Jennifer Bollyky

Opening clinical trial data: are the voluntary data-sharing portals enough?

Data generated by the numerous clinical trials conducted annually worldwide have the potential to be extremely beneficial to the scientific and patient communities. This potential is well recognized and efforts are being made to encourage the release of raw patient-level data from these trials to the public. The issue of sharing clinical trial data has recently gained attention, with many agreeing that this type of data should be made available for research in a timely manner. The availability of clinical trial data is most important for study reproducibility, meta-analyses, and improvement of study design. There is much discussion in the community over key data sharing issues, including the risks this practice holds. However, one aspect that remains to be adequately addressed is that of the accessibility, quality, and usability of the data being shared. Herein, experiences with the two current major platforms used to store and disseminate clinical trial data are described, discussing the issues encountered and suggesting possible solutions.

Association of Clinical Reactivity with Sensitization to Allergen Components in Multifood-Allergic Children

BACKGROUND Thirty percent of children with food allergies have multiple simultaneous allergies; however, the features of these multiple allergies are not well characterized serologically or clinically. OBJECTIVE We comprehensively evaluated 60 multifood-allergic patients by measuring serum IgE to key allergen components, evaluating clinical histories and medication use, performing skin tests, and conducting double-blind, placebo-controlled food challenges (DBPCFCs). METHODS Sixty participants with multiple food allergies were characterized by clinical history, DBPCFCs, total IgE, specific IgE, and component-resolved diagnostics (IgE and IgG4) data. The food allergens tested were almond, egg, milk, sesame, peanut, pecan, walnut, hazelnut, cashew, pistachio, soy, and wheat. RESULTS Our data demonstrate that of the reactions observed during a graded DBPCFC, gastrointestinal reactions occurred more often in boys than in girls, as well as in individuals with high levels of IgE to 2S albumins from cashew, walnut, and hazelnut. Certain food allergies often occurred concomitantly in individuals (ie, cashew/pistachio and walnut/pecan/hazelnut). IgE testing to components further corroborated serological relationships between and among these clustered food allergies. CONCLUSIONS Associations of certain food allergies were shown by DBPCFC outcomes as well as by correlations in IgE reactivity to structurally related food allergen components. Each of these criteria independently demonstrated a significant association between allergies to cashew and pistachio, as well as among allergies to walnut, pecan, and hazelnut.

Heterogeneity in recent-onset type 1 diabetes - a clinical trial perspective.

Type 1 diabetes (T1D) TrialNet is a National Institutes of Health‐sponsored clinical trial network aimed at altering the disease course of T1D. The purpose of this study is to evaluate age‐dependent heterogeneity in clinical, metabolic and immunologic characteristics of individuals with recent‐onset T1D, to identify cohorts of interest and to aid in planning of future studies.

The pharmacokinetics and dosing of oral 4-methylumbelliferone for inhibition of hyaluronan synthesis in mice.

Recently, there has been considerable interest in using 4‐methylumbelliferone (4‐MU) to inhibit hyaluronan (HA) synthesis in mouse models of cancer, autoimmunity and a variety of other inflammatory disorders where HA has been implicated in disease pathogenesis. In order to facilitate future studies in this area, we have examined the dosing, treatment route, treatment duration and metabolism of 4‐MU in both C57BL/6 and BALB/c mice. Mice fed chow containing 5% 4‐MU, a dose calculated to deliver 250 mg/mouse/day, initially lose substantial weight but typically resume normal weight gain after 1 week. It also takes up to a week to see a reduction in serum HA in these animals, indicating that at least a 1‐week loading period on the drug is required for most protocols. At steady state, more than 90% of the drug is present in plasma as the glucuronidated metabolite 4‐methylumbelliferyl glucuronide (4‐MUG), with the sulphated metabolite, 4‐methylumbelliferyl sulphate (4‐MUS) comprising most of the remainder. Chow containing 5% but not 0·65% 4‐MU was effective at preventing disease in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis, as well as in the DORmO mouse model of autoimmune diabetes. While oral 4‐MU was effective at preventing EAE, daily intraperitoneal injections of 4‐MU were not. Factors potentially affecting 4‐MU uptake and plasma concentrations in mice include its taste, short half‐life and low bioavailability. These studies provide a practical resource for implementing oral 4‐MU treatment protocols in mice.

Elimination diet and the development of multiple tree-nut allergies

BackgroundDespite its high prevalence, relatively little is known about the characteristics of patients with multiple tree-nut allergies.MethodsPatients (n=60, aged 4–15 years), recruited for a multiple food (tree nuts, peanut, milk, egg, soy, sesame, and wheat) oral immunotherapy (OIT) study, filled a questionnaire on their initial allergy evaluation. Medical records were reviewed. At OIT enrollment (median interval, 7.5 years), patients underwent oral food challenges (OFCs) to foods still eliminated.ResultsThere was significantly less evidence for eliminating tree nuts compared with other foods, as reflected by a lower rate of acute reaction to the offending food, either as the trigger for initial allergy evaluation (5.9% for tree-nuts vs. 20–40% for other foods, respectively P<0.001) or later in life (14.5% vs. 38–75%, respectively P=0.001), and a higher rate of negative skin prick test (SPT)/specific IgE (sIgE) at initial diagnosis (25% vs. <10%, P<0.001). SPT/sIgE increased significantly from past initial levels to present for tree nuts (P<0.001) and peanut (P=0.001) but not for other foods, and most OFCs performed at present were positive.ConclusionsTree nuts are often eliminated from the diet of multiple-food-allergic patients, despite their low probability for allergy. Sensitization and allergy to most tree nuts exist years later, suggesting that it developed during the period of elimination.

Towards the characterization of normal peripheral immune cells with data from ImmPort

To date, our understanding of a normal immune system is far behind that of other healthy organ systems. One reason for this is the lack of standardization in the lab techniques, especially flow cytometry. To take a step towards the characterization of a normal immune system, we re-analyzed and combined data that was made publicly available through the Immunology Database and Analysis Portal (ImmPort, immport.niaid.nih.gov) [1]. ImmPort is a public warehouse for the management and analysis of clinical and mechanistic data from NIAID/DAIT-funded research studies. Currently, 108 studies are made publicly available in ImmPort of which 27 contain raw FCS files from flow cytometry experiments run on samples of adults. Here we use ImmPort as a source of publicly available raw flow cytometry files from hundreds of participants in several trials, to study immune cells from the blood of healthy individuals. To characterize well-defined cells in a normal immune system, we used an unbiased method to compare data from different cytometers and antibody staining panels. As an initial step, we obtained the marker information from each raw FCS file in an automated fashion and made their nomenclature consistent. We applied and evaluated various transformation strategies and normalized the data on a per-channel basis using the R function warpSet [2] from the flowStats package of Bioconductor to make the flow cytometry data more comparable across studies. Initial promising results were observed for the cell-surface markers used to define T and B cells in general in automatically gated lymphocyte populations. Using our pipeline, the distribution of percentages of B cells as well as CD4+ and CD8+ T cells of subjects is in the range as immunologically expected and mostly comparable across the different studies originating from different laboratories. We plan to extend this approach to more cell types and eventually to studies of healthy individuals separated by gender, age group or ethnicity. Our approach promises to give further insights into the normal immune system.

Remote Lifestyle Coaching Plus a Connected Glucose Meter with Certified Diabetes Educator Support Improves Glucose and Weight Loss for People with Type 2 Diabetes

Background Connected health devices with lifestyle coaching can provide real-time support for people with type 2 diabetes (T2D). However, the intensity of lifestyle coaching needed to achieve outcomes is unknown. Methods Livongo provides connected, two-way messaging glucose meters, unlimited blood glucose (BG) test strips, and access to certified diabetes educators. We evaluated the incremental effects of adding lifestyle coaching on BG, estimated HbA1c, and weight. We randomized 330 eligible adults (T2D, HbA1c > 7.5%, BMI ≥ 25) to receive no further intervention (n = 75), a connected scale (n = 115), scale plus lightweight coaching (n = 73), or scale plus intense coaching (n = 67) for 12 weeks. We evaluated the change in outcomes using ANOVA. Results Livongo participation alone resulted in improved BG control (mean HbA1c declined: 8.5% to 7.5%, p = 0.01). Mean weight loss and additional BG decreases were higher in the intensive compared with the lightweight coaching and scale-only groups (weight change (lb): −6.4, −4.1, and −1.1, resp., p = 0.01; BG change (mg/dL): −19.4, −11.3, and −2.9, resp., p = 0.02). The estimated 12-week program costs were 5.5 times more for intensive than lightweight coaching. Conclusion Livongo participation significantly improves BG control in people with T2D. Additional lifestyle coaching may be a cost-effective intervention to achieve further glucose control and weight loss.