Figure 1 - uploaded by Sunyoung Kim
Content may be subject to copyright.
Flowchart of calcium-channel blockers (CCB) cohort study. MPR, medication possession ratio; NHIS, National Health Insurance Service. 

Flowchart of calcium-channel blockers (CCB) cohort study. MPR, medication possession ratio; NHIS, National Health Insurance Service. 

Source publication
Article
Full-text available
Background: Some disagreements surround the effects of calcium-channel blockers (CCBs) on the risk of dementia. The purpose of this study was to investigate the protective effects of CCBs on dementia among elderly hypertensive Koreans.Methods?and?Results:We conducted a large population-based cohort study using the senior cohort database of the Kor...

Contexts in source publication

Context 1
... were excluded if they had (1) diagnostic codes for dementia or cerebrovascu- lar disease during 2002-2005 (28,767 patients), (2) diagnostic codes of malignant cancers (13,008 patients), or (3) no history of use of antihypertensive medications (504 patients). The final group consisted of 50,755 patients (Figure 1). ...
Context 2
... total of 18,423 patients were included as final subjects, with 13,692 patients in the CCB user group (CCB+) and 4,731 patients in the non-CCB antihypertensive user group (non- CCB+; ARB, ACEI, BB, D) (Figure 1). We found that the frequencies of underlying diseases were, in order, CAD (19.0%), diabetes (18.8%), hypercholesterolemia (12.6%), and chronic kidney disease (0.5%; Table 2). ...
Context 3
... primary endpoint of this study was event-free survival, which was defined as the time from the evaluation of the induction to the date of incidence of any dementia. We com- pared the distribution of demographic and clinical factors and also examined the relationships between dementia events and variables. We used the Wilcoxon 2-sample test for continuous variables and Fisher's exact test for categorical variables. Survival analysis, including Kaplan-Meier and Cox proportional hazards regression methods, was performed. The log-rank test and Cox proportional hazard regression methods were performed to examine the differences in the CCB+ and non-CCB+ cohort populations. Finally, we evaluated hazard ratio (HR) adjusted for age, sex, BMI, BP, income, urbanization, smoking, alcohol drinking, and underlying diseases (CAD, hypercholesterol- population consisting of 558,147 subjects who accounted for approximately 10% of the target 5,500,000 patients aged ≥60 years in 2002-2013. Insurance coverage was continued until death, emigration or immigration was recorded. 17 A total of 672 strata were constructed by sex, location, and income level. The NHIS-SC database contains information on insurance membership and income, history of medical use, medical check- ups, and long-term care and provides medical health examina- tions every 2 years for all elderly beneficiaries, including blood pressure (BP) levels, health behaviors (smoking, alcohol), past medical history, etc. 17 During January 1, 2002 to December 31,2005, a total of 208,763 seniors had undergone medical check-ups. Of these, 88,139 had hypertension code (KCD-I10, I11, I12, I13, and I15 [KCD is the Korean Standard Classification of Diseases]) records for at least 1 admission or ≥3 outpatient visits 18 during January 1, 2003 to December 31, 2004. Patients were excluded if they had (1) diagnostic codes for dementia or cerebrovascu- lar disease during 2002-2005 (28,767 patients), (2) diagnostic codes of malignant cancers (13,008 patients), or (3) no history of use of antihypertensive medications (504 patients). The final group consisted of 50,755 patients (Figure ...
Context 4
... total of 18,423 patients were included as final subjects, with 13,692 patients in the CCB user group (CCB+) and 4,731 patients in the non-CCB antihypertensive user group (non- CCB+; ARB, ACEI, BB, D) (Figure 1). We found that the frequencies of underlying diseases were, in order, CAD (19.0%), diabetes (18.8%), hypercholesterolemia (12.6%), and chronic kidney disease (0.5%; Table 2). Among them, 2,881 patients (21.0%) in the CCB+ and 1,124 patients (23.8%) in the non- CCB+ groups were diagnosed with dementia (all causes). The average age of subjects was 67.25 years, and 57.2% were female. We observed that the incidence rate of dementia was 21.70 (95% CI 20.91-22.49) per 1,000 person-years in the CCB+ group and 25.83 (95% CI 24.32-27.34) per 1,000 per- son-years in the non-CCB+ group. The aHR of dementia emia, and ...

Similar publications

Article
Full-text available
Few studies have investigated the measurement error of the Mini-Mental State Examination (MMSE) in the same unit of measurement, also known as absolute reliability. This measurement can help determine whether an observed score change for an individual is likely to represent true change. The aim of this study was to investigate the absolute reliabil...
Article
Full-text available
Background It is widely supposed that there is no benefit, including extended survival and decreased rate of pneumonia, in patients with severe dementia receiving enteral tube feeding (TF). However, there have been few studies comparing the frequency of pneumonia before and after TF in severe dementia. Methods Nine psychiatric hospitals in Okayama...
Article
Full-text available
Background: Epidemiologic evidence has emerged to reveal an association of albuminuria and low estimated glomerular filtration rate (eGFR) with dementia, but the findings are inconsistent. In addition, there are limited studies addressing the association between albuminuria and Alzheimer disease (AD). Methods and results: A total of 1562 communi...
Article
Full-text available
BACKGROUND: Cerebrovascular lesions are a frequent finding in the elderly population. However, the impact of these lesions on cognitive performance, the prevalence of vascular dementia, and the pathophysiology behind characteristic in vivo imaging findings are subject to controversy. Moreover, there are no standardised criteria for the neuropatholo...
Article
Full-text available
It has been becoming important to identify modifiable risk factors to prevent dementia. We investigated the association of individual and combined cardiovascular health (CVH) on dementia risk in older adults. From the National Health Insurance Service of Korea-Senior database, 191,013 participants aged ≥ 65 years without prior dementia or cerebrova...

Citations

... Ford and coauthors provide a nice review of how structured and unstructured data from primary care electronic health records can be used to predict dementia [15]. Most research into predicting changes in cognition has focused on the use of structured data such as medication utilization [16][17][18][19][20][21][22], diagnoses [23][24][25][26][27][28][29], procedures [30], and social determinants of health [31][32][33][34][35][36] that are associated with developing full-blown Alzheimer's Disease or related dementias (ADRD) [15,[37][38][39][40][41][42][43]. We are not aware of any published studies that have tested models predicting development of mild cognitive impairment (MCI) or data abstracted from clinical notes using natural language processing to predict MCI or ADRD, though, Sanghavi and Noderer are conducting work in this area [44]. ...
Article
Full-text available
Background Patients and their loved ones often report symptoms or complaints of cognitive decline that clinicians note in free clinical text, but no structured screening or diagnostic data are recorded. These symptoms/complaints may be signals that predict who will go on to be diagnosed with mild cognitive impairment (MCI) and ultimately develop Alzheimer’s Disease or related dementias. Our objective was to develop a natural language processing system and prediction model for identification of MCI from clinical text in the absence of screening or other structured diagnostic information. Methods There were two populations of patients: 1794 participants in the Adult Changes in Thought (ACT) study and 2391 patients in the general population of Kaiser Permanente Washington. All individuals had standardized cognitive assessment scores. We excluded patients with a diagnosis of Alzheimer’s Disease, Dementia or use of donepezil. We manually annotated 10,391 clinic notes to train the NLP model. Standard Python code was used to extract phrases from notes and map each phrase to a cognitive functioning concept. Concepts derived from the NLP system were used to predict future MCI. The prediction model was trained on the ACT cohort and 60% of the general population cohort with 40% withheld for validation. We used a least absolute shrinkage and selection operator logistic regression approach (LASSO) to fit a prediction model with MCI as the prediction target. Using the predicted case status from the LASSO model and known MCI from standardized scores, we constructed receiver operating curves to measure model performance. Results Chart abstraction identified 42 MCI concepts. Prediction model performance in the validation data set was modest with an area under the curve of 0.67. Setting the cutoff for correct classification at 0.60, the classifier yielded sensitivity of 1.7%, specificity of 99.7%, PPV of 70% and NPV of 70.5% in the validation cohort. Discussion and conclusion Although the sensitivity of the machine learning model was poor, negative predictive value was high, an important characteristic of models used for population-based screening. While an AUC of 0.67 is generally considered moderate performance, it is also comparable to several tests that are widely used in clinical practice.
... 11 Of the many antihypertensive drug classes available, drugs targeting the renin-angiotensin system (RAS), namely, angiotensin II receptor blockers (ARBs) and ACE (angiotensinconverting enzyme)-inhibitors, have been highlighted as possibly conferring the greatest benefit. [11][12][13][14][15] However, other studies have also shown benefits of calcium channel blockers [16][17][18][19] and diuretics 20 on reducing dementia risk, and it must be acknowledged that results from research linking blood pressure control with RAS drugs to cognitive benefit have been mixed. [21][22][23] It is possible that older trials, which were not originally designed to evaluate cognition, did not include milder forms of cognitive impairment as end points. ...
Article
Hypertension is an established risk factor for cognitive decline and dementia in older adults, highlighting the potential importance of antihypertensive treatments in prevention efforts. Work surrounding antihypertensive treatments has suggested possible salutary effects on cognition and neuropathology. Several studies have specifically highlighted renin-angiotensin system drugs, including AT1-receptor blockers and angiotensin-converting-enzyme inhibitors, as potentially benefiting cognition in later life. A small number of studies have further suggested renin-angiotensin system drugs that cross the blood-brain barrier may be linked to lower dementia risk compared to their nonpenetrant counterparts. The present meta-analysis sought to evaluate the potential cognitive benefits of blood-brain barrier crossing renin-angiotensin system drugs relative to their nonpenetrant counterparts. We harmonized longitudinal participant data from 14 cohorts from 6 countries (Australia, Canada, Germany, Ireland, Japan, United States), for a total of 12 849 individuals at baseline, and assessed for blood-brain barrier crossing potential within antihypertensive medications used by cognitively normal participants. We analyzed 7 cognitive domains (attention, executive function, language, verbal memory learning, recall, mental status, and processing speed) using ANCOVA (adjusted for age, sex, and education) and meta-analyses. Older adults taking blood-brain barrier-crossing renin-angiotensin drugs exhibited better memory recall over up to 3 years of follow-up, relative to those taking nonpenetrant medications, despite their relatively higher vascular risk burden. Conversely, those taking nonblood-brain barrier-penetrant medications showed better attention over the same follow-up period, although their lower vascular risk burden may partially explain this result. Findings suggest links between blood-brain barrier crossing renin-angiotensin drugs and less memory decline.
... The study showed that the incidence rate of vascular dementia and AD dementia decreased by 50% in patients receiving nitrendipine compared to those receiving placebo [58]. Other studies also confirmed that CCBs can prevent dementia and reduce the risk of occurrence and transformation of dementia [59][60][61], which may be related to neuroprotection in elderly patients with hypertension independent of BP lowering efficacy [62,63]. In a meta-analysis of 13 studies, Angeli proposed that dihydropyridine showed a significant benefit in improving cognitive function in stroke patients, independent of lowering BP lowering, suggesting the possible neuroprotective effect of CCBs [64]. ...
Article
Hypertension is a common comorbidity that contributes to the development of various cardiovascular disorders in elderly patients. Moreover, hypertension has been associated with cognitive decline and dementia. Cognitive impairment leads to increased morbidity and mortality in elderly patients with hypertension. However, previous studies investigating the association between blood pressure (BP), BP variability (BPV), and antihypertensive drug use and the risk of cognitive impairment in elderly patients with hypertension have reported inconsistent findings. Given the global burden of hypertension, the aging population, and the low quality of life associated with cognitive impairment, a more comprehensive understanding of the association between hypertension and cognitive decline is needed. In this review, we summarized the current preclinical evidence and clinical research regarding the association of BP control, BPV, and antihypertensive drug use and cognitive function. We particularly focused on the differences among categories of antihypertensive drugs. We concluded that the correlation of BP and risk of cognitive function is non-linear and dependent on a patient's age. Intensive BP control is generally not recommended, particularly for the oldest-old. Increased BPV and characteristics of orthostatic hypotension in the elderly also increase the risk of cognitive decline. The current evidence does not support one category of antihypertensive drugs as superior to others for preventing dementia in elderly patients with hypertension.
... Noteworthy, nimodipine, a dihydropyridine derivative and LTCC antagonist, has beneficial effects in AD patients and slows the progression of the disease [206]. Although two large-population, long-term cohort studies have proved the protective role of Ca 2+ channel blockers over other types of antihypertensive drugs on the risk of dementia among elderly hypertensive populations [207,208], the clinical effects of each specific LTCC blocker remain controversial [209]. ...
Article
Full-text available
Intraneuronal amyloid β (Aβ) oligomer accumulation precedes the appearance of amyloid plaques or neurofibrillary tangles and is neurotoxic. In Alzheimer’s disease (AD)-affected brains, intraneuronal Aβ oligomers can derive from Aβ peptide production within the neuron and, also, from vicinal neurons or reactive glial cells. Calcium homeostasis dysregulation and neuronal excitability alterations are widely accepted to play a key role in Aβ neurotoxicity in AD. However, the identification of primary Aβ-target proteins, in which functional impairment initiating cytosolic calcium homeostasis dysregulation and the critical point of no return are still pending issues. The micromolar concentration of calmodulin (CaM) in neurons and its high affinity for neurotoxic Aβ peptides (dissociation constant ≈ 1 nM) highlight a novel function of CaM, i.e., the buffering of free Aβ concentrations in the low nanomolar range. In turn, the concentration of Aβ-CaM complexes within neurons will increase as a function of time after the induction of Aβ production, and free Aβ will rise sharply when accumulated Aβ exceeds all available CaM. Thus, Aβ-CaM complexation could also play a major role in neuronal calcium signaling mediated by calmodulin-binding proteins by Aβ; a point that has been overlooked until now. In this review, we address the implications of Aβ-CaM complexation in the formation of neurotoxic Aβ oligomers, in the alteration of intracellular calcium homeostasis induced by Aβ, and of dysregulation of the calcium-dependent neuronal activity and excitability induced by Aβ.
... Seventy-six articles were excluded because animal or in vitro studies, 420 because not original studies, 49 because including prevalent dementia cases, 36 because the use of ACEis or ARBs was not considered as exposure, 3 because the diagnosis of dementia was not made according to standardized criteria and, finally, 12 studies were excluded because they included in the reference category subjects untreated with AHs or not hypertensive. 15 studies, based on data from > 3 million subjects, were finally included in the meta-analysis [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]. ...
Article
Objective: To evaluate the association of all RAAS inhibitors, ACE inhibithors (ACEIs) and angiotensin II receptor blockers (ARBs) on dementia onset (any dementia, Alzheimer's disease and vascular dementia) using a meta-analytic approach. Methods: A systematic MEDLINE search was carried out to identify all observational studies published up to the 30th September 2020 evaluating the association between RAAS inhibitors and risk of dementia. Studies were included if original investigations considering incident dementia cases, with ACEIs and/or ARBs as exposure and other antihypertensives (AHs) use as reference, and if reporting association estimates and relative variability measures. Random effect pooled relative risks (pRR) and the corresponding 95% confidence intervals (95%CI) were calculated according to DerSimonian and Laird's (DL) or to Hartung Knapp Sidik Jonkman (HKSJ) method depending on the number of studies and between-studies heterogeneity. A linear mixed meta-regression model (MM) was applied to take into account correlation among association estimates from the same study. Results: 15 studies were included in the meta-analysis. ARBs but not ACEIs' use led to a significant reduction of the risk of any dementia (pRR 0.78, 95%CIMM 0.70-0.87) and Alzheimer's disease (pRR 0.73, 95%CIMM 0.60-0.90). Moreover, when compared to ACEIs, ARBs reduced of 14% the risk of any dementia (pRR 0.86, 95%CIDL 0.79-0.94). Conclusions: ARBs but not ACEIs led to a reduction in the risk of any dementia. The difference between ARBs and ACEIs in terms of preventive effectiveness could be due to distinct profiles of antagonism towards independent receptor pathways or to differential influences on amyloid metabolism.
... 41 Blood pressure control can be achieved by combining pharmacological and non-pharmacological approach. 43 Among all antihypertensives, angiostensin receptor blockers (ARBs) 44 and calcium channel blockers (CCBs) 45 have a more pronounced protective effect to reduce the risk of dementia. Older people with hypertension may not meet the target of recommended physical activity for young adults, thus functional capacity and preferences of each individual should be considered. ...
Article
Full-text available
Background: Indonesia is one of ten countries in the world with estimated number of dementia case exceeding a million. The number of elderly population living in Indonesian cities has exceeded the number in rural areas, but the country lacks data representing the urban population better related to modifiable risk factors for dementia, prevention of which is crucial. We aimed to identify the modifiable risk factors for dementia in Indonesia's urban population. Methods: this case-control study used five-year data in Indonesia's national general hospital by tracing back medical record books of individuals aged 60 years and above in geriatric medicine outpatient clinic to the first hospital visit. Statistical analyses included bivariate and multivariate analyses to adjust for confounding factors appropriately. Results: data from 345 patients suggested that the significant risk factors for dementia were history of smoking (adjusted OR 2.860, 95% CI 1.559-5.246), history of hearing loss (adjusted OR 7.962, 95% CI 3.534-17.941), history of depression (adjusted OR 12.473, 95% CI 2.533-61.417), hypertension (adjusted OR 1.751, 95% CI 1.006-3.048), and diabetes mellitus (adjusted OR 2.561, 95% CI 1.482-4.425). Dementia patients had longer median duration of diabetes mellitus (12 years) than elderly without dementia (9 years) before the diagnosis of dementia. Single point late-life underweight condition and low educational attainment were not associated with dementia in Indonesia's urban setting. The risk factors for vascular dementia were largely similar to those of dementia. Conclusion: in Indonesian urban population, history of smoking, hearing loss, depression, hypertension, and diabetes mellitus are associated with dementia.
... A more recent large cohort study used the database of the Korean National Health Insurance Service. It analyzed the effect of antihypertensive drugs in this group on the risk of dementia, showing that CCB-users have a significantly lower risk of dementia (in general, but also Alzheimer's dementia and vascular dementia) (Hwang et al. 2016). Unfortunately, one of the main study limitations was the study not being a prospective, double-blind placebo-controlled study. ...
... stimulating angiogenesis), 6,15 or chance/bias from the study's relatively small number of DiCCB users, high number of comparisons, and observational design. Previous studies have found both lower 7,9,41 and higher 42,43 dementia risks for CCBs compared to ARBs and also lower 42-44 and higher 7,9,41,45 dementia risks for CCBs compared to diuretics. However, none of these were significant in direct comparison. ...
... stimulating angiogenesis), 6,15 or chance/bias from the study's relatively small number of DiCCB users, high number of comparisons, and observational design. Previous studies have found both lower 7,9,41 and higher 42,43 dementia risks for CCBs compared to ARBs and also lower 42-44 and higher 7,9,41,45 dementia risks for CCBs compared to diuretics. However, none of these were significant in direct comparison. ...
Article
Full-text available
Objective To assess whether angiotensin-II stimulating antihypertensives (thiazides, dihydropyridine calcium channel blockers, and angiotensin-1 receptor blockers) convey a lower risk of incident dementia compared to angiotensin-II inhibiting antihypertensives (angiotensin-converting enzyme inhibitors, beta blockers, and non-dihydropyridine calcium channel blockers), in accordance with the “angiotensin hypothesis.” Methods Cox regression analyses of incident dementia (and/or mortality as competing risk) during 6–8 years of follow-up, in a population sample of 1909 non-demented community-dwelling individuals (54% women), aged 70–78 (mean: 74.5 ± 2.5) years. Results After a median of 6.7 years of follow-up, dementia status was available for 1,870 (98%) and mortality for 1,904 (>99%) participants. Dementia incidence was 5.6% (27/480) in angiotensin-II stimulating, 8.2% (59/721) in angiotensin-II inhibiting, and 6.9% (46/669) in both antihypertensive type users. Adjusted for dementia risk factors including blood pressure and medical history, angiotensin-II stimulating antihypertensive users had a 45% lower incident dementia rate (HR = 0.55, 95% CI = 0.34–0.89) without excess mortality (HR = 0.86, 95% CI = 0.64–1.16), and individuals using both types had a non-significant 20% lower dementia rate (HR = 0.80, 95% CI = 0.53–1.20) without excess mortality (HR = 0.97, 95% CI = 0.76–1.24), compared to angiotensin-II inhibiting antihypertensive users. Results were consistent for subgroups based on diabetes and stroke history, but may be specific for individuals without a history of cardiovascular disease. Conclusions Users of angiotensin-II stimulating antihypertensives had lower dementia rates compared to angiotensin-II inhibiting antihypertensive users, supporting the “angiotensin hypothesis.” Confounding by indication must be examined further, although sub-analyses suggest this did not influence results. If replicated, dementia prevention could become a compelling indication for older individuals receiving antihypertensive treatment.
... However, the severity of the disease at the beginning of the treatment seems to influence the outcome [89]. Indeed, several studies have shown that hypertense patients on treatment with this group of drugs could have a reduced risk of dementia [90][91][92], suggesting a potential use of these medications for the prevention of the disease that needs to be further confirmed. ...
Article
Full-text available
Aggregation and deposition of β-amyloid and/or tau protein are the key neuropathological features in neurodegenerative disorders such as Alzheimer's disease (AD) and other tauopathies including frontotemporal dementia (FTD). The interaction between oxidative stress, mitochondrial dysfunction and the impairment of calcium ions (Ca2+) homeostasis induced by misfolded tau and β-amyloid plays an important role in the progressive neuronal loss occurring in specific areas of the brain. In addition to the control of bioenergetics and ROS production, mitochondria are fine regulators of the cytosolic Ca2+ homeostasis that induce vital signalling mechanisms in excitable cells such as neurons. Impairment in the mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) or release through the Na+/Ca2+ exchanger may lead to mitochondrial Ca2+ overload and opening of the permeability transition pore inducing neuronal death. Recent evidence suggests an important role for these mechanisms as the underlying causes for neuronal death in β-amyloid and tau pathology. The present review will focus on the mechanisms that lead to cytosolic and especially mitochondrial Ca2+ disturbances occurring in AD and tau-induced FTD, and propose possible therapeutic interventions for these disorders.
... [7][8][9] Several observational studies have previously investigated repurposing antihypertensives for dementia prevention, but non-genetic instrumental variable analysis has not been applied in this setting. [10][11][12][13][14][15][16][17] Instrumental variable analysis, which estimates the causal effect of an exposure on an outcome by using a third variable (the instrument), can be robust to confounding and reverse causation if certain assumptions are met ( Figure 1). That is, the instrument must (1) be associated with the exposure of interest; (2) affect the outcome only through its effect on the exposure; and (3) have no common causes with the outcome (i.e., no confounders of the instrument-outcome association). ...
... A meta-analysis by Larsson et al. 10 identified seven prospective observational studies that have compared antihypertensives against each other. [10][11][12][13][14][15][16][17] Two of these studies also make use of the CPRD (eText 4; http://links.lww.com/EDE/ B711). ...
... B711). 13,16 Among the studies identified by Larsson et al. 10 Davies et al. 13 estimated angiotensin II receptor blockers to have a relative risk of 0.55 (95% CI = 0.49, 0.62), and Hwang et al. 17 estimated calcium-channel blockers to have a relative risk of 0.81 (95% CI = 0.75, 0.87) when compared with other antihypertensives for dementia prevention. These relative risks correspond to −13 (95% CI = −15, −11) additional cases per 1000 for angiotensin II receptor blockers and −6 (95% CI = −7, −4) for calcium-channel blockers (see eText 5; http://links.lww.com/EDE/B711 for estimate conversion). ...
Article
Full-text available
Background: Hypertension in midlife is associated with increased risk of Alzheimer disease and vascular dementia in late life. In addition, some antihypertensive drugs have been proposed to have cognitive benefits, independent of their effect on hypertension. Consequently, there is potential to repurpose antihypertensive drugs for the prevention of dementia. This study systematically compared seven antihypertensive drug classes for this purpose, using the Clinical Practice Research Datalink. Methods: We assessed treatments for hypertension in an instrumental variable (IV) analysis to address potential confounding and reverse causation. We used physicians' prescribing preference as an ordinal instrument, defined by the physicians' last seven prescriptions. Participants were new antihypertensive users between 1996-2016, aged 40 and over. Results: We analyzed 849,378 patients with total follow up of 5,497,266 patient-years. We estimated that beta-adrenoceptor blockers and vasodilator antihypertensives conferred small protective effects - for example, beta-adrenoceptor blockers was associated with 13 (95% CI: 6 to 20) fewer cases of any dementia per 1000 treated compared with other antihypertensives. Conclusions: We estimated small differences in effects of antihypertensive drug classes on dementia outcomes. We also show that the magnitude of the differences between drug classes is smaller than previously reported. Future research should look to implement other causal analysis methods to address biases in conventional observational research with the ultimate aim of triangulating the evidence concerning this hypothesis.