Causal inference in medical records and complementary systems pharmacology for metformin drug repurposing towards dementia

Charpignon, Marie-Laure; Vakulenko‐Lagun, Bella; Zheng, Bang; Magdamo, Colin; Su, Bowen; Evans, Kyle; Rodriguez, Steve; Sokolov, Artem; Boswell, Sarah A.; Sheu, Yi-han; Somai, Melek; Middleton, Lefkos; Hyman, Bradley T.; Betensky, Rebecca A.; Finkelstein, Stan N.; Welsch, Roy E.; Tzoulaki, Ioanna; Blacker, Deborah; Das, Sudeshna; Albers, Mark W.

doi:10.1038/s41467-022-35157-w

Cited by 27 publications

(28 citation statements)

References 73 publications

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“…Classification of ADRD was determined as previously described. 31 This approach involves using dementia-related International Classification of Diseases, Ninth Revision (ICD-9) (290.X, 294.X, 331.X, and 780.93.X) or International Statistical Classification of Diseases and Related Health Problems, Charlson Comorbidity Index score was computed using the R, version 4.2.1 comorbidity package (R Foundation for Statistical Computing) 33 and the Quan ICD-9 and ICD-10 weighting schemes. 34 The score was categorized as mild (0-2), moderate (3)(4), severe (Ն5), and missing.…”

Section: Adrd Designationmentioning

confidence: 99%

Association of BCG Vaccine Treatment With Death and Dementia in Patients With Non–Muscle-Invasive Bladder Cancer

et al. 2023

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ImportanceThe BCG vaccine—used worldwide to prevent tuberculosis—confers multiple nonspecific beneficial effects, and intravesical BCG vaccine is currently the recommended treatment for non–muscle-invasive bladder cancer (NMIBC). Moreover, BCG vaccine has been hypothesized to reduce the risk of Alzheimer disease and related dementias (ADRD), but previous studies have been limited by sample size, study design, or analyses.ObjectiveTo evaluate whether intravesical BCG vaccine exposure is associated with a decreased incidence of ADRD in a cohort of patients with NMIBC while accounting for death as a competing event.Design, Setting, and ParticipantsThis cohort study was performed in patients aged 50 years or older initially diagnosed with NMIBC between May 28, 1987, and May 6, 2021, treated within the Mass General Brigham health care system. The study included a 15-year follow-up of individuals (BCG vaccine treated or controls) whose condition did not clinically progress to muscle-invasive cancer within 8 weeks and did not have an ADRD diagnosis within the first year after the NMIBC diagnosis. Data analysis was conducted from April 18, 2021, to March 28, 2023.Main Outcomes and MeasuresThe main outcome was time to ADRD onset identified using diagnosis codes and medications. Cause-specific hazard ratios (HRs) were estimated using Cox proportional hazards regression after adjusting for confounders (age, sex, and Charlson Comorbidity Index) using inverse probability scores weighting.ResultsIn this cohort study including 6467 individuals initially diagnosed with NMIBC between 1987 and 2021, 3388 patients underwent BCG vaccine treatment (mean [SD] age, 69.89 [9.28] years; 2605 [76.9%] men) and 3079 served as controls (mean [SD] age, 70.73 [10.00] years; 2176 [70.7%] men). Treatment with BCG vaccine was associated with a lower rate of ADRD (HR, 0.80; 95% CI, 0.69-0.99), with an even lower rate of ADRD in patients aged 70 years or older at the time of BCG vaccine treatment (HR, 0.74; 95% CI, 0.60-0.91). In competing risks analysis, BCG vaccine was associated with a lower risk of ADRD (5-year risk difference, −0.011; 95% CI, −0.019 to −0.003) and a decreased risk of death in patients without an earlier diagnosis of ADRD (5-year risk difference, −0.056; 95% CI, −0.075 to −0.037).Conclusions and RelevanceIn this study, BCG vaccine was associated with a significantly lower rate and risk of ADRD in a cohort of patients with bladder cancer when accounting for death as a competing event. However, the risk differences varied with time.

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Section: Adrd Designationmentioning

confidence: 99%

Association of BCG Vaccine Treatment With Death and Dementia in Patients With Non–Muscle-Invasive Bladder Cancer

et al. 2023

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“…The relative contribution of each of the above mechanisms to metformin’s antiaging activities likely varies with different experimental models (e.g., cultured cells, mice, or C. elegans ). Nevertheless, substantial evidence supports metformin as an effective antiaging drug in mammals [ 65 ] and potentially in humans as well [ 66 , 67 ]. Notably, through cytokine profiling and bioinformatic analyses of CD4 + T cells from older (60 years of age) and younger (30 years of age) people, a recent study by Bharath et al showed that metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated inflammation [ 68 ].…”

Section: Novel Molecular Targets Involved In Other Biological Activitiesmentioning

confidence: 99%

Molecular mechanisms of action of metformin: latest advances and therapeutic implications

Zhu

Jia

et al. 2023

Clin Exp Med

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Metformin is among the most widely used antidiabetic drugs. Studies over the past few years have identified multiple novel molecular targets and pathways that metformin acts on to exert its beneficial effects in treating type 2 diabetes as well as other disorders involving dysregulated inflammation and redox homeostasis. In this mini-review, we discuss the latest cuttingedge research discoveries on novel molecular targets of metformin in glycemic control, cardiovascular protection, cancer intervention, anti-inflammation, antiaging, and weight control. Identification of these novel targets and pathways not only deepens our understanding of the molecular mechanisms by which metformin exerts diverse beneficial biological effects, but also provides opportunities for developing new mechanistically based drugs for human diseases.

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“…Constrain methods using a general multi-domain causal structure [23][24][25] Treatment effects Learn models that respect identification assumptions [26][27][28][29][30][31][32][33][34][35][36][37][38][39] Drug repurposing Relate multi-modal data using causal structure [40][41][42][43][44] Recommendation Infer causal effect of recommendation [45][46][47][48][49] Table 1: Real-world impact. We list exemplary real-world applications of CDL.…”

Section: Generalisationmentioning

confidence: 99%

“…At the intersection of generalisation and treatment effects is drug repurposing, an incredibly exciting area for CDL to have impact [43,44]. With applications in COVID-19 [40] and dementia [41,42], CDL is already proving to be a useful framework. However, as pointed out in table 3, these highstakes application domains are a clear example of why we require a careful analysis of the made assumptions.…”

Section: Real-world Applicationsmentioning

confidence: 99%

Causal Deep Learning

Berrevoets¹,

Kacprzyk²,

Qian³

et al. 2023

Preprint

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Causality has the potential to truly transform the way we solve a large number of realworld problems. Yet, so far, its potential remains largely unlocked since most work so far requires strict assumptions which do not hold true in practice. To address this challenge and make progress in solving real-world problems, we propose a new way of thinking about causality -we call this causal deep learning. The framework which we propose for causal deep learning spans three dimensions: (1) a structural dimension, which allows incomplete causal knowledge rather than assuming either full or no causal knowledge; (2) a parametric dimension, which encompasses parametric forms which are typically ignored; and finally, (3) a temporal dimension, which explicitly allows for situations which capture exposure times or temporal structure. Together, these dimensions allow us to make progress on a variety of real-world problems by leveraging (sometimes incomplete) causal knowledge and/or combining diverse causal deep learning methods. This new framework also enables researchers to compare systematically across existing works as well as identify promising research areas which can lead to real-world impact.

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Causal inference in medical records and complementary systems pharmacology for metformin drug repurposing towards dementia

Cited by 27 publications

References 73 publications

Association of BCG Vaccine Treatment With Death and Dementia in Patients With Non–Muscle-Invasive Bladder Cancer

Association of BCG Vaccine Treatment With Death and Dementia in Patients With Non–Muscle-Invasive Bladder Cancer

Molecular mechanisms of action of metformin: latest advances and therapeutic implications

Causal Deep Learning

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