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Alzheimer's disease (AD) is a complex form of dementia and due to its high phenotypic variability, its diagnosis and monitoring can be quite challenging. Biomarkers play a crucial role in AD diagnosis and monitoring, but interpreting these biomarkers can be problematic due to their spatial and temporal heterogeneity. Therefore, researchers are increasingly turning to imaging-based biomarkers that employ data-driven computational approaches to examine the heterogeneity of AD. In this comprehensive review article, we aim to provide health professionals with a comprehensive view of past applications of data-driven computational approaches in studying AD heterogeneity and planning future research directions. We first define and offer basic insights into different categories of heterogeneity analysis, including spatial heterogeneity, temporal heterogeneity, and spatial-temporal heterogeneity. Then, we scrutinize 22 articles relating to spatial heterogeneity, 14 articles relating to temporal heterogeneity, and five articles relating to spatial-temporal heterogeneity, highlighting the strengths and limitations of these strategies. Furthermore, we discuss the importance of understanding spatial heterogeneity in AD subtypes and their clinical manifestations, biomarkers for abnormal orderings and AD stages, the recent advancements in spatial-temporal heterogeneity analysis for AD, and the emerging role of omics data integration in advancing personalized diagnosis and treatment for AD patients. By emphasizing the significance of understanding AD heterogeneity, we hope to stimulate further research in this field to facilitate the development of personalized interventions for AD patients.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/terapia , Encéfalo/diagnóstico por imagen , Neuroimagen , BiomarcadoresRESUMEN
Timelines of events, such as symptom appearance or a change in biomarker value, provide powerful signatures that characterise progressive diseases. Understanding and predicting the timing of events is important for clinical trials targeting individuals early in the disease course when putative treatments are likely to have the strongest effect. However, previous models of disease progression cannot estimate the time between events and provide only an ordering in which they change. Here, we introduce the temporal event-based model (TEBM), a new probabilistic model for inferring timelines of biomarker events from sparse and irregularly sampled datasets. We demonstrate the power of the TEBM in two neurodegenerative conditions: Alzheimer's disease (AD) and Huntington's disease (HD). In both diseases, the TEBM not only recapitulates current understanding of event orderings but also provides unique new ranges of timescales between consecutive events. We reproduce and validate these findings using external datasets in both diseases. We also demonstrate that the TEBM improves over current models; provides unique stratification capabilities; and enriches simulated clinical trials to achieve a power of 80% with less than half the cohort size compared with random selection. The application of the TEBM naturally extends to a wide range of progressive conditions.
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BACKGROUND: Alzheimer's disease and related dementia (ADRD) are characterized by multiple and progressive anatomo-clinical changes including accumulation of abnormal proteins in the brain, brain atrophy and severe cognitive impairment. Understanding the sequence and timing of these changes is of primary importance to gain insight into the disease natural history and ultimately allow earlier diagnosis. Yet, modeling changes over disease course from cohort data is challenging as the usual timescales (time since inclusion, chronological age) are inappropriate and time-to-clinical diagnosis is available on small subsamples of participants with short follow-up durations prior to diagnosis. One solution to circumvent this challenge is to define the disease time as a latent variable. METHODS: We developed a multivariate mixed model approach that realigns individual trajectories into the latent disease time to describe disease progression. In contrast with the existing literature, our methodology exploits the clinical diagnosis information as a partially observed and approximate reference to guide the estimation of the latent disease time. The model estimation was carried out in the Bayesian Framework using Stan. We applied the methodology to the MEMENTO study, a French multicentric clinic-based cohort of 2186 participants with 5-year intensive follow-up. Repeated measures of 12 ADRD markers stemmed from cerebrospinal fluid (CSF), brain imaging and cognitive tests were analyzed. RESULTS: The estimated latent disease time spanned over twenty years before the clinical diagnosis. Considering the profile of a woman aged 70 with a high level of education and APOE4 carrier (the main genetic risk factor for ADRD), CSF markers of tau proteins accumulation preceded markers of brain atrophy by 5 years and cognitive decline by 10 years. However we observed that individual characteristics could substantially modify the sequence and timing of these changes, in particular for CSF level of A[Formula: see text]. CONCLUSION: By leveraging the available clinical diagnosis timing information, our disease progression model does not only realign trajectories into the most homogeneous way. It accounts for the inherent residual inter-individual variability in dementia progression to describe the long-term anatomo-clinical degradations according to the years preceding clinical diagnosis, and to provide clinically meaningful information on the sequence of events. TRIAL REGISTRATION: clinicaltrials.gov, NCT01926249. Registered on 16 August 2013.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Femenino , Humanos , Teorema de Bayes , Escolaridad , Progresión de la EnfermedadRESUMEN
The prediction of Alzheimer's disease (AD) progression plays a very important role in the early intervention of patients and the improvement of life quality. Cognitive scales are commonly used to assess the patient's status. However, due to the complicated pathogenesis of AD and the individual differences in AD, the prediction of AD progression is challenging. This paper proposes a novel coupling model (P-E model) that takes into account the processes of physiological degradation and emotional state transition of AD patients. We conduct experiments on synthetic data to validate the effectiveness of the proposed P-E model. Next, we conduct experiments on 134 subjects with more than 10 follow-ups from the Alzheimer's Disease Neuroimaging Initiative. The prediction performance of the P-E model is significantly better than other state-of-the-art methods, which achieves the mean squared error of 7.137 ± 0.035. The experimental results show that the P-E model can well characterize the non-monotonic properties of AD cognitive data and can also have a good predictive ability for time series data with individual differences.
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Mixed models for repeated measures (MMRMs) are ubiquitous when analyzing outcomes of clinical trials. However, the linearity of the fixed-effect structure in these models largely restrict their use to estimating treatment effects that are defined as linear combinations of effects on the outcome scale. In some situations, alternative quantifications of treatment effects may be more appropriate. In progressive diseases, for example, one may want to estimate if a drug has cumulative effects resulting in increasing efficacy over time or whether it slows the time progression of disease. This article introduces a class of nonlinear mixed-effects models called progression models for repeated measures (PMRMs) that, based on a continuous-time extension of the categorical-time parametrization of MMRMs, enables estimation of novel types of treatment effects, including measures of slowing or delay of the time progression of disease. Compared to conventional estimates of treatment effects where the unit matches that of the outcome scale (eg, 2 points benefit on a cognitive scale), the time-based treatment effects can offer better interpretability and clinical meaningfulness (eg, 6 months delay in progression of cognitive decline). The PMRM class includes conventionally used MMRMs and related models for longitudinal data analysis, as well as variants of previously proposed disease progression models as special cases. The potential of the PMRM framework is illustrated using both simulated and historical data from clinical trials in Alzheimer's disease with different types of artificially simulated treatment effects. Compared to conventional models it is shown that PMRMs can offer substantially increased power to detect disease-modifying treatment effects where the benefit is increasing with treatment duration.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Proyectos de Investigación , Progresión de la EnfermedadRESUMEN
BACKGROUND: People live a long time in pre-diabetes/early diabetes without a formal diagnosis or management. Heterogeneity of progression coupled with deficiencies in electronic health records related to incomplete data, discrete events, and irregular event intervals make identification of pre-diabetes and critical points of diabetes progression challenging. METHODS: We utilized longitudinal electronic health records of 9298 patients with type 2 diabetes or prediabetes from 2005 to 2016 from a large regional healthcare delivery network in China. We optimized a generative Markov-Bayesian-based model to generate 5000 synthetic illness trajectories. The synthetic data were manually reviewed by endocrinologists. RESULTS: We build an optimized generative progression model for type 2 diabetes using anchor information to reduce the number of parameters learning in the third layer of the model from [Formula: see text] to [Formula: see text], where [Formula: see text] is the number of clinical findings, [Formula: see text] is the number of complications, [Formula: see text] is the number of anchors. Based on this model, we infer the relationships between progression stages, the onset of complication categories, and the associated diagnoses during the whole progression of type 2 diabetes using electronic health records. DISCUSSION: Our findings indicate that 55.3% of single complications and 31.8% of complication patterns could be predicted early and managed appropriately to potentially delay (as it is a progressive disease) or prevented (by lifestyle modifications that keep patient from developing/triggering diabetes in the first place). CONCLUSIONS: The full type 2 diabetes patient trajectories generated by the chronic disease progression model can counter a lack of real-world evidence of desired longitudinal timeframe while facilitating population health management.
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Diabetes Mellitus Tipo 2 , Estado Prediabético , Teorema de Bayes , China/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Humanos , Estado Prediabético/complicaciones , Estado Prediabético/epidemiologíaRESUMEN
Mucopolysaccaridosis IIIA (MPS IIIA) is a rare genetic disease that afflicts children and leads to neurocognitive degeneration. We develop a Bayesian disease progression model (DPM) of MPS IIIA that characterizes the pattern of cognitive growth and decline in this disease. The DPM is a repeated measures model that incorporates a nonlinear developmental trajectory and shape-invariant random effects. This approach quantifies the pattern of cognitive development in MPS IIIA and addresses differences in biological age, length of follow-up, and clinical outcomes across natural history subjects. The DPM can be used in clinical trials to estimate the percent slowing in disease progression for treatment relative to natural history. Simulations demonstrate that the DPM provides substantial improvements in power relative to alternative analyses.
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Mucopolisacaridosis III , Teorema de Bayes , Niño , Cognición , Progresión de la Enfermedad , Humanos , Mucopolisacaridosis III/tratamiento farmacológico , Mucopolisacaridosis III/genética , Mucopolisacaridosis III/psicologíaRESUMEN
The use of Disease progression models (DPMs) in Drug Development has been widely adopted across therapeutic areas as a method for integrating previously obtained disease knowledge to elucidate the impact of novel therapeutics or vaccines on disease course, thus quantifying the potential clinical benefit at different stages of drug development programs. This paper provides a brief overview of DPMs and the evolution in data types, analytic methods, and applications that have occurred in their use by Quantitive Clinical Pharmacologists. It also provides examples of how these models have informed decisions and clinical trial design across several therapeutic areas and at various stages of development. It briefly describes potential new applications of DPMs utilizing emerging data sources, and utilizing new analytic techniques, and discuss new challenges faced such as requiring description of multiple endpoints, rapid model development, application of machine learning-based analytics, and use of high dimensional and real-world data. Considerations for the continued evolution future of DPMs to serve as community-maintained expert systems are also provided.
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Progresión de la Enfermedad , Desarrollo de Medicamentos , Ensayos Clínicos como Asunto , Humanos , Proyectos de InvestigaciónRESUMEN
Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions.
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Demencia Frontotemporal , Biomarcadores , Proteína C9orf72/genética , Complemento C1q , Estudios Transversales , Progresión de la Enfermedad , Demencia Frontotemporal/diagnóstico , Demencia Frontotemporal/genética , Proteína Ácida Fibrilar de la Glía , Humanos , Estudios Longitudinales , Mutación , Proteínas tau/genéticaRESUMEN
Understanding the order and progression of change in biomarkers of neurodegeneration is essential to detect the effects of pharmacological interventions on these biomarkers. In Huntington's disease (HD), motor, cognitive and MRI biomarkers are currently used in clinical trials of drug efficacy. Here for the first time we use directly compare data from three large observational studies of HD (total N = 532) using a probabilistic event-based model (EBM) to characterise the order in which motor, cognitive and MRI biomarkers become abnormal. We also investigate the impact of the genetic cause of HD, cytosine-adenine-guanine (CAG) repeat length, on progression through these stages. We find that EBM uncovers a broadly consistent order of events across all three studies; that EBM stage reflects clinical stage; and that EBM stage is related to age and genetic burden. Our findings indicate that measures of subcortical and white matter volume become abnormal prior to clinical and cognitive biomarkers. Importantly, CAG repeat length has a large impact on the timing of onset of each stage and progression through the stages, with a longer repeat length resulting in earlier onset and faster progression. Our results can be used to help design clinical trials of treatments for Huntington's disease, influencing the choice of biomarkers and the recruitment of participants.
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Analyzing the progression of Alzheimer's disease (AD) is challenging due to lacking sensitivity in currently available measures. AD stages are typically defined based on cognitive cut-offs, but this results in heterogeneous patient groups. More accurate modeling of the continuous progression of the disease would enable more accurate patient prognosis. To address these issues, we propose a new multivariate continuous-time disease progression (MCDP) model. The model is formulated as a nonlinear mixed-effects model that aligns patients based on their predicted disease progression along a continuous latent disease timeline. The model is evaluated using long-term follow-up data from 2152 participants in the Alzheimer's Disease Neuroimaging Initiative. The MCDP model was used to simultaneously model three cognitive scales; the Alzheimer's Disease Assessment Scale-cognitive subscale, the Mini-Mental State Examination, and the Clinical Dementia Rating scale-sum of boxes. Compared with univariate modeling and previously proposed multivariate disease progression models, the MCDP model showed superior ability to predict future patient trajectories. Finally, based on the multivariate disease timeline estimated using the MCDP model, the sensitivity of the individual items of the cognitive scales along the different stages of disease was analyzed. The analysis showed that delayed memory recall items had the highest sensitivity in the early stages of disease, whereas language and attention items were sensitive later in disease.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Cognición , Progresión de la Enfermedad , Humanos , Neuroimagen , Pruebas NeuropsicológicasRESUMEN
BACKGROUND: Centronuclear myopathies are severe rare congenital diseases. The clinical variability and genetic heterogeneity of these myopathies result in major challenges in clinical trial design. Alternative strategies to large placebo-controlled trials that have been used in other rare diseases (e.g., the use of surrogate markers or of historical controls) have limitations that Bayesian statistics may address. Here we present a Bayesian model that uses each patient's own natural history study data to predict progression in the absence of treatment. This prospective multicentre natural history evaluated 4-year follow-up data from 59 patients carrying mutations in the MTM1 or DNM2 genes. METHODS: Our approach focused on evaluation of forced expiratory volume in 1 s (FEV1) in 6- to 18-year-old children. A patient was defined as a responder if an improvement was observed after treatment and the predictive probability of such improvement in absence of intervention was less than 0.01. An FEV1 response was considered clinically relevant if it corresponded to an increase of more than 8%. RESULTS: The key endpoint of a clinical trial using this model is the rate of response. The power of the study is based on the posterior probability that the rate of response observed is greater than the rate of response that would be observed in the absence of treatment predicted based on the individual patient's previous natural history. In order to appropriately control for Type 1 error, the threshold probability by which the difference in response rates exceeds zero was adapted to 91%, ensuring a 5% overall Type 1 error rate for the trial. CONCLUSIONS: Bayesian statistical analysis of natural history data allowed us to reliably simulate the evolution of symptoms for individual patients over time and to probabilistically compare these simulated trajectories to actual observed post-treatment outcomes. The proposed model adequately predicted the natural evolution of patients over the duration of the study and will facilitate a sufficiently powerful trial design that can cope with the disease's rarity. Further research and ongoing dialog with regulatory authorities are needed to allow for more applications of Bayesian statistics in orphan disease research.
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Miopatías Estructurales Congénitas , Adolescente , Teorema de Bayes , Niño , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Humanos , Estudios ProspectivosRESUMEN
Alzheimer's disease (AD) is a degenerative neurological disease with unclear pathogenesis. The disease progress/trajectory of AD patients can be adequately described by establishing quantitative pharmacological disease progression model. Integrating biomarker information into the model can provide more insight to understand the potential pathological mechanisms and facilitate the optimization of future trial design. Several empirical and semi-mechanism disease progression models have been published. This mini-review is expected to offer some references for the further AD clinical research and new drug development.
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INTRODUCTION: This work aims to characterize the sequence in which cognitive deficits appear in two dementia syndromes. METHODS: Event-based modeling estimated fine-grained sequences of cognitive decline in clinically-diagnosed posterior cortical atrophy (PCA) ( n=94 ) and typical Alzheimer's disease (tAD) ( n=61 ) at the UCL Dementia Research Centre. Our neuropsychological battery assessed memory, vision, arithmetic, and general cognition. We adapted the event-based model to handle highly non-Gaussian data such as cognitive test scores where ceiling/floor effects are common. RESULTS: Experiments revealed differences and similarities in the fine-grained ordering of cognitive decline in PCA (vision first) and tAD (memory first). Simulation experiments reveal that our new model equals or exceeds performance of the classic event-based model, especially for highly non-Gaussian data. DISCUSSION: Our model recovered realistic, phenotypical progression signatures that may be applied in dementia clinical trials for enrichment, and as a data-driven composite cognitive end-point.
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Enfermedad de Alzheimer/patología , Encéfalo/patología , Disfunción Cognitiva/patología , Modelos Teóricos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/psicología , Atrofia/diagnóstico por imagen , Atrofia/patología , Atrofia/psicología , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/psicología , Progresión de la Enfermedad , Humanos , Imagen por Resonancia MagnéticaRESUMEN
Multimorbidity is a major problem for patients and health services. However, we still do not know much about the common trajectories of disease accumulation that patients follow. We apply a data-driven method to an electronic health record dataset (CPRD) to analyse and condense the main trajectories to multimorbidity into simple networks. This analysis has never been done specifically for multimorbidity trajectories and using primary care based electronic health records. We start the analysis by evaluating temporal correlations between diseases to determine which pairs of disease appear significantly in sequence. Then, we use patient trajectories together with the temporal correlations to build networks of disease accumulation. These networks are able to represent the main pathways that patients follow to acquire multiple chronic conditions. The first network that we find contains the common diseases that multimorbid patients suffer from and shows how diseases like diabetes, COPD, cancer and osteoporosis are crucial in the disease trajectories. The results we present can help better characterize multimorbid patients and highlight common combinations helping to focus treatment to prevent or delay multimorbidity progression.
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Registros Electrónicos de Salud , Afecciones Crónicas Múltiples , Enfermedad Crónica , Humanos , Multimorbilidad , Atención Primaria de SaludRESUMEN
BACKGROUND: Our objectives were to develop a disease progression model for cognitive decline in Alzheimer's disease (AD) and to determine whether disease progression of AD is related to the year of publication, add-on trial design, and geographical regions. METHODS: Placebo-controlled randomized AD clinical trials were systemically searched in public databases. Longitudinal placebo response (mean change from baseline in the cognitive subscale of the Alzheimer's Disease Assessment Scale [ADAS-cog]) and the corresponding demographic information were extracted to establish a disease progression model. Covariate screening and subgroup analyses were performed to identify potential factors affecting the disease progression rate. RESULTS: A total of 134 publications (140 trials) were included in this model-based meta-analysis. The typical disease progression rate was 5.82 points per year. The baseline ADAS-cog score was included in the final model using an inverse U-type function. Age was found to be negatively correlated with disease progression rate. After correcting the baseline ADAS-cog score and the age effect, no significant difference in the disease progression rate was found between trials published before and after 2008 and between trials using an add-on design and those that did not use an add-on design. However, a significant difference was found among different trial regions. Trials in East Asian countries showed the slowest decline rate and the largest placebo effect. CONCLUSIONS: Our model successfully quantified AD disease progression by integrating baseline ADAS-cog score and age as important predictors. These factors and geographic location should be considered when optimizing future trial designs and conducting indirect comparisons of clinical outcomes.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/epidemiología , Método Doble Ciego , HumanosRESUMEN
Cancer metastasis is the main cause of death in various types of cancer. However, in the field of pharmacometrics, cancer disease progression models focus on the growth of primary tumors with tumor volume or weight as target values, while the metastasis process is less mentioned. We propose a series of mathematical models to quantitatively describe and predict the disease progression of 4T1 breast cancer in the aspect of primary breast tumor, lung metastasis and white blood cell. The 4T1 cells were injected into breast fat pad of female BALB/c mice to establish an animal model of breast cancer metastasis. The number and volume of lung metastases at different times were measured. Based on the above data, a disease progression model of breast cancer lung metastasis was established and parameter values were estimated. The white blood cell growth and the primary tumor growth of 4T1 mouse are also modeled. The established models can describe the lung metastasis of 4T1 breast cancer in three aspects: (1) the increase in metastasis number; (2) the growth of metastasis volume; (3) metastasis number-size distribution at different time points. Compared with the prior metastasis models based on von Forester equation, our models distinguished the growth rate of primary tumor and metastasis and got parameter values for 4T1 mouse model. And the current models optimized the metastasis number-size distribution model by utilizing logistic function instead of the prior power function. This study provides a comprehensive description of lung metastasis progression for 4T1 breast cancer model, as well as an alternative disease progression model structure for further pharmacodynamics modeling.
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Neoplasias de la Mama/patología , Metástasis de la Neoplasia/patología , Animales , Peso Corporal/fisiología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos BALB C , Células Tumorales CultivadasRESUMEN
Duchenne muscular dystrophy (DMD) is a rare X-linked genetic pediatric disease characterized by a lack of functional dystrophin production in the body, resulting in muscle deterioration. Lower body muscle weakness progresses to non-ambulation typically by early teenage years, followed by upper body muscle deterioration and ultimately death by the late twenties. The objective of this study was to enhance the quantitative understanding of DMD disease progression through nonlinear mixed effects modeling of the population mean and variability of the 6-min walk test (6MWT) clinical endpoint. An indirect response model with a latent process was fit to digitized literature data using full Bayesian estimation. The modeling data set consisted of 22 healthy controls and 218 DMD patients from one interventional and four observational trials. The model reasonably described the central tendency and population variability of the 6MWT in healthy subjects and DMD patients. An exploratory categorical covariate analysis indicated that there was no apparent effect of corticosteroid administration on DMD disease progression. The population predicted 6MWT began to rise at 1.32 years of age, plateauing at 654 meters (m) at 17.2 years of age for the healthy population. The DMD trajectory reached a maximum of 411 m at 8.90 years before declining and falling below 1 m at age 18.0. The model has potential to be used as a Bayesian estimation and posterior simulation tool to make informed model-based drug development decisions that incorporate prior knowledge with new data.
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Distrofia Muscular de Duchenne/fisiopatología , Adolescente , Corticoesteroides/uso terapéutico , Teorema de Bayes , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiopatología , Distrofia Muscular de Duchenne/tratamiento farmacológico , Factores de Tiempo , Prueba de PasoRESUMEN
Current models of progression in neurodegenerative diseases use neuroimaging measures that are averaged across pre-defined regions of interest (ROIs). Such models are unable to recover fine details of atrophy patterns; they tend to impose an assumption of strong spatial correlation within each ROI and no correlation among ROIs. Such assumptions may be violated by the influence of underlying brain network connectivity on pathology propagation - a strong hypothesis e.g. in Alzheimer's Disease. Here we present DIVE: Data-driven Inference of Vertexwise Evolution. DIVE is an image-based disease progression model with single-vertex resolution, designed to reconstruct long-term patterns of brain pathology from short-term longitudinal data sets. DIVE clusters vertex-wise (i.e. point-wise) biomarker measurements on the cortical surface that have similar temporal dynamics across a patient population, and concurrently estimates an average trajectory of vertex measurements in each cluster. DIVE uniquely outputs a parcellation of the cortex into areas with common progression patterns, leading to a new signature for individual diseases. DIVE further estimates the disease stage and progression speed for every visit of every subject, potentially enhancing stratification for clinical trials or management. On simulated data, DIVE can recover ground truth clusters and their underlying trajectory, provided the average trajectories are sufficiently different between clusters. We demonstrate DIVE on data from two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Dementia Research Centre (DRC), UK. The DRC cohort contains patients with Posterior Cortical Atrophy (PCA) as well as typical Alzheimer's disease (tAD). DIVE finds similar spatial patterns of atrophy for tAD subjects in the two independent datasets (ADNI and DRC), and further reveals distinct patterns of pathology in different diseases (tAD vs PCA) and for distinct types of biomarker data - cortical thickness from Magnetic Resonance Imaging (MRI) vs amyloid load from Positron Emission Tomography (PET). We demonstrate that DIVE stages have potential clinical relevance, despite being based only on imaging data, by showing that the stages correlate with cognitive test scores. Finally, DIVE can be used to estimate a fine-grained spatial distribution of pathology in the brain using any kind of voxelwise or vertexwise measures including Jacobian compression maps, fractional anisotropy (FA) maps from diffusion tensor imaging (DTI) or other PET measures.
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Modelos Neurológicos , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/patología , Neuroimagen/métodos , Progresión de la Enfermedad , HumanosRESUMEN
Chronic heart failure (CHF) is an ongoing clinical syndrome with cardiac dysfunction that can be traced to alterations in cardiac metabolism. The identification of metabolic biomarkers in easily accessible fluids to improve the early diagnosis of CHF has been elusive to date. In this study, we took multidimensional analytical techniques to discover potentially new diagnostic biomarkers by focusing on the dynamic changes of metabolites in serum during the progression of CHF. Using mass-spectrometry-based untargeted metabolomics, we identified 23 cardiac metabolites that were altered in a rat model of myocardial infarction induced CHF. Among these differential metabolites, branched-chain amino acids (BCAAs) in serum, especially leucine and valine, showed a high capability to differentiate between CHF and sham-operated rats, of which area under the receiver operating characteristic curve was greater than 0.75. Combining with targeted analysis of the amino acids and related proteins and genes, we confirmed that BCAA metabolic pathway was significantly inhibited in rat failing hearts. On the basis of the time series data of serum samples, we characterized the fluctuation pattern of circulating BCAAs by the disease progression model. Finally, the time-resolved diagnostic potential of serum BCAAs was evaluated by the machine-learning-based classifier, and high diagnostic accuracy of 93.75% was achieved within 3 weeks after surgery. These findings provide a promising metabolic signature that can be further exploited for CHF early diagnostic development.