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A Novel Method to Estimate Long-Term Chronological Changes From Fragmented Observations in Disease Progression.

ABSTRACT: Clinical observations of patients with chronic diseases are often restricted in terms of duration. Therefore, obtaining a quantitative and comprehensive understanding of the chronology of chronic diseases is challenging, because of the inability to precisely estimate the patient's disease stage at the time point of observation. We developed a novel method to reconstitute long-term disease progression from temporally fragmented data by extending the nonlinear mixed-effects model to incorporate the estimation of "disease time" of each subject. Application of this method to sporadic Alzheimer's disease successfully depicted disease progression over 20 years. The covariate analysis revealed earlier onset of amyloid-β accumulation in male and female apolipoprotein E ε4 homozygotes, whereas disease progression was remarkably slower in female ε3 homozygotes compared with female ε4 carriers and males. Simulation of a clinical trial suggests patient recruitment using the information of precise disease time of each patient will decrease the sample size required for clinical trials.

SUBMITTER: Ishida T

PROVIDER: S-EPMC6617977 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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A Novel Method to Estimate Long-Term Chronological Changes From Fragmented Observations in Disease Progression.

Ishida Takaaki T Tokuda Keita K Hisaka Akihiro A Honma Masashi M Kijima Shinichi S Takatoku Hiroyuki H Iwatsubo Takeshi T Moritoyo Takashi T Suzuki Hiroshi H

Clinical pharmacology and therapeutics 20180820 2

Clinical observations of patients with chronic diseases are often restricted in terms of duration. Therefore, obtaining a quantitative and comprehensive understanding of the chronology of chronic diseases is challenging, because of the inability to precisely estimate the patient's disease stage at the time point of observation. We developed a novel method to reconstitute long-term disease progression from temporally fragmented data by extending the nonlinear mixed-effects model to incorporate th ...[more]

PMID: 29951994

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Project description:Stopping denosumab after 8 years of continued treatment was associated with bone loss during a 1-year observation study in patients who were not prescribed osteoporosis treatment. Bone loss was attenuated in patients who began another osteoporosis therapy. Treatment to prevent bone loss upon stopping denosumab should be considered.IntroductionThis study aimed to understand osteoporosis management strategies during a 1-year observational follow-up after up to 8 years of denosumab treatment in a phase 2 study.MethodsDuring the observational year, patients received osteoporosis management at the discretion of their physician and returned to the clinic for BMD assessment and completion of an osteoporosis management questionnaire. Incidence of serious adverse events and fractures was collected. Analyses were descriptive.ResultsOf 138 eligible patients, 82 enrolled in and completed the observation study. Most (65 [79%]) did not receive prescription osteoporosis medication, with "my doctor felt I no longer needed a medication" being the most common reason (23 [35%]). Of the 17 patients who took osteoporosis medications, 8 discontinued therapy during the observation study. In patients treated with denosumab for 8 years (N = 52), BMD decreased during the 1-year observation study (6.7% [lumbar spine], 6.6% [total hip]). Those who took osteoporosis medication during the observation study showed a smaller decline in BMD than those who did not. No new safety concerns were identified. Eight patients (9.8%), all of whom had at least one predisposing risk factor, experienced 17 fractures. This included seven patients who experienced one or more vertebral fractures.ConclusionsConsistent with denosumab's mechanism of action, treatment cessation led to reversal of the drug's effect on BMD and perhaps fracture risk. For patients who took osteoporosis therapy, bone loss was attenuated. For patients at high fracture risk, switching to another osteoporosis therapy if denosumab is discontinued seems appropriate.

Dataset Information

A Novel Method to Estimate Long-Term Chronological Changes From Fragmented Observations in Disease Progression.

Publications

A Novel Method to Estimate Long-Term Chronological Changes From Fragmented Observations in Disease Progression.

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