The associations between insulin, hypoglycemia, and dementia: Combating threats to internal validity in a series of population-based cohort studies
Bibliographic record
Abstract
Although the association between type 2 diabetes and dementia is recognized, findings from the epidemiology literature on the effect of insulin and one of its side effects, hypoglycemia, are less clear. The currently available observational studies assessing these associations suffer from a wide range of methodological limitations that diminish their internal validity and lead to contradictory evidence. The aim of this thesis is to implement design and analysis techniques to combat bias and confounding in previous studies and to further extend knowledge on the risk of dementia associated with four interconnected diabetes-related exposures, each assessed in a separate study: 1) severe hypoglycemia, 2) age of severe hypoglycemia, 3) insulin use, and 4) the mediating effect of severe hypoglycemia from insulin use. \nHerein, a series of cohort studies were conducted using population-based health administrative data (1996-2018) from British Columbia, Canada housed by Population Data BC. First, we identified individuals newly diagnosed with type 2 diabetes between 01 January 1998 and 31 December 2016. Each cohort was then designed based on the research question, wherein exposure was defined accordingly. For studies 1 and 2, the exposure of interest was severe hypoglycemia compared to no hypoglycemia. For studies 3 and 4, the exposure of interest was insulin initiation compared to initiating a non-insulin class. For all cohorts, the outcome of interest was all-cause dementia. Confounding adjustment techniques including inverse probability of treatment weighting (IPTW) were used in all studies. In each study, a wide range of sensitivity analyses were conducted to ensure the robustness of results. \nFindings from study 1 confirm the previously reported higher risk of all-cause dementia with severe hypoglycemia after implementing exposure density sampling, a lag period, and IPTW (HR 1.83; 95% CI 1.31-2.57). Findings from study 2 show that the increased risk of dementia observed in study 1 is consistent whether hypoglycemia occurs in midlife (HR 2.85; 95% CI 1.72-4.72) or late life (HR 2.38; 95% CI 1.83-3.11). Conversely, findings from study 3 negate existing evidence and do not show an increased risk of dementia associated with insulin use (HR 1.14; 95% CI 0.81-1.60). Lastly, findings from study 4 indicate a potential role of severe hypoglycemia as a mediator of the association between insulin and dementia (Natural Indirect Effect HR 1.04; 95% CI 1.01-1.08). \nCollectively these studies provide further insight on the complex associations between insulin, hypoglycemia, and the risk of all-cause dementia to inform both clinicians and patients with type 2 diabetes on the need to prevent hypoglycemia. Importantly, these studies showcase the need for robust methodology when conducting observational studies for type 2 diabetes-related exposures.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.490 | 0.656 |
| Meta-epidemiology (narrow) | 0.002 | 0.002 |
| Meta-epidemiology (broad) | 0.003 | 0.009 |
| Bibliometrics | 0.007 | 0.008 |
| Science and technology studies | 0.004 | 0.008 |
| Scholarly communication | 0.010 | 0.005 |
| Open science | 0.006 | 0.007 |
| Research integrity | 0.004 | 0.006 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; the direct Gemma label and the distilled Codex classifier agree on what is shown here.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".