Newly Developed DIRAC Framework Accurately Predicts Outcomes of Combining Multiple Models

Mathematical models are essential tools for making predictions in areas as diverse as personalized medicine, insurance pricing and portfolio management. Combining multiple, predictive models may sound like a good way to gain more power, but the outcomes of doing so have not been predictable and improvements are not guaranteed. Investigators from the Brigham and their collaborator from Fordham University have developed a framework, known as DIRAC (DIVERSITY of Ranks and ACCURACY), that, for the first time, makes it possible to predict the outcome of system-level fusions — which integrate data from more than one scoring system — based on characteristics of the input models that are being fused. The team validated DIRAC using biological imaging data and identified the mechanism underpinning their framework. Their findings have broad implication that may resound across many fields.

“We are elucidating the underlying math, following the framework’s implications for data science, and using this approach on real-world problems,” said corresponding author Bruce Kristal, PhD, of the Division of Sleep and Circadian Disorders. “We’re laying the groundwork to say, ‘Here’s why you can combine two things and gain information.’ Our findings begin to tell us why accuracy and diversity of data matters and how the two work together. We hope our paper provides a new way of thinking about how models work.”

Read more in Patterns.

Newly Identified Mediator of Inflammation Resolution Stimulates Tissue Regeneration and Controls Granuloma Formation

After acute inflammation, the body typically returns to homeostasis, a process that involves specialized pro-resolving mediators (SPMs), molecules that help resolve inflammation. In some cases, however, chronic inflammation can lead to the formation of small nodules called granulomas. To better understand the biosynthetic reactions that take place after inflammation, researchers at the Brigham investigated the role of 4S, 5S-epoxy-resolvin, an intermediate molecule that plays a critical role in synthesizing two resolvins (D3 and D4) and a previously unknown cysteinyl-resolvin isomer. 4S, 5S-epoxy-resolvin is found within human phagocytes and is thought to mediate the resolution of acute inflammation necessary for tissue regeneration and wound healing. The biosynthetic product, cysteinyl-resolvin isomer, that the group discovered accelerates tissue regeneration in surgically injured planaria and inhibition of granuloma developing in human peripheral blood leukocytes.

“Unresolved or chronic inflammation is a central pathobiology to many widely occurring life-threatening and fibrotic diseases,” said Ashley E. Shay, PhD, a senior member of Serhan’s group at the Brigham. “The identification of 4,5-RCTR1 highlights a potential therapeutic avenue for development of cys-SPM mimetics to stimulate tissue regeneration and repair in diseases with high unmet medical need.”

“Because of COVID-19, there’s a heightened interest in inflammation and understanding how to control the inflammatory response,” said Charles N. Serhan, PhD, DSc, of the Department of Anesthesiology, Perioperative and Pain Medicine. “This paper represents the work of an international, multidisciplinary collaboration among three teams. We wanted to nail down the biosynthetic enzymes involved in the production of D3 and D4 by human leukocytes, and in the process, found a new mediator that could give us a lead on how to design therapeutics to regulate granulomas.”

Read more in The Proceedings of the National Academy of Sciences.

Adjustable Intragastric Balloons, when Combined with Lifestyle Changes, Show Promise as Obesity Treatment

A research team at the Brigham has shown that adjustable intragastric balloons (aIGB) provide a personalized, adaptable treatment for obesity when diet, lifestyle changes and medications have only been minimally effective. By 2030, nearly half of U.S. adults will likely have obesity, a condition involved in cardiovascular disease, type 2 diabetes, chronic joint disease and other life-threatening maladies. As part of a multi-center, open-label, randomized clinical trial, minimally invasive and anatomy-preserving aIGB were implanted into the stomach of roughly 185 patients. During clinical visits, the volume of the balloon could be increased to improve weight loss outcomes or decreased to improve tolerance of the device. Patients prescribed an aIGB, who combined the treatment with lifestyle and diet counseling, showed an average 15 percent reduction in bodyweight over 32 weeks, compared with a 3 percent reduction in the control group who only received lifestyle modification. Seventy-five percent of patients reduced the volume of their balloons so they could complete the study, and only 17 percent needed it removed. Four percent of patients experienced device-related serious adverse events, without any deaths. Those who could tolerate a volume expansion experienced a 2 percent increase in weight loss. In addition, 74 percent of aIGB patients maintained their weight loss 14 months after the study’s conclusion.

“The aIGB, combined with lifestyle modification, facilitated clinically significant weight loss with maintenance after device removal,” said senior author Christopher C. Thompson, MD, Co-Director of the Brigham and Women’s Hospital, Center for Weight Management and Wellness. “The novel feature of upward or downward volume adjustment affords a patient-tailored approach to improve efficacy and tolerability. The results of this trial further add to the available safe and effective endoscopic obesity therapies.”

Read more in The Lancet.

Researchers Assess Cardiovascular Safety of Continuous Infusion of Exenatide in Patients with Type 2 Diabetes

Researchers at the Brigham sought to assess cardiovascular safety of continuous infusion of exenatide (ITCA 650), a medication for patients with type 2 diabetes (T2D) that can be infused under the skin through the use of an osmotic mini-pump. Exenatide is a glucagon-like peptide 1 receptor agonist. Previous studies have found that anti-diabetic drugs in the same class have shown promise in reducing risk of cardiovascular events. The research team examined safety of continuous infusion of ITCA 650 compared to placebo in 4,156 patients (2,075 and 2,081 receiving ITCA 650 and placebo, respectively). Researchers discovered that the primary composite outcome (non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, hospitalization for unstable angina) was 4.6 percent in the ITCA 650 group, compared to 3.8 percent in the placebo group. Additionally, the ITCA 650 group was reported to have an increased number of gastrointestinal events and disorders while on treatment likely causing the 72 percent adverse events reported in the treatment group compared to the 63.9 percent in placebo. Overall, ITCA 650 was reported to be non-inferior to placebo.

“Our preliminary discovery yields that in patients with T2D at risk for Atherosclerotic Cardiovascular Disease, ITCA 650 was non-inferior to placebo when assessing the primary outcome of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina,” said Christian T. Ruff, MD, MPH, of the Division of Cardiovascular Medicine. “Future studies should include a larger and longer-duration cardiovascular outcomes trial to better understand the cardiovascular effects of ITCA 650 in patients with T2D.”

Read more in Nature Medicine.

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