Personalized Computational Causal Modeling of the Alzheimer Disease Biomarker Cascade.

BACKGROUND: Mathematical models of complex diseases, such as Alzheimer's disease, have the potential to play a significant role in personalized medicine. Specifically, models can be personalized by fitting parameters with individual data for the purpose of discovering primary underlying disease drivers, predicting natural history, and assessing the effects of theoretical interventions. Previous work in causal/mechanistic modeling of Alzheimer's Disease progression has modeled the disease at the cellular level and on a short time scale, such as minutes to hours. No previous studies have addressed mechanistic modeling on a personalized level using clinically validated biomarkers in individual subjects. OBJECTIVES: This study aimed to investigate the feasibility of personalizing a causal model of Alzheimer's Disease progression using longitudinal biomarker data. DESIGN/SETTING/PARTICIPANTS/MEASUREMENTS: We chose the Alzheimer Disease Biomarker Cascade model, a widely-referenced hypothetical model of Alzheimer's Disease based on the amyloid cascade hypothesis, which we had previously implemented mathematically as a mechanistic model. We used available longitudinal demographic and serial biomarker data in over 800 subjects across the cognitive spectrum from the Alzheimer's Disease Neuroimaging Initiative. The data included participants that were cognitively normal, had mild cognitive impairment, or were diagnosed with dementia (probable Alzheimer's Disease). The model consisted of a sparse system of differential equations involving four measurable biomarkers based on cerebrospinal fluid proteins, imaging, and cognitive testing data. RESULTS: Personalization of the Alzheimer Disease Biomarker Cascade model with individual serial biomarker data yielded fourteen personalized parameters in each subject reflecting physiologically meaningful characteristics. These included growth rates, latency values, and carrying capacities of the various biomarkers, most of which demonstrated significant differences across clinical diagnostic groups. The model fits to training data across the entire cohort had a root mean squared error (RMSE) of 0.09 (SD 0.081) on a variable scale between zero and one, and were robust, with over 90% of subjects showing an RMSE of < 0.2. Similarly, in a subset of subjects with data on all four biomarkers in at least one test set, performance was high on the test sets, with a mean RMSE of 0.15 (SD 0.117), with 80% of subjects demonstrating an RMSE < 0.2 in the estimation of future biomarker points. Cluster analysis of parameters revealed two distinct endophenotypic groups, with distinct biomarker profiles and disease trajectories. CONCLUSION: Results support the feasibility of personalizing mechanistic models based on individual biomarker trajectories and suggest that this approach may be useful for reclassifying subjects on the Alzheimer's clinical spectrum. This computational modeling approach is not limited to the Alzheimer Disease Biomarker Cascade hypothesis, and can be applied to any mechanistic hypothesis of disease progression in the Alzheimer's field that can be monitored with biomarkers. Thus, it offers a computational platform to compare and validate various disease hypotheses, personalize individual biomarker trajectories and predict individual response to theoretical prevention and therapeutic intervention strategies.

Antenatal glucocorticoids: where are we after forty years?

Since their introduction more than forty years ago, antenatal glucocorticoids have become a cornerstone in the management of preterm birth and have been responsible for substantial reductions in neonatal mortality and morbidity. Clinical trials conducted over the past decade have shown that these benefits may be increased further through administration of repeat doses of antenatal glucocorticoids in women at ongoing risk of preterm and in those undergoing elective cesarean at term. At the same time, a growing body of experimental animal evidence and observational data in humans has linked fetal overexposure to maternal glucocorticoids with increased risk of cardiovascular, metabolic and other disorders in later life. Despite these concerns, and somewhat surprisingly, there has been little evidence to date from randomized trials of longer-term harm from clinical doses of synthetic glucocorticoids. However, with wider clinical application of antenatal glucocorticoid therapy there has been greater need to consider the potential for later adverse effects. This paper reviews current evidence for the short- and long-term health effects of antenatal glucocorticoids and discusses the apparent discrepancy between data from randomized clinical trials and other studies.

Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.

BACKGROUND: Respiratory distress syndrome (RDS) is a serious complication of preterm birth and the primary cause of early neonatal mortality and disability. OBJECTIVES: To assess the effects on fetal and neonatal morbidity and mortality, on maternal mortality and morbidity, and on the child in later life of administering corticosteroids to the mother before anticipated preterm birth. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (30 October 2005). SELECTION CRITERIA: Randomised controlled comparisons of antenatal corticosteroid administration (betamethasone, dexamethasone, or hydrocortisone) with placebo or with no treatment given to women with a singleton or multiple pregnancy, expected to deliver preterm as a result of either spontaneous preterm labour, preterm prelabour rupture of the membranes or elective preterm delivery. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial quality and extracted data independently. MAIN RESULTS: Twenty-one studies (3885 women and 4269 infants) are included. Treatment with antenatal corticosteroids does not increase risk to the mother of death, chorioamnionitis or puerperal sepsis. Treatment with antenatal corticosteroids is associated with an overall reduction in neonatal death (relative risk (RR) 0.69, 95% confidence interval (CI) 0.58 to 0.81, 18 studies, 3956 infants), RDS (RR 0.66, 95% CI 0.59 to 0.73, 21 studies, 4038 infants), cerebroventricular haemorrhage (RR 0.54, 95% CI 0.43 to 0.69, 13 studies, 2872 infants), necrotising enterocolitis (RR 0.46, 95% CI 0.29 to 0.74, eight studies, 1675 infants), respiratory support, intensive care admissions (RR 0.80, 95% CI 0.65 to 0.99, two studies, 277 infants) and systemic infections in the first 48 hours of life (RR 0.56, 95% CI 0.38 to 0.85, five studies, 1319 infants). Antenatal corticosteroid use is effective in women with premature rupture of membranes and pregnancy related hypertension syndromes. AUTHORS' CONCLUSIONS: The evidence from this new review supports the continued use of a single course of antenatal corticosteroids to accelerate fetal lung maturation in women at risk of preterm birth. A single course of antenatal corticosteroids should be considered routine for preterm delivery with few exceptions. Further information is required concerning optimal dose to delivery interval, optimal corticosteroid to use, effects in multiple pregnancies, and to confirm the long-term effects into adulthood.

Long term effects of antenatal betamethasone on lung function: 30 year follow up of a randomised controlled trial.

BACKGROUND: Antenatal betamethasone is routinely used for the prevention of neonatal respiratory distress syndrome in preterm infants. However, little is known of the long term effects of exposure to antenatal betamethasone on lung function in adulthood. METHODS: Five hundred and thirty four 30 year olds whose mothers had participated in the first and largest randomised controlled trial of antenatal betamethasone were followed. Lung function was assessed by portable spirometric testing. The prevalence of asthma symptoms was assessed using the European Community Respiratory Health Survey questionnaire. RESULTS: Fifty (20%) betamethasone exposed and 53 (19%) placebo exposed participants met the criteria for current asthma (relative risk 0.98 (95% CI 0.74 to 1.30), p = 0.89). 181 betamethasone exposed and 202 placebo exposed participants had acceptable spirometric data. There were no differences in lung function between betamethasone and placebo exposed groups (mean (SD) forced vital capacity in the betamethasone and placebo groups 105.9 (12.0) v 106.6 (12.6)% predicted, difference = -0.7 (95% CI -3.2 to 1.8), p = 0.59; mean (SD) forced expiratory volume in 1 second in the betamethasone and placebo groups 98.9 (13.4) v 98.5 (13.6)% predicted, difference = 0.3 (95% CI -2.4 to 3.1, p = 0.80)). CONCLUSIONS: Antenatal exposure to a single course of betamethasone does not alter lung function or the prevalence of wheeze and asthma at age 30.

Modelling the global efficiency of dissolved air flotation.

The purpose of this paper is to examine how the efficiency of dissolved air flotation is affected by the size of bubbles and particles. The rise speed of bubble/particle agglomerates is modelled as a function of bubble and particle size, while the kinematics of the bubble attachment process is modelled using the population balance approach adopted by Matsui, Fukushi and Tambo. It is found that flotation, in general, is enhanced by the use of larger particles and larger bubbles. In particular, it is concluded that for the ultra-high surface loading rates of 25 m/hr or more planned for future flotation tanks, bubble size will have to be increased by a factor of two over the size currently employed in many facilities during dissolved air flotation.

Out-of-hours attendance and outcomes for asthmatic patients at two primary care services.

AIM: To describe patients who choose different primary care services for asthma care at Wellington general practitioner run After-hours Medical Centre (AMC) and Wellington hospital emergency department (WED). METHOD: Two month prospective study of patients attending out-of-hours. RESULTS: Eighteen percent of 249 AMC patients and 47% of 126 WED patients had a community services card and 6% and 7% respectively had high user health cards (p < 0.0001). AMC patients were more likely to:- be younger (mean age 19.3 vs 24.9 years, p < 0.006), live further from the service mean distance 5.3 km vs 4.1 km, p < 0.003), be given a repeat prescription for asthma medication (20% vs 3%, p < 0.0001), and be sent back to their GP (67% vs 25%, p < 0.0001). AMC patients were less likely to be referred by a GP (4% vs 9%, p < 0.05) and be admitted (1% vs 30%, p < 0.0001). 22.5% of patients admitted for asthma had seen a general practitioner prior to admission. CONCLUSION: Asthmatic patients had different outcomes at the two services which reflects different management policies at the two services. More research is needed on access factors influencing attendance for asthma such as the direct cost to the patient, the distance services are located from patients homes, and the time when services are convenient for patients.

The benefits of group occupational therapy for patients with Parkinson's disease.

The medical treatment of idiopathic Parkinson's disease has improved the quality of life and increased survival of patients with Parkinson's disease. However, as the illness progresses, impairments in daily living activities occur. A clinical trial for a group rehabilitation program was initiated to maintain the functional status of these patients. The research protocol consisted of a pretreatment evaluation, random assignment to experimental or control groups, and posttreatment evaluations after therapy, at 6 months and at 1 year. The results showed that the subjects of the treated experimental group maintained their functional status after 1 year, demonstrated a significant decrease of bradykinesia, and perceived a significant improvement in their psychological well-being. This study confirms the value of an occupational therapy group approach and its benefits to the functional independence, to the improvement of physical and motor symptoms, and to the quality of life of persons with Parkinson's disease.