Association between anticholinergic burden and dementia in UK Biobank

Abstract Previous studies on the association between the long-term use of anticholinergic drugs and dementia report heterogenous results. This variability could be due to, among other factors, different anticholinergic scales used, and differential effects of distinct classes of anticholinergic drugs. Here, we use 171,775 participants of UK Biobank with linked GP prescription records to calculate the cumulative annual anticholinergic burden (ACB) and ascertain dementia diagnoses through GP- and inpatient records. We then use Cox proportional hazards models to compare 13 anticholinergic scales and anticholinergic burden (ACB) due to different classes of drugs in their association with dementia. We find dementia to be more strongly predicted by ACB than by polypharmacy across most anticholinergic scales (standardised ORs range: 1.027-1.125). Furthermore, not only the baseline ACB, but the slope of the longitudinal trajectory of ACB (HR=1.094; 95% CI: 1.068-1.119) is predictive of dementia. However, the association between ACB and dementia holds only for some classes of drugs – especially antidepressants, antiepileptics, and high-ceiling antidiuretics. Moreover, we do not find a clear relationship between reported anticholinergic potency and dementia risk. The heterogeneity in findings on the association between ACB and dementia may in part be due to different effects for different classes of drugs. Future studies should establish such differences in more detail and further examine the practicality of using a general measure of anticholinergic potency as it relates to the risk of dementia.

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Association between anticholinergic burden and dementia in UK Biobank

10.1101/2021.08.04.21261330 ◽

2021 ◽

Author(s):

Jure Mur ◽

Tom C Russ ◽

Simon R Cox ◽

Riccardo Marioni ◽

Graciela Muniz-Terrera

Keyword(s):

Clear Relationship ◽

Anticholinergic Drugs ◽

Uk Biobank ◽

General Measure ◽

Future Studies ◽

Differential Effects ◽

Dementia Risk ◽

Anticholinergic Burden

Previous studies on the association between the long-term use of anticholinergic drugs and dementia report heterogenous results. This variability could be due to, among other factors, different anticholinergic scales used, and differential effects of distinct classes of anticholinergic drugs. Here, we use 171,775 participants of UK Biobank with linked GP prescription records to calculate the cumulative yearly anticholinergic burden (ACB) and ascertain dementia diagnoses through GP- and inpatient records. We then compare 13 anticholinergic scales and anticholinergic burden (ACB) due to different classes of drugs in their association with dementia. We find dementia to be more strongly predicted by ACB than by polypharmacy across most anticholinergic scales (standardised ORs range: 1.027-1.125). Furthermore, not only the baseline ACB, but the slope of the longitudinal trajectory of ACB (HR=1.094; 95% CI: 1.068-1.119) is predictive of dementia. However, the association between ACB and dementia holds only for some classes of drugs - especially antidepressants, antiepileptics, and high-ceiling antidiuretics. Moreover, we do not find a clear relationship between reported anticholinergic potency and dementia risk. The heterogeneity in findings on the association between ACB and dementia may in part be due to different effects for different classes of drugs. Future studies should establish such differences in more detail and further examine the practicality of using a general measure of anticholinergic potency as it relates to the risk of dementia.

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A semi-supervised approach for rapidly creating clinical biomarker phenotypes in the UK Biobank using different primary care EHR and clinical terminology systems

JAMIA Open ◽

10.1093/jamiaopen/ooaa047 ◽

2020 ◽

Author(s):

Spiros Denaxas ◽

Anoop D Shah ◽

Bilal A Mateen ◽

Valerie Kuan ◽

Jennifer K Quint ◽

...

Keyword(s):

Primary Care ◽

Proportional Hazards ◽

Biomarker Discovery ◽

Data Extraction ◽

Cox Proportional Hazards ◽

Research Quality ◽

Uk Biobank ◽

Expert Review ◽

Cox Proportional Hazards Models ◽

The Uk

Abstract Objectives The UK Biobank (UKB) is making primary care electronic health records (EHRs) for 500 000 participants available for COVID-19-related research. Data are extracted from four sources, recorded using five clinical terminologies and stored in different schemas. The aims of our research were to: (a) develop a semi-supervised approach for bootstrapping EHR phenotyping algorithms in UKB EHR, and (b) to evaluate our approach by implementing and evaluating phenotypes for 31 common biomarkers. Materials and Methods We describe an algorithmic approach to phenotyping biomarkers in primary care EHR involving (a) bootstrapping definitions using existing phenotypes, (b) excluding generic, rare, or semantically distant terms, (c) forward-mapping terminology terms, (d) expert review, and (e) data extraction. We evaluated the phenotypes by assessing the ability to reproduce known epidemiological associations with all-cause mortality using Cox proportional hazards models. Results We created and evaluated phenotyping algorithms for 31 biomarkers many of which are directly related to COVID-19 complications, for example diabetes, cardiovascular disease, respiratory disease. Our algorithm identified 1651 Read v2 and Clinical Terms Version 3 terms and automatically excluded 1228 terms. Clinical review excluded 103 terms and included 44 terms, resulting in 364 terms for data extraction (sensitivity 0.89, specificity 0.92). We extracted 38 190 682 events and identified 220 978 participants with at least one biomarker measured. Discussion and conclusion Bootstrapping phenotyping algorithms from similar EHR can potentially address pre-existing methodological concerns that undermine the outputs of biomarker discovery pipelines and provide research-quality phenotyping algorithms.

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Abstract 2791: Silent Brain Infarction Predicts Cardiovascular Events And Mortality In Long-term Hemodialysis Patients

Circulation ◽

10.1161/circ.116.suppl_16.ii_620 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Toru Aoyama ◽

Hideki Ishii ◽

Hiroshi Takahashi ◽

Takanobu Toriyama ◽

Toru Aoyama ◽

...

Keyword(s):

Proportional Hazards ◽

Brain Infarction ◽

Cox Proportional Hazards ◽

Powerful Predictor ◽

Cardiac Events ◽

Cox Proportional Hazards Models ◽

Silent Brain Infarction ◽

Cv Disease ◽

Overall Mortality

Background: The cardiovascular (CV) events and mortality are significantly higher in hemodialysis (HD) patents compared to the general population. Although it is of clinical concern to predict the occurrence of CV events in long-term HD patients, more powerful predictor has under exploration. We investigated as to whether silent brain infarction (SBI) would be a predictable factor for future CV events and mortality in a large cohort of patients with long-term HD patients. Methods: After cranial magnetic resonance imaging to detect SBI, 202 long-term HD patients (7.1 ± 5.9 years) without symptomatic stroke were prospectively followed up until the incident of CV events (stroke, cardiac events, and death). We analyzed the prognostic role of SBI in CV events with the Kaplan-Meier method and Cox proportional hazards analysis. Results: The prevalence of SBI was quite higher compared to the previous reports (71.8% in all the patients). In overall patients, 60 patients suffered from CV disease (31 for coronary artery disease, 7 for congestive heart failure, 14 for symptomatic stroke) and 29 patients died (16 for CV death) during a follow up period (mean= 23 ± 13 months). In subgroup analysis regarding the presence of SBI, CV event-free survival rate for 4 years was significantly lower in the patients with SBI compared to those without SBI (54.6% vs. 86.7%, p=0.0003). CV and overall mortality were also significantly higher in SBI patients compared with No-SBI patients (CV mortality; 20.5 % vs. 4.3 %, overall mortality; 29.0% vs. 9.1% p< 0.01, respectively). Cox proportional hazards models showed that the presence of SBI was a significant predictor of cerebrovascular and CV events and CV and overall mortality even after adjustment for other CV risk factors listed on the Table . Conclusion: SBI detected with MRI would be powerful predictor of CV events and mortality in long-term HD patients. Hazard ratio (HR) of SBI for future events and mortality

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Intoxicated Donors and Heart Transplant Outcomes: Long-Term Safety

Circulation Heart Failure ◽

10.1161/circheartfailure.120.007433 ◽

2021 ◽

Author(s):

David A. Baran ◽

Justin Lansinger ◽

Ashleigh Long ◽

John M. Herre ◽

Amin Yehya ◽

...

Keyword(s):

Drug Use ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Heart Transplants ◽

Term Survival ◽

Ischemic Time ◽

Cox Proportional Hazards Models ◽

Donor Shortage ◽

United Network

Background: The opioid crisis has led to an increase in available donor hearts, although questions remain about the long-term outcomes associated with the use of these organs. Prior studies have relied on historical information without examining the toxicology results at the time of organ offer. The objectives of this study were to examine the long-term survival of heart transplants in the recent era, stratified by results of toxicological testing at the time of organ offer as well as comparing the toxicology at the time of donation with variables based on reported history. Methods: The United Network for Organ Sharing database was requested as well as the donor toxicology field. Between 2007 and 2017, 23 748 adult heart transplants were performed. United Network for Organ Sharing historical variables formed a United Network for Organ Sharing Toxicology Score and the measured toxicology results formed a Measured Toxicology Score. Survival was examined by the United Network for Organ Sharing Toxicology Score and Measured Toxicology Score, as well as Cox proportional hazards models incorporating a variety of risk factors. Results: The number and percent of donors with drug use has significantly increased over the study period ( P <0.0001). Cox proportional hazards modeling of survival including toxicological and historical data did not demonstrate differences in post-transplant mortality. Combinations of drugs identified by toxicology were not associated with differences in survival. Lower donor age and ischemic time were significantly positively associated with survival ( P <0.0001). Conclusions: Among donors accepted for transplantation, neither history nor toxicological evidence of drug use was associated with significant differences in survival. Increasing use of such donors may help alleviate the chronic donor shortage.

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Illiteracy, dementia risk, and cognitive trajectories among older adults with low education

Neurology ◽

10.1212/wnl.0000000000008587 ◽

2019 ◽

Vol 93 (24) ◽

pp. e2247-e2256 ◽

Cited By ~ 3

Author(s):

Miguel Arce Rentería ◽

Jet M.J. Vonk ◽

Gloria Felix ◽

Justina F. Avila ◽

Laura B. Zahodne ◽

...

Keyword(s):

Older Adults ◽

Cognitive Decline ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Independent Effect ◽

Growth Curve Models ◽

Cox Proportional Hazards Models ◽

Dementia Risk ◽

Incident Dementia ◽

Low Education

ObjectiveTo investigate whether illiteracy was associated with greater risk of prevalent and incident dementia and more rapid cognitive decline among older adults with low education.MethodsAnalyses included 983 adults (≥65 years old, ≤4 years of schooling) who participated in a longitudinal community aging study. Literacy was self-reported (“Did you ever learn to read or write?”). Neuropsychological measures of memory, language, and visuospatial abilities were administered at baseline and at follow-ups (median [range] 3.49 years [0–23]). At each visit, functional, cognitive, and medical data were reviewed and a dementia diagnosis was made using standard criteria. Logistic regression and Cox proportional hazards models evaluated the association of literacy with prevalent and incident dementia, respectively, while latent growth curve models evaluated the effect of literacy on cognitive trajectories, adjusting for relevant demographic and medical covariates.ResultsIlliterate participants were almost 3 times as likely to have dementia at baseline compared to literate participants. Among those who did not have dementia at baseline, illiterate participants were twice as likely to develop dementia. While illiterate participants showed worse memory, language, and visuospatial functioning at baseline than literate participants, literacy was not associated with rate of cognitive decline.ConclusionWe found that illiteracy was independently associated with higher risk of prevalent and incident dementia, but not with a more rapid rate of cognitive decline. The independent effect of illiteracy on dementia risk may be through a lower range of cognitive function, which is closer to diagnostic thresholds for dementia than the range of literate participants.

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Cumulative Consumption of Sulfur Amino Acids Intake and Incidence of Diabetes

Current Developments in Nutrition ◽

10.1093/cdn/nzab053_103 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 1110-1110

Author(s):

Dong Zhen ◽

John Jr Richie ◽

Xiang Gao ◽

Biyi Shen ◽

David Orentreich

Keyword(s):

Amino Acids ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Third Generation ◽

Offspring Cohort ◽

The Third ◽

Total Intake ◽

Cox Proportional Hazards Models ◽

Hazard Ratios

Abstract Objectives Increasing evidence in animal models and humans suggests that diets high in sulfur-containing amino acids (SAA) could be associated a greater risk for type 2 diabetes (T2D). However, data from longitudinal human studies linking dietary SAA intake with T2D is lacking. The present study aimed to examine the association between long-term dietary intake of SAA including total SAAs, methionine, and cysteine and incident T2D in participants of the Framingham Heart Study (FHS). Methods Adult participants were selected from two prospective FHS cohorts: The Offspring Cohort (followed from 1991 to 2015, n = 3799) and the Third Generation Cohort (followed from 2002 to 2011, n = 4096). Individuals identified as diabetes patients before baseline, having missing diet or covariates data, or reported extreme daily energy intake were excluded. Energy-adjusted intake of dietary SAAs was calculated from responses to a 131-item food frequency questionnaire. Cox proportional hazards models were used to evaluate associations between intakes of SAAs (in quintiles) and risk of T2D in each cohort. A combined analysis was also performed pooling subjects from both cohorts. Results Overall, we documented 471 T2D events during 9–23 years of follow-up. In both cohorts, higher SAA intake was associated with a higher risk of T2D after adjustment for demographics, traditional risk factors and related nutrients. Comparing participants in the highest quintile with those in the lowest quintile of intake, adjusted hazard ratios (95% CI) were 1.98 (1.15–3.41) for total intake (P for trend = 0.04) in the Offspring cohort, and 4.37 (1.40–13.67) (P for trend = 0.01) in the Third Generation cohort. In the combination analysis of two cohorts, adjusted hazard ratios (95% CI) were 1.98 (1.23–3.21) for total intake, 2.21 (1.38–3.53) for methionine, and 1.79 (1.12–2.87) for cysteine (P for trends < 0.03). Conclusions Higher long-term SAA intake was associated with higher risk for T2D in humans, suggesting that dietary patterns emphasizing low SAA intake are protective against development of T2D. Funding Sources No funding.

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A Combined Prospective and Retrospective Comparison of Long-Term Functional Outcomes Suggests Delayed Loss of Ambulation and Pulmonary Decline with Long-Term Eteplirsen Treatment

Journal of Neuromuscular Diseases ◽

10.3233/jnd-210665 ◽

2021 ◽

pp. 1-14 ◽

Cited By ~ 1

Author(s):

Olga Mitelman ◽

Hoda Z. Abdel-Hamid ◽

Barry J. Byrne ◽

Anne M. Connolly ◽

Peter Heydemann ◽

...

Keyword(s):

Natural History ◽

Repeated Measures ◽

Proportional Hazards ◽

Clinical Care ◽

Standard Of Care ◽

Cox Proportional Hazards ◽

Kaplan Meier ◽

Cox Proportional Hazards Models

Background: Studies 4658-201/202 (201/202) evaluated treatment effects of eteplirsen over 4 years in patients with Duchenne muscular dystrophy and confirmed exon-51 amenable genetic mutations. Chart review Study 4658-405 (405) further followed these patients while receiving eteplirsen during usual clinical care. Objective: To compare long-term clinical outcomes of eteplirsen-treated patients from Studies 201/202/405 with those of external controls. Methods: Median total follow-up time was approximately 6 years of eteplirsen treatment. Outcomes included loss of ambulation (LOA) and percent-predicted forced vital capacity (FVC%p). Time to LOA was compared between eteplirsen-treated patients and standard of care (SOC) external controls and was measured from eteplirsen initiation in 201/202 or, in the SOC group, from the first study visit. Comparisons were conducted using univariate Kaplan-Meier analyses and log-rank tests, and multivariate Cox proportional hazards models with regression adjustment for baseline characteristics. Annual change in FVC%p was compared between eteplirsen-treated patients and natural history study patients using linear mixed models with repeated measures. Results: Data were included from all 12 patients in Studies 201/202 and the 10 patients with available data from 405. Median age at LOA was 15.16 years. Eteplirsen-treated patients experienced a statistically significant longer median time to LOA by 2.09 years (5.09 vs. 3.00 years, p < 0.01) and significantly attenuated rates of pulmonary decline vs. natural history patients (FVC%p change: –3.3 vs. –6.0 percentage points annually, p < 0.0001). Conclusions: Study 405 highlights the functional benefits of eteplirsen on ambulatory and pulmonary function outcomes up to 7 years of follow-up in comparison to external controls.

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Distinct eGFR trajectories are associated with risk of myocardial infarction in people with diabetes or pre-diabetes

10.21203/rs.3.rs-25392/v1 ◽

2020 ◽

Author(s):

Yingting Zuo ◽

Anxin Wang ◽

Shuohua Chen ◽

Xue Tian ◽

Shouling Wu ◽

...

Keyword(s):

Myocardial Infarction ◽

Proportional Hazards ◽

Exposure Period ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Models ◽

Hazard Ratios ◽

Increased Risk ◽

And Control ◽

Incident Cases

Abstract Background The relationship between estimated glomerular filtration rate (eGFR) trajectories and myocardial infarction (MI) remains unclear in people with diabetes or prediabetes. We aimed to identify common eGFR trajectories in people with diabetes or prediabetes and to examine their association with MI risk. Methods The data of this analysis was derived from the Kailuan study, which was a prospective community-based cohort study. The eGFR trajectories of 24,723 participants from year 2006 to 2012 were generated by latent mixture modeling. Incident cases of MI occurred during 2012 to 2017, confirmed by review of medical records. Cox proportional hazards models were used to calculate hazard ratios (HR) and their 95% confidence intervals (CIs) for the subsequent risk of MI of different eGFR trajectories. Results We identified 5 distinct eGFR trajectories, and named them as low-stable (9.4%), moderate-stable (31.4%), moderate-increasing (29.5%), high-decreasing (13.9%) and high-stable (15.8%) according to their range and pattern. During a mean follow-up of 4.61 years, there were a total of 235 incident MI. Although, the high-decreasing group had similar eGFR levels with the moderate-stable group at last exposure period, the risk was much higher (adjusted HR, 3.43; 95%CI, 1.56–7.54 versus adjusted HR, 2.82; 95%CI, 1.34–5.95). Notably, the moderate-increasing group had reached to the normal range, still had a significantly increased risk (adjusted HR, 2.55; 95%CI, 1.21–5.39). Conclusions eGFR trajectories were associated with MI risk in people with diabetes or prediabetes. Emphasis should be placed on early and long-term detection and control of eGFR decreases to further reduce MI risk.

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Visual impairment and risk of dementia in two population-based prospective cohorts: UK Biobank and EPIC-Norfolk

The Journals of Gerontology Series A ◽

10.1093/gerona/glab325 ◽

2021 ◽

Author(s):

Thomas J Littlejohns ◽

Shabina Hayat ◽

Robert Luben ◽

Carol Brayne ◽

Megan Conroy ◽

...

Keyword(s):

Visual Impairment ◽

Proportional Hazards ◽

Population Based ◽

Cox Proportional Hazards ◽

Uk Biobank ◽

Cox Proportional Hazards Models ◽

Hazard Ratios ◽

Promising Target ◽

Increased Risk

Abstract Visual impairment has emerged as a potential modifiable risk factor for dementia. However, there are a lack of large studies with objective measures of vison and with more than ten years of follow-up. We investigated whether visual impairment is associated with an increased risk of incident dementia in UK Biobank and EPIC-Norfolk. In both cohorts, visual acuity was measured using a “logarithm of the minimum angle of resolution” (LogMAR) chart and categorised as no (≤0.30 LogMAR), mild (>0.3 - ≤0.50 LogMAR), and moderate to severe (>0.50 LogMAR) impairment. Dementia was ascertained through linkage to electronic medical records. After restricting to those aged ≥60 years, without prevalent dementia and with eye measures available, the analytic samples consisted of 62,206 UK Biobank and 7,337 EPIC-Norfolk participants, respectively. In UK Biobank and EPIC-Norfolk. respectively, 1,113 and 517 participants developed dementia over 11 and 15 years of follow-up. Using multivariable cox proportional-hazards models, the hazard ratios for mild and moderate to severe visual impairment were 1.26 (95% Confidence Interval [CI] 0.92-1.72) and 2.16 (95% CI 1.37-3.40), in UK Biobank, and 1.05 (95% CI 0.72-1.53) and 1.93 (95% CI 1.05-3.56) in EPIC-Norfolk, compared to no visual impairment. When excluding participants censored within 5 years of follow-up or with prevalent poor or fair self-reported health, the direction of the associations remained similar for moderate impairment but were not statistically significant. Our findings suggest visual impairment might be a promising target for dementia prevention, however the possibility of reverse causation cannot be excluded.

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Long-Term Exposure to Ambient Hydrocarbons Increases Dementia Risk in People Aged 50 Years and above in Taiwan

Current Alzheimer Research ◽

10.2174/1567205017666200103112443 ◽

2020 ◽

Vol 16 (14) ◽

pp. 1276-1289

Author(s):

Han-Wei Zhang ◽

Victor C. Kok ◽

Shu-Chun Chuang ◽

Chun-Hung Tseng ◽

Chin-Teng Lin ◽

...

Keyword(s):

Air Pollutants ◽

Proportional Hazards ◽

The Elderly ◽

Cox Proportional Hazards ◽

Proportional Hazards Regression ◽

Hazard Ratios ◽

Dementia Risk ◽

Disease Exposure ◽

Total Hydrocarbons

Background: Alzheimer’s disease, the most common cause of dementia among the elderly, is a progressive and irreversible neurodegenerative disease. Exposure to air pollutants is known to have adverse effects on human health, however, little is known about hydrocarbons in the air that can trigger a dementia event. Objective: We aimed to investigate whether long-term exposure to airborne hydrocarbons increases the risk of developing dementia. Method: The present cohort study included 178,085 people aged 50 years and older in Taiwan. Cox proportional hazards regression analysis was used to fit the multiple pollutant models for two targeted pollutants, including total hydrocarbons and non-methane hydrocarbons, and estimated the risk of dementia. Results: Before controlling for multiple pollutants, hazard ratios with 95% confidence intervals for the overall population were 7.63 (7.28-7.99, p <0.001) at a 0.51-ppm increases in total hydrocarbons, and 2.94 (2.82-3.05, p <0.001) at a 0.32-ppm increases in non-methane hydrocarbons. The highest adjusted hazard ratios for different multiple-pollutant models of each targeted pollutant were statistically significant (p <0.001) for all patients: 11.52 (10.86-12.24) for total hydrocarbons and 9.73 (9.18-10.32) for non-methane hydrocarbons. Conclusion: Our findings suggest that total hydrocarbons and non-methane hydrocarbons may be contributing to dementia development.

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