial, although gastrointestinal side effects to the magnesium supplement were common, adherence, measured by pill counts, was very good and, as a consequence, magnesium concentrations were greater for those randomly assigned to the magnesium supplement compared to placebo. Participant acceptance of the planned monitoring with ZioPatch was also very good. While the difference in the change in PACs was not significant, this pilot study was small, short-term, and did not include participants at high risk of AF. Thus, we could not reliably evaluate the effect of magnesium supplementation on PACs.\n\nClinicaltrials.gov registrationNCT02837328

clinical trials↗

bioRxiv2018

Non-invasive Assessment of Liver Disease in Rats Using Multiparametric Magnetic Resonance Imaging: A Feasibility Study

Background & AimsNon-invasive quantitation of chronic liver disease using multiparametric MRI has the potential to refine clinical care pathways, trial design and preclinical drug development. The aim of the study was to evaluate the use of multiparametric liver MRI in experimental rat models of chronic liver disease. Methods: Liver injury was induced in male wild-type Sprague-Dawley rats using 4 or 12 weeks carbon tetrachloride (CCl4) intoxication and 4 or 8 weeks methionine and choline deficient (MCD) diet. Liver MRI was performed using a 7.0 Tesla small animal scanner at baseline and specified timepoints after liver injury. Multiparametric liver MRI parameters (T1 mapping, T2* mapping and proton density fat fraction (PDFF)) were correlated with gold standard histopathological measures, assessed by a blinded expert adjudicator. One-way analysis of variance with Tukeys post-hoc test was used to assess differences between groups and Spearmans rank-order correlation to examine associations.\n\nResultsMean hepatic T1 increased significantly in rats treated with CCl4 for 12 weeks compared to controls (1122{+/-}78 ms vs. 959{+/-}114 ms; d=162.7, 95% CI (11.92, 313.4), P=0.038) and correlated strongly with histological collagen content (rs=0.717, P=0.037). In MCD diet-treated rats, hepatic PDFF correlated strongly with histological fat content (rs=0.819, P<0.0001), steatosis grade (rs=0.850, P<0.0001) and steatohepatitis score (rs=0.818, P<0.0001). Although there was minimal histological iron, progressive fat accumulation in MCD diet-treated liver significantly shortened T2*.\n\nConclusionsIn preclinical models, quantitative MRI markers correlated with histopathological assessments, especially for fatty liver disease. Validation in longitudinal studies is required.\n\nKey pointsO_LINon-invasive quantitative measures of chronic liver injury are needed for stratification and monitoring of disease in clinical practice and in drug development\nC_LIO_LIWe adapted and applied a clinically-relevant non-contrast multiparametric MRI protocol in well-established preclinical liver disease models, for simultaneous quantitation of hepatic fat, fibro-inflammatory injury and iron\nC_LIO_LIMultiparametric liver MRI was feasible at 7.0 Tesla in experimental rat models and imaging parameters correlated with gold standard histopathological assessments, especially characteristics of fatty liver disease\nC_LIO_LIFurther development of multiparametric liver MRI could refine drug development strategies and impact upon trial design and clinical care pathways\nC_LI

pathology↗

bioRxiv2018

Microcrystalline hydroxyapatite is not inferior to fluorides in clinical caries prevention: a randomized, double-blind, non-inferiority trial

Recent evidence for a significant interference of microcrystalline hydroxapatite (HAP) particles with re- and demineralisation processes at the tooth-biofilm interface suggested, that they may be promising candidates for efficacious caries prevention. This multicenter randomized controlled non-inferiority trial evaluated the impact of the 2 x daily use of a HAP dentifrice without fluoride on the progression of enamel caries in adolescent caries-risk patients subjected to orthodontic therapy, with a fluoridated AmF/SnF dentifrice serving as a positive control. Primary study outcome was the occurrence of enamel caries lesions [≥] ICDAS (International Caries Detection and Assessment System) code 1 around orthodontic brackets on the vestibular surfaces of teeth 15-25 within the 168 days observation period. Secondary study outcomes were the occurrence of enamel caries lesion [≥] ICDAS code 2, Plaque Index (PlI) and Gingival Index (GI). Out of 150 recruited patients, 147 were included in the intent to treat analysis (ITT); 133 finished the study per protocol (PP). PP data analysis revealed the occurrence of enamel caries [≥] ICDAS code 1 in 54.7% of the HAP group patients compared to 60.9% of the fluoride control. In the ITT analysis the corresponding numbers were 56.8% (HAP) and 61.6% (control). Non-inferiority testing of the ITT as well as the PP data set proved that the caries preventive efficacy of the HAP dentifrice was not inferior to the protection provided by the fluoridated AmF/SnF control. Regarding all assessed secondary outcomes (enamel caries [≥] ICDAS code 2, GI, PlI) no significant differences between both experimental groups were observed. Within the restraints set by design and study population of this trial microcrystalline HAP as ingredient of toothpaste may thus be regarded a promising supplement to fluorides in clinical caries prevention (ClinicalTrials.gov: NCT02705456).

clinical trials↗

bioRxiv2018

Signaling pathway screening platforms are an efficient approach toidentify therapeutic targets in precision-medicine oriented early phaseclinical trials

Precision medicine aims to tailor cancer therapies to target specific tumorpromoting aberrations. For tumors that lack actionable drivers, extensive molecular characterization and pre-clinical drug efficacy studies will be required to match patients with the appropriate targeted therapy. A cell line maintained at low passage and a patient-derived xenograft model (PDX) were generated using a fresh biopsy from a patient with a poorly-differentiated neuroendocrine tumor of unknown primary origin. Next-generation sequencing, high throughput signaling network analysis, and drug efficacy trials were then conducted to identify actionable targets for therapeutic intervention. No actionable mutations were identified after whole exome sequencing of the patients DNA; however, whole genome sequencing revealed amplification of the 3q and 5p chromosomal arms, that include the PIK3CA and RICTOR genes, respectively. Consistent with amplification of these genes, pathway analysis revealed activation of the AKT pathway. Based on this analysis, efficacy of PIK3CA and AKT inhibitors were evaluated in the tumor biopsy-derived cell culture and PDX, and response to the AKT inhibitor AZD5363 was observed both in vitro and in vivo indicating the patient would benefit from targeted therapies directed against the serine/threonine kinase AKT. In conclusion, our study demonstrates that high throughput signaling pathway analysis complements next-generation sequencing approaches for detection of actionable alterations and will aid in patient stratification into early-phase clinical trials.

clinical trials↗

bioRxiv2018

Clinical data specification and coding for cross-analyses with omics data in autoimmune disease trials

ObjectivesAutoimmune and inflammatory diseases (AIDs) form a continuum of autoimmune and inflammatory diseases, yet AIDs nosology is based on syndromic classification. The TRANSIMMUNOM trial (NCT02466217) was designed to re-evaluate AIDs nosology through clinic-biological and multi-omics investigations of patients with one of 19 selected AIDs. To allow cross-analyses of clinic-biological data together with omics data, we needed to integrate clinical data in a harmonized database.\n\nMaterials and MethodsWe assembled a clinical expert consortium (CEC) to select relevant clinic-biological features to be collected for all patients and a cohort management team comprising biologists, clinicians and computer scientists to design an electronic case report form (eCRF). The eCRF design and implementation has been done on OpenClinica, an open-source CFR-part 11 compliant electronic data capture system.\n\nResultsThe CEC selected 865 clinical and biological parameters. The CMT selected coded the items using CDISC standards into 5835 coded values organized in 28 structured eCRFs. Examples of such coding are check boxes for clinical investigation, numerical values with units, disease scores as a result of an automated calculations, and coding of possible treatment formulas, doses and dosage regimens per disease.\n\nDiscussion21 CRFs were designed using OpenClinica v3.14 capturing the 5835 coded values per patients. Technical adjustment have been implemented to allow data entry and extraction of this amount of data, rarely achieved in classical eCRFs designs.\n\nConclusionsA multidisciplinary endeavour offers complete and harmonized CRFs for AID clinical investigations that are used in TRANSIMMUNOM and will benefit translational research team.

clinical trials↗

bioRxiv2018

Performance Metrics for an Application-driven Selection and Optimization of Psychophysical Sampling Procedures

When estimating psychometric functions with sampling procedures, psychophysical assessments should be precise and accurate while being as efficient as possible to reduce assessment duration. The estimation performance of sampling procedures is commonly evaluated in computer simulations for single psychometric functions and reported using metrics as a function of number of trials. However, the estimation performance of a sampling procedure may vary for different psychometric functions. Therefore, the results of these type of evaluations may not be generalizable to a heterogeneous population of interest. In addition, the maximum number of trials is often imposed by time restrictions, especially in clinical applications, making trial-based metrics suboptimal. Hence, the benefit of these simulations to select and tune an ideal sampling procedure for a specific application is limited. We suggest to evaluate the estimation performance of sampling procedures in simulations covering the entire range of psychometric functions found in a population of interest, and propose a comprehensive set of performance metrics for a detailed analysis. To illustrate the information gained from these metrics in an application example, six sampling procedures were evaluated in a computer simulation based on prior knowledge on the population distribution and requirements from proprioceptive assessments. The metrics revealed limitations of the sampling procedures, such as inhomogeneous or systematically decreasing performance depending on the psychometric functions, which can inform the tuning process of a sampling procedure. More advanced metrics allowed directly comparing overall performances of different sampling procedures and select the best-suited sampling procedure for the example application. The proposed analysis metrics can be used for any sampling procedure and the estimation of any parameter of a psychometric function, independent of the shape of the psychometric function and of how such a parameter was estimated. This framework should help to accelerate the development process of psychophysical assessments.

neuroscience↗

bioRxiv2018

Choices in Vaccine Trial Design for Epidemics of Emerging Infections

The 2014-2016 Ebola epidemic highlighted the lack of consensus on the design of trials for investigational vaccine products in an emergency setting. With the advent of the ring vaccination strategy, it also underscored that the range of design options is evolving according to scientific need and creativity. Ideally, principles and protocols will be drawn up in advance, facilitating expediency and trust, for rapid deployment early in an epidemic. Here, we attempt a summary of the scientific, ethical and feasibility considerations relevant to different trial designs. We focus on four elements of design choices which, in our view, are most fundamental to designing an experimental vaccine trial and for which the most distinctive issues arise in the setting of an emerging infectious disease for which no proven vaccines exist: 1) randomization unit, 2) trial population, 3) comparator intervention and 4) trial implementation. Likewise, we focus on three of several ethical considerations in clinical research, namely the trials social and scientific value, its risk-benefit profile and its participant selection. A catalogue of possible designs to guide trial design choices is offered, along with a systematic evaluation of the benefits and drawbacks of each in given contexts.

epidemiology↗

bioRxiv2017

Brain-Computer Interfaces for Post-Stroke Motor Rehabilitation: A Meta-Analysis

ObjectiveBrain-computer interfaces (BCIs) can provide sensory feedback of ongoing brain oscillations enabling stroke survivors to modulate their sensorimotor rhythms purposefully. A number of recent clinical studies indicate that repeated use of such BCIs might trigger neurological recovery and hence improvement in motor function. Here we provide a first meta-analysis evaluating the clinical effectiveness of BCI-based post-stroke motor rehabilitation.\n\nMethodsTrials were identified using MEDLINE, CENTRAL, PEDro and by inspection of references in several review articles. We selected randomized controlled trials that used BCIs for post-stroke motor rehabilitation and provided motor impairment scores before and after the intervention. A random-effects inverse variance method was used to calculate the summary effect size.\n\nResultsWe initially identified 524 articles and, after removing duplicates, we screened titles and abstracts of 473 articles. We found 26 articles corresponding to BCI clinical trials, of these, there were nine studies that involved a total of 235 post-stroke survivors fulfilling the inclusion criterion (randomized controlled trials that examined motor performance as an outcome measure) for the meta-analysis. Motor improvements, mostly quantified by the upper limb Fugl-Meyer Assessment (FMA-UE), exceeded the minimal clinical important difference (MCID=5.25) in six BCI studies, while such improvement was reached only in three control groups. Overall, the BCI training was associated with a standardized mean difference (SMD) of 0.79 (95% CI: 0.37 to 1.20) in FMA-UE compared to control conditions, which is in the range of medium to large summary effect size. In addition, several studies indicated BCI-induced functional and structural neuroplasticity at a sub-clinical level.\n\nInterpretationWe found a medium to large effect size of BCI therapy compared to controls. This suggests that BCI technology might be an effective intervention for post-stroke upper limb rehabilitation. However, more studies with larger sample size are required to increase the reliability of these results.

neuroscience↗

bioRxiv2018

Standardized Informatics Computing Platform for Advancing Biomedical Discovery Through Data Sharing

ObjectiveThe goal is to develop a standardized informatics computing system that can support end-to-end research data lifecycle management for biomedical research applications.\n\nMaterials and MethodsDesign and implementation of biomedical research informatics computing system (BRICS) is demonstrated. The system architecture is modular in design with several integrated tools: global unique identifier, validation, upload, download and query tools that support user friendly informatics system capability.\n\nResultsBRICS instances were deployed to support research for improvements in diagnosis of traumatic brain injury, biomarker discovery for Parkinsons Disease, the National Ophthalmic Disease Genotyping and Phenotyping network, the informatics core for the Center for Neuroscience and Regenerative Medicine, the Common Data Repository for Nursing Science, Global Rare Diseases Patient Registry, and National Institute of Neurological Disorders and Stroke Clinical Informatics system for trials and research.\n\nDiscussionData deidentification is conducted by using global unique identifier methodology. No personally identifiable information exists on the BRICS supported repositories. The Data Dictionary provides defined Common Data Elements and Unique Data Elements, specific to each of the BRICS instance that enables Query Tool to search through research data. All instances are supported by the Medical Imaging Processing, statistical analysis R, and Visualization software program.\n\nConclusionThe BRICS core modules can be easily adapted for various biomedical research needs thereby reducing cost in developing new instances for additional biomedical research needs. It provides user friendly tools for researchers to query and aggregate genetic, phenotypic, clinical and medical imaging data. Data sets are findable, accessible and reusable for researchers to foster new research on various diseases.

bioinformatics↗

bioRxiv2018

Predictive Modelling of The Dynamic Patterns of Thinkingin Attention-Deficit/Hyperactivity Disorder: DiagnosticAccuracy of Spatiotemporal Fractal Measures

BackgroundAttention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental condition characterized by executive function (EF) dynamics disturbances. Notwithstanding, current advances in translational neuroscience, no ADHD objective, clinically useful, diagnostic marker is available to date.\n\nObjectivesUsing a customized definition of EF and a new clinical paradigm, we performed a prospective diagnostic accuracy trial to assess the diagnostic value of several fractal measures from the thinking processes or inferences in a cohort of ADHD children and typically developing controls.\n\nMethodWe included children from age five to twelve diagnosed with a reference standard based on case history, physical and neurological examination, Conners 3rd Edition, and DSM-V. The index test consisted of a computer-based inference task with a set of eight different instances of the \"Battleships\" game to be solved. A consecutive series of 18 cases and 18 controls (n = 36) recruited at the primary paediatrics service from the Nelson Marlborough Health in New Zealand underwent the reference standard and the index test. Several fractal measures were obtained from the inference task to produce supervised classification models.\n\nResultsNotably, the summarized logistic regressions predicted probabilities from the eight games played by each children yielded a 100% classification accuracy, sensitivity and specificity in both a training and an independent testing/validating cohort.\n\nConclusionsFrom a translational vantage point the expeditious method and the robust results make this technique a promising candidate to develop a screening, diagnostic and monitoring system for ADHD, and may serve to assess other EF disturbances.

clinical trials↗