ArticlePharmaceutical statistics
Natural cubic splines for the analysis of Alzheimer's clinical trials.
Article in Pharmaceutical statistics. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
25 citing papers in PubMed.
- Late-life body mass index and amyloid interaction on cognitive decline in unimpaired older adults.The journal of prevention of Alzheimer's disease · 2026Trial
- Characterizing Clinical Progression in Cognitively Unimpaired Older Individuals with Brain Amyloid: Results from the A4 Study.The journal of prevention of Alzheimer's disease · 2024Trial
- Longitudinal Trajectories of the Cognitive Function Index in the A4 Study.The journal of prevention of Alzheimer's disease · 2024Trial
- Amyloid and Tau Prediction of Cognitive and Functional Decline in Unimpaired Older Individuals: Longitudinal Data from the A4 and LEARN Studies.The journal of prevention of Alzheimer's disease · 2024Trial
- Trial of Solanezumab in Preclinical Alzheimer's Disease.The New England journal of medicine · 2023Trial
- Consistency of efficacy results across various clinical measures and statistical methods in the lecanemab phase 2 trial of early Alzheimer's disease.Alzheimer's research & therapy · 2022Trial
- Article
- Cognitive Trajectories from Preclinical Alzheimer's Disease to Dementia.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Divergent patterns of cognitive decline in preclinical Alzheimer's disease: Implications for secondary prevention trials.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Independent and interactive contributions of white matter hyperintensities and Alzheimer's disease imaging and plasma biomarkers to cognitive decline in older adults without dementia.Alzheimer's research & therapy · 2026Article
- The prognostic value of blood-based p-tau217 levels on progression to clinical impairment.medRxiv : the preprint server for health sciences · 2026Article
- Whole blood gene expression moderates associations between AD biomarkers and cognitive decline in cognitively unimpaired older adults.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Multi-organ AI endophenotypes chart the heterogeneity of brain, eye and heart pan-disease.Nature. Mental health · 2026Article
- Divergent patterns of cognitive decline in preclinical Alzheimer's disease: implications for secondary prevention trials.medRxiv : the preprint server for health sciences · 2026Article
- Emergency department wait time in Newfoundland and Labrador, Canada: Trends and projections of physician initial assessment 2015-2026.PloS one · 2026Article
- MRI-based multi-organ clocks for healthy aging and disease assessment.Nature medicine · 2026Article
- Predicting future cognitive impairment in preclinical Alzheimer's disease using multimodal imaging: a multisite machine learning study.medRxiv : the preprint server for health sciences · 2025Article
- Predicting cognitive decline with amyloid-PET, plasma p-tau217, Aβ42/40, and p-tau217/Aβ42 in a community-based cohort - relevance for clinical trial enrollment.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Multi-organ MRI digitizes biological aging clocks across proteomics, metabolomics, and genetics.medRxiv : the preprint server for health sciences · 2025Article
- Comments on "Novel Non-Linear Models for Clinical Trial Analysis With Longitudinal Data: A Tutorial Using SAS for Both Frequentist and Bayesian Methods".Statistics in medicine · 2025Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors.
Funding
Abstract
Mixed model repeated measures (MMRM) is the most common analysis approach used in clinical trials for Alzheimer's disease and other progressive diseases measured with continuous outcomes over time. The model treats time as a categorical variable, which allows an unconstrained estimate of the mean for each study visit in each randomized group. Categorizing time in this way can be problematic when assessments occur off-schedule, as including off-schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem has been exacerbated by clinical trial visits which have been delayed due to the COVID19 pandemic. As an alternative to MMRM, we propose a constrained longitudinal data analysis with natural cubic splines that treats time as continuous and uses test version effects to model the mean over time. Compared to categorical-time models like MMRM and models that assume a proportional treatment effect, the spline model is shown to be more parsimonious and precise in real clinical trial datasets, and has better power and Type I error in a variety of simulation scenarios.
Indexed as
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.