Penalised maximum likelihood estimation in multi-state models for interval-censored data

Continuous-time multi-state Markov models can be used to describe transitions over time across health states. Given longitudinal interval-censored data on transitions between states, statistical inference on changing health is possible by specifying models for transition hazards. Parametric time-dependent hazards can be restrictive, and nonparametric hazard specifications using splines are presented as an alternative. The smoothing of the splines is controlled by using penalised maximum likelihood estimation. With multiple time-dependent hazards in a multi-state model, there are multiple penalty parameters and selecting the optimal amount of smoothing is a challenge. A grid search to estimate the penalty parameters is computational intensive especially when combined with methods to deal with interval-censored transition times. A new and efficient method is proposed to estimate multi-state models with splines where the estimation of the penalty parameters is automatic. A simulation study is undertaken to validate the method and to illustrate the effect of interval censoring. The feasibility of the method is illustrated with two applications

Modelling of heat treatment of soy

Soybeans are used as raw material for human nutrition and animal feed because of their high nutritional value. Consumption of raw beans has negative effects on the growth and health of human beings and animals. These effects are caused by antinutritional. factors (ANFs). Trypsin inhibitors (TIs) are generally considered as the most important ANFs in soybeans. TIs can be divided in two main groups: the Kunitz soybean trypsin inhibitor (KSTI) and the Bowman-Birk inhibitor (BBI). TIs and some of the other ANFs are heat labile and are inactivated by heat treatments such as steaming (toasting) and extrusion cooking. Optimal design and optimisation of the heat treatment are necessary because over-processing reduces the protein availability to the animals. In practice, design and optimisation are based on experience and 'trial- and-error'. In some studies 'black-box' models are presented. No explicit models were developed in previous studies to predict the influence of a heat treatment on the feed quality of soybeans.The aim of this research is to develop 'white-box' models to predict the influence of a heat treatment on the product quality of soybeans. Kinetics and process models are developed to predict the change of the product quality during the process. Particular attention is paid to the mechanistic background of the inactivation of Us in soy flour, and to the influence of shear forces on the inactivation of TIs during extrusion cooking.In order to develop an inactivation kinetics model, the inactivation of TIs in soy flour is measured within a large range of temperatures and moisture contents. The inactivation of TIs exhibits a two-phase inactivation behaviour. Six different mechanistic kinetics models are used to describe the experimental data. These models are compared statistically. Two parsimonious models are able to describe the two-phase inactivation behaviour of TIs well with a minimal number of kinetics parameters. One model describes the difference in heat stability of two TI groups, e.g. (KSTI) and (BBI). The second model describes the irreversible inactivation of a native TI to a partially active intermediate TI followed by the denaturation to a complete inactive form of TIThe hypothesis that the two-phase inactivation behaviour of TIs is caused by a difference in heat stability of two TI groups is further examined. The activity of (KSTI) and (BBI). is determined in different heat treated soy samples. The results show that the two-phase inactivation behaviour of TIs cannot be explained by the difference in heat stability of (KSTI) and (BBI). Additional experiments show that the addition of a thiol (cysteine) resulted in a two-phase inactivation behaviour of (KSTI) and (BBI). respectively, in starch. We suggest that TIs in soy flour inactivate by sulphydryl-disulfide interchange during the first inactivation phase, and by heat during the second phase.During extrusion cooking, TIs in soy flour are inactivated by heat and possibly also by the deformation of the TI-molecules due to the shear forces. First, the theoretical influence of these shear forces on the inactivation of TIs is examined. The calculations show that some influence of shear forces on the inactivation of TIs can not be excluded. Furthermore, single screw extrusion experiments are performed to examine to effect of shear experimentally. The decrease of TIA due to heat inactivation during extrusion cooking is calculated by combining the extrusion conditions (temperature profile and residence time distribution) with the inactivation kinetics model of TIs The results show that the measured residual trypsin inhibitor activity TIA values of the extrudates can be predicted properly by only heat inactivation. There is no indication that shear forces are involved in the inactivation of TIs during extrusion cooking.Atmospheric steaming (toasting) is the most used heat treatment of soybeans and flakes. A process model is developed to describe the temperature and moisture profiles in the beans during steaming. In order to evaluate the effect of steaming on the protein availability, the kinetics of nitrogen solubility index (NSI) change is measured and modelled. The kinetics models of TIA and NSI are combined with the process model for steaming to predict TIA and NSI levels in the steamed soybeans. The model predictions are validated with experimental data. The possibility for the optimisation of the product quality of soybeans during steaming is investigated by performing simulations. These simulations indicate that the steaming process can be optimised using TIA and NSI as quality parameters. Initial moisture content rather than steam temperature should be used to optimise the process

CBT for people with intellectual disabilities : emerging evidence, cognitive ability and IQ effects

Historically people with intellectual disabilities have not been offered or received cognitive behavioural interventions that have been shown to be effective for mental health and emotional problems experienced by those without such disabilities. This is despite many people with intellectual disabilities having life experiences that potentially result in them having an increased risk to such problems. This paper discusses whether such therapeutic disdain is justified based on the evidence that is available and emerging concerning the application of cognitive behavioural interventions for this population. Issues concerning access to services, the ability of people with intellectual disabilities to engage in and benefit from the cognitive components of CBT, and the effect of cognitive abilities and IQ level on treatment effectiveness are explored in relation to this question

Estimating dementia-free life expectancy for Parkinson's patients using Bayesian inference and microsimulation

Interval-censored longitudinal data taken from a Norwegian study of individuals with Parkinson's disease are investigated with respect to the onset of dementia. Of interest are risk factors for dementia and the subdivision of total life expectancy (LE) into LE with and without dementia. To estimate LEs using extrapolation, a parametric continuous-time 3-state illness–death Markov model is presented in a Bayesian framework. The framework is well suited to allow for heterogeneity via random effects and to investigate additional computation using model parameters. In the estimation of LEs, microsimulation is used to take into account random effects. Intensities of moving between the states are allowed to change in a piecewise-constant fashion by linking them to age as a time-dependent covariate. Possible right censoring at the end of the follow-up can be incorporated. The model is applicable in many situations where individuals are followed over a long time period. In describing how a disease develops over time, the model can help to predict future need for health care

Особенности деонтологии в сексологической практике

Описаны основные принципы врачебной этики в сексологической практике. Рассмотрены особенности взаимоотношений врача−сексолога и пациента. Подчеркивается, что выполнение врачом деонтологических принципов будет способствовать гармонизации семейно−сексуальных отношений.Basic principles of medical ethics in sexological practice are presented. The peculiarities of mutual relations of the doctor sexologist and the patient are discussed. It is emphasized that adherence of the doctor−sexologist of ethical principles will promote harmonization of family sexual relations

Vulnerability in acquisition, language impairments in Dutch: Creating a VALID data archive

The VALID Data Archive is an open multimedia data archive (under construction) with data from speakers suffering from language impairments. We report on a pilot project in the CLARIN-NL framework in which five data resources were curated. For all data sets concerned, written informed consent from the participants or their caretakers has been obtained. All materials were anonymized. The audio files were converted into wav (linear PCM) files and the transcriptions into CHAT or ELAN format. Research data that consisted of test, SPSS and Excel files were documented and converted into CSV files. All data sets obtained appropriate CMDI metadata files. A new CMDI metadata profile for this type of data resources was established and care was taken that ISOcat metadata categories were used to optimize interoperability. After curation all data are deposited at the Max Planck Institute for Psycholinguistics Nijmegen where persistent identifiers are linked to all resources. The content of the transcriptions in CHAT and plain text format can be searched with the TROVA search engin

Burden of illness of Pompe disease in patients only receiving supportive care

Background: Pompe disease is an orphan disease for which enzyme replacement therapy (ERT) recently became available. This study aims to estimate all relevant aspects of burden of illness-societal costs, use of home care and informal care, productivity losses, and losses in health-related quality of life (HRQoL)-for adult Pompe patients only receiving supportive care. Methods: We collected data on all relevant aspects of burden of illness via a questionnaire. We applied a societal perspective in calculating costs. The EQ-5D was used to estimate HRQoL. Results: Eighty adult patients (87% of the total Dutch adult Pompe population) completed a questionnaire. Disease severity ranged from mild to severe. Total annual costs were estimated at €22,475 (range €0-169,539) per adult Pompe patient. Patients on average received 8 h of home care and 19 h of informal care per week. Eighty-five percent of the patients received informal care from one or more caregivers; 40% had stopped working due to their disease; another 20% had reduced their working hours. HRQoL for Pompe patients who only received supportive care was estimated at 0.72, 17% lower than the Dutch population at large. Conclusions: Adult Pompe disease is associated with a considerable burden of illness at both the societal and patient levels. The disease leads to substantial costs and dependency on medical devices, home care, and informal care, and has a high impact on the patient's social network. In addition, patients are limited in their ability to work and have significantly reduced HRQoL

Facial-muscle weakness, speech disorders and dysphagia are common in patients with classic infantile Pompe disease treated with enzyme therapy

Classic infantile Pompe disease is an inherited generalized glycogen storage disorder caused by deficiency of lysosomal acid α-glucosidase. If left untreated, patients die before one year of age. Although enzyme-replacement therapy (ERT) has significantly prolonged lifespan, it has also revealed new aspects of the disease. For up to 11 years, we investigated the frequency and consequences of facial-muscle weakness, speech disorders and dysphagia in long-term survivors. Sequential photographs were used to determine the timing and severity of facial-muscle weakness. Using standardized articulation tests and fibreoptic endoscopic evaluation of swallowing, we investigated speech and swallowing function in a subset of patients. This study included 11 patients with classic infantile Pompe disease. Median age at the start of ERT was 2.4 months (range 0.1-8.3 months), and median age at the end of the study was 4.3 years (range 7.7 months −12.2 years). All patients developed facial-muscle weakness before the age of 15 months. Speech was studied in four patients. Articulation was disordered, with hypernasal resonance and reduced speech intelligibility in all four. Swallowing function was studied in six patients, the most important findings being ineffective swallowing with residues of food (5/6), penetration or aspiration (3/6), and reduced pharyngeal and/or laryngeal sensibility (2/6). We conclude that facial-muscle weakness, speech disorders and dysphagia are common in long-term survivors receiving ERT for classic infantile Pompe disease. To improve speech and reduce the risk for aspiration, early treatment by a speech therapist and regular swallowing assessments are recommended

Cardiac outcome in classic infantile Pompe disease after 13\xe2\x80\xafyears of treatment with recombinant human acid alpha-glucosidase

Background: Cardiac failure is the main cause of death in untreated classic infantile Pompe disease, an inheritable metabolic myopathy characterized by progressive hypertrophic cardiomyopathy. Since the introduction of enzyme replacement therapy (ERT), survival has increased significantly due to reduced cardiac hypertrophy and improved cardiac function. However, little is known about ERT\'s long-term effects on the heart. Methods: Fourteen patients were included in this prospective study. Cardiac dimensions, function, conduction and rhythm disturbances were evaluated at baseline and at regular intervals thereafter. Results: Treatment duration ranged from 1.1 to 13.9 years (median 4.8 years). At baseline, all patients had increased left ventricular mass index (LVMI) (median LVMI 226 g/m2, range 98 to 599 g/m2, Z-score median 7, range 2.4\xe2\x80\x9312.4). During the first four weeks, LVMI continued to increase in six patients. Normalization of LVMI was observed in 13 patients (median 30 weeks; range 3 to 660 weeks). After clinical deterioration, LVMI increased again slightly in one patient. At baseline, PR interval was shortened in all patients; it normalized in only three. A delta-wave pattern on ECG was seen in six patients and resulted in documented periods of supraventricular tachycardias (SVTs) in three patients, two of whom required medication and/or ablation. One patient had severe bradycardia (35 beats/min). Conclusion: This study shows that ERT significantly reduced LVMI, and sustained this effect over a period of 13.9 years. The risk for rhythm disturbances remains. Regular cardiac evaluations should be continued, also after initially good response to ERT