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Principal Investigator: Clement McDonald
Organization: NATIONAL LIBRARY OF MEDICINE
Fiscal Year: 2024
Award: $1,454,664
Funding agency: National Library of Medicine
A. Possible Beneficial and Adverse Drug Effects on SARS-COV-2 Infections (COVID-19)
We have identified one set of drugs used in ambulatory care that might reduce or increase incidence and/or severity of COVID-19. This combination is being tested in clinical trials, but the number of subjects has been small and observational data will likely be needed to support these studies. Some drugs that might reduce or aggravate COVID-19 include non-steroidals, anticoagulants, H2 blockers, anti-platelet agents, ACE inhibitors, and ARBs that treat rheumatologic disease (Tocilizumab, Rituximab, Sarilumab). We will study the association with the incidence and severity of COVID-19 infections.
B. Long COVID syndrome in Elderly Patients
Incidence of long COVID in the elderly is difficult to estimate because the long COVID may be masked by existing chronic diseases and thus they can be under-reported. We estimate the incidence of long COVID among elderly Medicare beneficiaries over 65 by a constellation of 11 symptoms, the WHOs clinical definition. With the same set of symptoms, we identify cases of postulated long Flu. Then we compare long COVID with long Flu in terms of incidence, symptomatology, and healthcare utilization.
C. Nirmatrelvir and Molnupiravir and Post–COVID-19 Condition in Older Patients
There are still no US Food and Drug Administration–approved drugs for the treatment or prevention of Post-COVID-19 Condition (PCC). We used the WHO consensus definition based on symptoms rather than disease diagnosis (eg, ischemic heart disease), which is more akin to how PCC is identified clinically and found that nirmatrelvir and molnupiravir were associated with a small reduction in incidence of PCC.
D. Maintenance drugs and longevity
A large proportion of elderly Medicare beneficiaries aged 65 and over suffer from hypertension and hyperlipidemia. They are treated with multiple maintenance drugs according to whether the condition is chronic. Studies that reported the efficacy of a maintenance drug did not include multiple drugs that were taken simultaneously by real-life patients in one unified analysis. An effect of one drug could be confounded with that of other drugs and thus conclusions often contradict. We include 6 maintenance drugs: 5 antihypertensive medications (diuretics, beta-blockers, calcium-channel blockers, ACE inhibitors, and ARBs) and 1 lipid-lowering drug (statin). We further separate some antihypertensive drug classes into subclasses to differentiate varieties of indication within a class and antihypertensive potency: 2 subclasses of calcium-channel blockers, 7 subclasses of diuretics and 3 subclasses of beta-blockers. Then, we report comparative effectiveness of each of 15 maintenance drugs on all-cause mortality among 2 million elderly Medicare beneficiaries.
E. Association between Female Hormone replacement therapy (HRT) and longevity, cardiovascular diseases and cancers
HRT is an effective treatment for the typical menopause-related symptoms (such as hot flashes, night sweats, irregular periods etc.) and long-term health problems associated with menopause (the risk of osteoporosis, cardiovascular disease and stroke). Reports of some studies have trumpeted negative effects of HRT on outcomes such as cardiovascular diseases, cancers, and all-cause mortality. However, the evidence behind them is weak or has been reversed. In this study, we traced about 1.5 million female Medicare beneficiaries from Medicare Part D entry to the onset of each outcome, death, switching to capitated plan, disenrollment from Medicare, or end of data availability whichever comes first and then we compared each risk among women treated with HRT of various kinds with to those not treated, and we treated almost all covariates as time time-dependent in a Cox proportional hazard regression analysis. Estrogen use, but not combined estrogen+progestin use, was associated with less risk of breast and other studied cancers and a significant reduction in mortality risk.
F. Evaluating the risk of fractures among elderly women enrolled in Medicare
Osteoporosis characterized by progressive deterioration of bone structure due to decreased bone mineral density (BMD) has been found to be closely associated with fractures. There are several pharmacotherapies available for prevention and treatment of postmenopausal osteoporosis including bisphosphonate, estrogen, raloxifene, denosumab and more. However, their beneficial and/or detrimental effect on fractures is not well addressed. We are conducting a nationwide cohort study of patients with osteoporosis to compare risks of any, hip and atypical femur fractures among patients treated with any of the drugs.
G. Risk and benefit profiles of Testosterone replacement therapy among senior hypogonadal males
Clinical guidelines recommend testosterone replacement therapy (TRT) for adult men with late-onset testosterone deficiency (TD), with the goal of improving symptoms and elevating testosterone levels into the normal reference range. Benefits are clearly established for sexual function, increase in lean muscle mass and strength, mood and cognitive function, with possible reduction in frailty and osteoporosis. However, there remains insufficient evidence that TRT is associated with increased risk of mortality, prostate cancer, prostatic hyperplasia, venous thromboembolism, and cardiovascular diseases. We are conducting a nationwide cohort study of senior male patients with hypogonadism to establish risk and benefit profiles of testosterone replacement therapy.
H. Risks of neurodegenerative disorders associated the use of alpha blocking agents prescribed for benign prostatic hyperplasia
Benign prostatic hyperplasia (BPH) is a disease that cause lower urinary tract symptoms and urology guidelines recommend alpha-blockers as primary treatment of BPH. However, previous studies reported increased risk of neurodegenerative disorders such as Parkinsons disease (PD) associated with widely prescribed alpha-blocker, tamsulosin. Currently, there are 5 alpha-blockers available: tamsulosin, terazosin, alfuzosin, doxazocin, and silodosin. Recent data suggests beneficial effect of 3 alpha-blockers (terazosin, alfuzosin, doxazocin) on PD pathogenesis and null effect of tamsulosin. We are conducting a nationwide cohort study of senior male patients with BPH to estimate risks of 5 alpha blockers on mortality, PD, Alzheimers disease.
I. Developing a method to combine machine learning methodology with time-to-event data analysis.
Several new methods for survival analysis have been proposed by extending the Cox proportional hazard model with neural networks. They were compared to classical Cox regression analysis and were found to be highly competitive, yielding the best performance in terms of Brier score and binomial log-likelihood. Though classical Cox regression analysis yields instantaneous hazards based on covariates that change over time during the follow-up period, none of newly proposed methods do not incorporate the effects of time-varying covariates. We are updating a currently available Python package combining Cox model with neural networks, a.k.a PyCOX, to incorporate time-varying covariates and comparing it with a conventional Cox regression with time-varying covariates in terms of hazard ratios and the concordance index using a real-word Medicare data.
Terms: <21+ years old><65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><ACE Inhibitors><AD dementia><Actemra><Active Follow-up><Address><Adrenergic alpha-Antagonists><Adrenergic alpha-Blockers><Adrenergic alpha-Receptor Blockaders><Adrenergic beta-Antagonists><Adrenergic beta-Blockers><Adrenergic α-Antagonists><Adrenergic α-Blockers><Adult><Adult Human><Adverse drug effect><Adverse effects><Aged 65 and Over><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Ambulatory Care><Angiotensin I-Converting Enzyme Inhibitors><Angiotensin-Converting Enzyme Antagonists><Angiotensin-Converting Enzyme Inhibitors><Anti-Hypertensive Agents><Anti-Hypertensive Drugs><Anti-Hypertensives><Anticoagulant Agents><Anticoagulant Drugs><Anticoagulants><Antiplatelet Agents><Antiplatelet Drugs><Apoplexy><Benefits and Risks><Benign Prostatic Hyperplasia><Benign Prostatic Hypertrophy><Big Data><BigData><Bisphosphonates><Bone Density><Bone Mineral Density><Bone structure><Brain Vascular Accident><Breast><C2B8 Monoclonal Antibody><COVID disease severity><COVID severity><COVID-19><COVID-19 disease severity><COVID-19 infection><COVID-19 severity><COVID-19 virus infection><COVID19 disease severity><COVID19 infection><COVID19 severity><CV-19><Calcium Channel Blockers><Calcium Channel Blocking Drugs><Cancers><Cardiovascular Diseases><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Cessation of life><Chronic><Chronic Disease><Chronic Illness><Clinical><Clinical Trials><Cohort Studies><Concurrent Studies><Consensus><Corlutina><Corluvite><Coronavirus Infectious Disease 2019><Cox Models><Cox Proportional Hazards Models><Coxa><Cyclogest><Data><Data Analyses><Data Analysis><Death><Degenerative Neurologic Disorders><Deterioration><Diagnosis><Disease><Disorder><Diuretics><Drug Therapy><Drug usage><Drugs><Elderly><Elderly woman><Enrollment><Epidemiology><Estrogens><Event><Exogenous Calcium Antagonists><Exogenous Calcium Blockaders><Exogenous Calcium Inhibitors><Female><Femoral Fractures><Food and Drug Administration><Fracture><Gestagenic Agents><Gestagens><Gestiron><Gestone><Goals><Guidelines><Health><Health Care Utilization><Health Insurance for Aged and Disabled, Title 18><Health Insurance for Disabled Title 18><Hip><Hip region structure><Hormone Replacement Rx><Hormone replacement therapy><Hot flushes><Hyperlipemia><Hyperlipidemia><Hyperplasia of Prostate Gland><Hypertension><Hypogonadism><Hypotensive Agent><Hypotensive Drugs><Incidence><Informatics><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><Keoxifene><Kininase II Antagonists><Kininase II Inhibitors><Leanness><Length of Life><Life><Lipids><Lipo-Lutin><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><Longevity><Luteohormone><Lutocyclin><Lutocylin M><Lutogyl><Lutromone><MabThera><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Masks><Medicare><Medication><Menopause><Methodology><Methods><Moods><Musculoskeletal Pain Disorder><Myocardial Ischemia><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Night Sweating><Osteoporosis><Outcome><Outpatient Care><Paralysis Agitans><Parkinson><Parkinson Disease><Pathogenesis><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Performance><Perimenopausal Bone Loss><Pharmaceutical Preparations><Pharmacotherapy><Post-Menopausal Osteoporosis><Postmenopausal Bone Loss><Postmenopausal Osteoporosis><Prevention><Primary Parkinsonism><Primary Senile Degenerative Dementia><Progestagenic Agents><Progestasert><Progestational Agents><Progestational Compounds><Progestational Hormones><Progesterone Agents><Progestins><Progestogel><Progestogens><Progestol><Progeston><Prolidon><Proluton><Prostate CA><Prostate Cancer><Prostate malignancy><Prostatic Cancer><Prostatic Hyperplasia><Prostatic hypertrophy><Publishing><Pythons><Raloxifene><Recommendation><Reference Ranges><Reference Values><Regression Analyses><Regression Analysis><Regression Diagnostics><Reporting><Research><Rheumatic Diseases><Rheumatism><Rheumatologic Diseases><Rheumatologic Disorder><Risk><Risk Estimate><Rituxan><SARS-CoV-2 disease severity><SARS-CoV-2 infection><SARS-CoV-2 severity><SARS-CoV2 infection><Severe acute respiratory syndrome coronavirus 2 infection><Sex Functioning><Statistical Regression><Stroke><Survival Analyses><Survival Analysis><Symptoms><Syndrome><Syngesterone><Testing><Testosterone><Therapeutic Estrogen><Therapeutic Progestin><Therapeutic Testosterone><Thinness><Time><Title 18><Trans-Testosterone><USFDA><United States Food and Drug Administration><Update><Urology><Utrogestan><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><above age 65><active followup><adulthood><advanced age><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age of 65 years onward><aged 65 and greater><aged 65+><aged ≥65><alfusozine><alfuzosin><alpha adrenergic blockade><alpha antiadrenergic agent><alpha blocker><alpha-Adrenergic Blocking Agents><alphuzosine><anti-hypertension><beneficiary><benign prostate hyperplasia><beta blocker><beta-Adrenergic Blocking Agents><beta-Adrenergic Receptor Blockaders><biphosphonate><bisphosphonate><blood thinner><bone fracture><brain attack><calcium antagonist><cardiac ischemia><cardiovascular disorder><cerebral vascular accident><cerebrovascular accident><chronic COVID><chronic COVID-19><chronic disorder><chronic novel coronavirus disease 2019><clinical database><cognitive function><comparative effectiveness><coronary ischemia><coronavirus disease 2019><coronavirus disease 2019 disease severity><coronavirus disease 2019 infection><coronavirus disease 2019 severity><coronavirus disease severity><coronavirus disease-19><coronavirus infectious disease-19><data interpretation><death risk><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><diphosphonate><disease diagnosis><drug maintenance><drug safety><drug treatment><drug use><drug-related adverse effects><drug/agent><effective therapy><effective treatment><elderly patient><enroll><epidemiologic><epidemiological><female treatment><femur fracture><flu><follow up><follow-up><followed up><followup><fracture risk><frailty><geriatric><hazard><health care service use><health care service utilization><health insurance for disabled><healthcare service use><healthcare service utilization><healthcare utilization><heart ischemia><high blood pressure><hot flash><human old age (65+)><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><improve symptom><indexing><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><informatics infrastructure><long haul COVID><long haul COVID-19><long haul coronavirus disease><long haul coronavirus disease 2019><long-hauler COVID><long-hauler COVID-19><long-hauler coronavirus disease 2019><long-hauler syndrome><long-term COVID><long-term COVID-19><long-term coronavirus disease><long-term coronavirus disease 2019><longterm COVID><longterm COVID-19><longterm coronavirus disease><longterm coronavirus disease 2019><lower urinary tract symptoms><machine learning based method><machine learning method><machine learning methodologies><male><malignancy><medication safety><men><molnupiravir><mortality><mortality risk><muscle bulk><muscle form><muscle mass><muscle strength><myocardial ischemia/hypoxia><myocardium ischemia><neoplasm/cancer><neural network><neurodegenerative illness><nirmatrelvir><old age><older patient><outpatient treatment><over 65 years><patient oriented outcomes><persistent COVID-19><pharmaceutical safety><post COVID syndrome><post COVID-19 syndrome><post acute COVID syndrome><post acute COVID-19><post acute COVID-19 syndrome><post acute SARS-CoV-2><post acute coronavirus disease 2019><post acute coronavirus disease 2019 syndrome><post acute coronavirus disease syndrome><post acute severe acute respiratory syndrome coronavirus 2><post coronavirus disease 2019 syndrome><post coronavirus disease syndrome><post-COVID><post-COVID-19><post-acute phases of COVID-19><post-coronavirus disease 2019><primary degenerative dementia><prolonged COVID-19 symptoms><prostate hyperplasia><rituximab><senile dementia of the Alzheimer type><senior citizen><severe acute respiratory syndrome coronavirus 2 disease severity><severe acute respiratory syndrome coronavirus 2 severity><sexual functioning><skeletal structure><stroked><strokes><symptom improvement><symptomatic improvement><symptomatology><tamsulosin><terazosin><terazosine><testosterone replacement therapy><thrombopoiesis inhibitor><tocilizumab><treat females><treat women><treatment among females><treatment among women><treatment in females><treatment in women><venous thromboembolism><women's treatment><α blocker><≥65 years>