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The effect of three-dimensional shape optimization on the probabilistic response of a cemented femoral hip prosthesis.

Probabilistic analyses allow the effect of uncertainty in system parameters on predicted model performance measures to be determined. Furthermore, using performance functions to describe a failure event, the probability of failure can be quantified. The effect of three-dimensional prosthesis shape optimization on the probabilistic response and failure probability of a cemented hip prosthesis system is investigated. Random variables include joint and muscle loading, cortical and cancellous bone and PMMA bone cement elastic properties, and strength parameters describing failure of the bone cement and the prosthesis-bone cement interface. Several performance functions describing the bone cement and prosthesis-cement interface are used to compute the probability of failure. When evaluated deterministically, most performance functions indicated a safe design, with the exception of interface tensile failure. However, when evaluated probabilistically, finite probabilities of failure were computed, some significant. The most likely mode of failure before shape optimization was prosthesis-bone cement interface tensile failure with a predicted probability of failure of 97.9%. Deterministic prosthesis shape optimization reduced the probability of failure for all performance functions and reduced prosthesis-bone cement interface tensile failure by 31.7%. Probability sensitivity factors indicate that the uncertainty in the joint loading, cement strength, and implant-cement interface strength have the greatest effect on the computed probability of failure. Implant shape optimization results in a more robust implant design that is less sensitive to uncertainties in joint loading, which cannot be easily controlled, and more sensitive to cement and interface properties, which are easier to modify.

Cementation↗

Amplification of trial-to-trial response variability by neurons in visual cortex.

The visual cortex responds to repeated presentations of the same stimulus with high variability. Because the firing mechanism is remarkably noiseless, the source of this variability is thought to lie in the membrane potential fluctuations that result from summated synaptic input. Here this hypothesis is tested through measurements of membrane potential during visual stimulation. Surprisingly, trial-to-trial variability of membrane potential is found to be low. The ratio of variance to mean is much lower for membrane potential than for firing rate. The high variability of firing rate is explained by the threshold present in the function that converts inputs into firing rates. Given an input with small, constant noise, this function produces a firing rate with a large variance that grows with the mean. This model is validated on responses recorded both intracellularly and extracellularly. In neurons of visual cortex, thus, a simple deterministic mechanism amplifies the low variability of summated synaptic inputs into the large variability of firing rate. The computational advantages provided by this amplification are not known.

Action Potentials↗

Assessing dose of the representative person for the purpose of radiation protection of the public. ICRP publication 101. Approved by the Commission in September 2005.

The Commission intended that its revised recommendations should be based on a simple, but widely applicable, system of protection that would clarify its objectives and provide a basis for the more formal systems needed by operating managers and regulators. The recommendations would establish quantified constraints, or limits, on individual dose from specified sources. These dose constraints apply to actual or representative people who encounter occupational, medical, and public exposures. This report updates the previous guidance for estimating dose to the public. Dose to the public cannot be measured directly and, in some cases, it cannot be measured at all. Therefore, for the purpose of protection of the public, it is necessary to characterise an individual, either hypothetical or specific, whose dose can be used for determining compliance with the relevant dose constraint. This individual is defined as the 'representative person'. The Commission's goal of protection of the public is achieved if the relevant dose constraint for this individual for a single source is met and radiological protection is optimised. This report explains the process of estimating annual dose and recognises that a number of different methods are available for this purpose. These methods range from deterministic calculations to more complex probabilistic techniques. In addition, a mixture of these techniques may be applied. In selecting characteristics of the representative person, three important concepts should be borne in mind: reasonableness, sustainability, and homogeneity. Each concept is explained and examples are provided to illustrate their roles. Doses to the public are prospective (may occur in the future) or retrospective (occurred in the past). Prospective doses are for hypothetical individuals who may or may not exist in the future, while retrospective doses are generally calculated for specific individuals. The Commission recognises that the level of detail afforded by its provision of dose coefficients for six age categories is not necessary in making prospective assessments of dose, given the inherent uncertainties usually associated with estimating dose to the public and with identification of the representative person. It now recommends the use of three age categories for estimating annual dose to the representative person for prospective assessments. These categories are 0-5 years (infant), 6-15 years (child), and 16-70 years (adult). For practical implementation of this recommendation, dose coefficients and habit data for a 1-year-old infant, a 10-year-old child, and an adult should be used to represent the three age categories. In a probabilistic assessment of dose, whether from a planned facility or an existing situation, the Commission recommends that the representative person should be defined such that the probability is less than about 5% that a person drawn at random from the population will receive a greater dose. If such an assessment indicates that a few tens of people or more could receive doses above the relevant constraint, the characteristics of these people need to be explored. If, following further analysis, it is shown that doses to a few tens of people are indeed likely to exceed the relevant dose constraint, actions to modify the exposure should be considered. The Commission recognises the role that stakeholders can play in identifying characteristics of the representative person. Involvement of stakeholders can significantly improve the quality, understanding, and acceptability of the characteristics of the representative person and the resulting estimated dose.

Body Burden↗

Modeling the euglycemic hyperinsulinemic clamp by stochastic differential equations.

The Euglycemic Hyperinsulinemic Clamp (EHC) is the most widely used experimental procedure for the determination of insulin sensitivity. In the present study, 16 subjects with BMI between 18.5 and 63.6 kg/m(2) have been studied with a long-duration (5 hours) EHC. In order to explain the oscillations of glycemia occurring in response to the hyperinsulinization and to the continuous glucose infusion at varying speeds, we first hypothesized a system of ordinary differential equations (ODEs), with limited success. We then extended the model and represented the experiment using a system of stochastic differential equations (SDEs). The latter allow for distinction between (i) random variation imputable to observation error and (ii) system noise (intrinsic variability of the metabolic system), due to a variety of influences which change over time. The stochastic model of the EHC was fitted to data and the system noise was estimated by means of a (simulated) maximum likelihood procedure, for a series of different hypothetical measurement error values. We showed that, for the whole range of reasonable measurement error values: (i) the system noise estimates are non-negligible; and (ii) these estimates are robust to changes in the likely value of the measurement error. Explicit expression of system noise is physiologically relevant in this case, since glucose uptake rate is known to be affected by a host of additive influences, usually neglected when modeling metabolism. While in some of the studied subjects system noise appeared to only marginally affect the dynamics, in others the system appeared to be driven more by the erratic oscillations in tissue glucose transport rather than by the overall glucose-insulin control system. It is possible that the quantitative relevance of the unexpressed effects (system noise) should be considered in other physiological situations, represented so far only with deterministic models.

Blood Glucose↗

Parameter estimation in a stochastic model of the tubuloglomerular feedback mechanism in a rat nephron.

A key parameter in the understanding of renal hemodynamics is the gain of the feedback function in the tubuloglomerular feedback mechanism. A dynamic model of autoregulation of renal blood flow and glomerular filtration rate has been extended to include a stochastic differential equations model of one of the main parameters that determines feedback gain. The model reproduces fluctuations and irregularities in the tubular pressure oscillations that the former deterministic models failed to describe. This approach assumes that the gain exhibits spontaneous erratic variations that can be explained by a variety of influences, which change over time (blood pressure, hormone levels, etc.). To estimate the key parameters of the model we have developed a new estimation method based on the oscillatory behavior of the data. The dynamics is characterized by the spectral density, which has been estimated for the observed time series, and numerically approximated for the model. The parameters have then been estimated by the least squares distance between data and model spectral densities. To evaluate the estimation procedure measurements of the proximal tubular pressure from 35 nephrons in 16 rat kidneys have been analyzed, and the parameters characterizing the gain and the delay have been estimated. There was good agreement between the estimated values, and the values obtained for the same parameters in independent, previously published experiments.

Animals↗

Principles for the design of the economic evaluation of COLOR II: an international clinical trial in surgery comparing laparoscopic and open surgery in rectal cancer.

OBJECTIVES: The objective is to describe the principles for the design of the economic evaluation of COLOR II, a randomized, multi-country study comparing laparoscopic and open surgery for rectal cancer. METHODS: By using the experiences gained in a recent economic evaluation in colon cancer, where the same surgical techniques were compared, we could improve the method for identifying and measuring resource use items and also accommodate the use of data from the global study population. RESULTS: In the design of the study, the uncertainty in the resource-use variables was reduced by considering (i) what aspects drive each variable, (ii) what resource use is related to the intervention, (iii) how data from different countries affects the variable. CONCLUSIONS: The aim was to refine the data collection so that the economic research question could be answered in the best possible way, given the circumstances in the clinical study. Thus, (i) some variables were treated as stochastic variables and others as deterministic variables, (ii) aggregate key cost-driving resource items were developed that corresponded to clinical events, and (iii) a surrogate variable was selected, instead of the "obvious variable", to reduce the impact of confounding factors for one particular resource unit.

Clinical Trials as Topic↗

Stochastic models for mainland-island metapopulations in static and dynamic landscapes.

This paper has three primary aims: to establish an effective means for modelling mainland-island metapopulations inhabiting a dynamic landscape; to investigate the effect of immigration and dynamic changes in habitat on metapopulation patch occupancy dynamics; and to illustrate the implications of our results for decision-making and population management. We first extend the mainland-island metapopulation model of Alonso and McKane [Bull. Math. Biol. 64:913-958, 2002] to incorporate a dynamic landscape. It is shown, for both the static and the dynamic landscape models, that a suitably scaled version of the process converges to a unique deterministic model as the size of the system becomes large. We also establish that, under quite general conditions, the density of occupied patches, and the densities of suitable and occupied patches, for the respective models, have approximate normal distributions. Our results not only provide us with estimates for the means and variances that are valid at all stages in the evolution of the population, but also provide a tool for fitting the models to real metapopulations. We discuss the effect of immigration and habitat dynamics on metapopulations, showing that mainland-like patches heavily influence metapopulation persistence, and we argue for adopting measures to increase connectivity between this large patch and the other island-like patches. We illustrate our results with specific reference to examples of populations of butterfly and the grasshopper Bryodema tuberculata.

Algorithms↗

Uterine artery embolization: reduced radiation with refined technique.

PURPOSE: To determine the estimated absorbed ovarian dose (EAOD) and absorbed skin dose (ASD) that occurs during uterine artery embolization (UAE) using pulsed fluoroscopy and a refined procedure protocol. MATERIALS AND METHODS: The absorbed dose was measured in 20 patients who underwent UAE procedures. Radiation was limited by using low frequency pulsed fluoroscopy, bilateral catheter technique with simultaneous injections for embolization as well as pre-and postembolization exposures and focus on limitation of magnified and oblique fluoroscopy. Lithium fluoride dosimeters were placed both in the posterior vaginal fornix and on the skin at the beam entrance site. The vaginal dose was used to approximate the EAOD. Fluoroscopy time and exposures were recorded. The mean values for all patients were calculated and compared to our previous results obtained with conventional fluoroscopy and to threshold doses for the induction of deterministic skin injury. RESULTS: Mean fluoroscopy time was 10.95 min. (range 6-21.3 min.) and the mean number of angiographic exposures was 20.9 (range 14-53). The mean EAOD was 9.5 cGy (range 2.21-23.21 cGy) and the mean ASD was 47.69 cGy (range 10.83-110.14 cGy). This compares to previous results with non-pulsed fluoroscopy of an EAOD of 22.34 cGy (range 4.25-65.08 cGy) and an ASD of 162.32 cGy (range 66.01-303.89 cGy) as well as threshold doses for induction of deterministic radiation injury to the skin (400-500 cGy). CONCLUSION: When pulsed fluoroscopy is used with emphasis on dose reduction techniques, the EAOD and ASD can be substantially reduced to less than 1/2 (P = .017) and 1/3 (P < .0001) when compared to UAE performed with nonpulsed fluoroscopy. These radiation reduction tools should therefore be applied whenever possible.

Arteries↗

Fractal analysis of steady-state-flicker visual evoked potentials: feasibility.

Electrophysiological models of visual evoked potential recording have assumed that response variability is caused predominantly by random noise added to a true steady signal. Since neuronal geometry has a fractal structure, neural activity may demonstrate deterministic nonlinear dynamics, i.e., chaos. We recorded several-minute time-series traces of the visual evoked potential magnitude in response to full-field flicker from three glaucoma patients and one normal subject. When plotted in phase space, the steady-state response derived from a lock-in amplifier shows an apparent so-called strange attractor (extended nonrepeating loops) rather than the pattern expected from a signal-plus-noise model (a fuzzy dot). The fractal dimension of this attractor may be a more sensitive indicator of early optic-nerve damage than are visual evoked potential latency or amplitude measures.

Electrophysiology↗

Economic evaluation of specific immunotherapy versus symptomatic treatment of allergic rhinitis in Germany.

OBJECTIVE: To use published data to compare the economic consequences of specific immunotherapy (SIT) lasting 3 years with those of continuous symptomatic treatment in patients with either pollen or mite allergy. DESIGN AND SETTING: The evaluation was conducted from the following 3 perspectives in Germany: (i) society; (ii) healthcare system; and (iii) statutory health insurance (SHI) provider. A modelling approach was used which was based on secondary analysis of existing data. The follow-up period was 10 years. The break-even point of cumulated costs, their difference per patient and the additional cost per additional patient free from asthma symptoms [incremental cost-effectiveness ratio (ICER)] were used as target variables, each from the viewpoint of SIT. The types of costs were direct and indirect (society), direct (healthcare system) and those incurred by SHI (i.e. expenses). In the base-case analysis, the average values of the clinical parameters and average case-related costs/expenses were applied. MAIN OUTCOME MEASURES AND RESULTS: The break-even point was reached between year 6 and year 8 after the start of therapy, resulting in net savings of between 650 and 1190 deutschmarks (DM) per patient after 10 years. The ICERs of SIT were between -DM3640 and -DM7410, depending on study perspective and nature of the allergy (1990 values for symptomatic treatment and treatment of asthma, 1995 values for SIT; DM1 approximately $US0.58). The sensitivity analysis demonstrated the robustness of the model and its results. First, all the independent variables of the model were varied. Secondly, the influence of the model variables was quantified using a deterministic model. SIT was more likely to result in net savings than in additional costs. An economic parameter (cost for symptomatic treatment) had the highest influence on the results. CONCLUSIONS: This evaluation showed that SIT for 3 years is economically advantageous in patients who are allergic to pollen or mites and whose symptoms are inadequately controlled by continuous symptomatic treatment. After 10 years, the administration of SIT leads to net savings from the perspectives of society, the healthcare system and SHI (third-party payer) in Germany.

Delivery of Health Care↗

Cost effectiveness of ramipril in patients with non-diabetic nephropathy and hypertension: economic evaluation of Ramipril Efficacy in Nephropathy (REIN) Study for Germany from the perspective of statutory health insurance.

BACKGROUND: In the Ramipril Efficacy In Nephropathy (REIN) trial, ramipril significantly lowered the rate of reaching the combined end-point of doubling of baseline serum creatinine levels or end-stage renal failure (ESRF). OBJECTIVE: To determine the additional cost per patient-year of chronic (long term) dialysis avoided (PYCDA) when the ACE inhibitor, ramipril, was added to conventional treatment of patients with non-diabetic nephropathy and hypertension. STUDY PERSPECTIVE: Statutory Health Insurance (SHI) provider in Germany. DESIGN AND SETTING: Data from the REIN Study were used in a cost-effectiveness analysis (CEA). A modelling approach was used, which was based on secondary analysis of published data, and costs were those incurred by the SHI provider (i.e. SHI expenses). In the base-case analysis, average case-related SHI expenses were applied and PYCDA were quantified using the cumulative incidence of ESRF as observed in the REIN trial. MAIN OUTCOME MEASURES AND RESULTS: The incremental cost-effectiveness ratios (ICERs) of ramipril varied between about -76,700 deutschmarks (DM) and -DM81,900 per PYCDA (DM 1 approximately equals 0.55 US dollars; 1999 values), according to the treatment periods of 1 year and 3 years, respectively. In the sensitivity,analysis, the robustness of the model and its results were shown when the extent of influence of different model variables on the base-case results was investigated. First, probabilities of ESRF and PYCDA were estimated according to the Weibull method. Second, the influence of the model variables on the target variable was quantified using a deterministic model. Third, the dependency of the target variable (ICER) on random variables was described in a simulation. The cost for chronic dialysis had by far the greatest impact on the target variable, which was 28 times greater than the impact of clinical effectiveness of ramipril, i.e. the number of PYCDA. There were net savings per PYCDA with ramipril treatment after 1, 2 and 3 years: 95% of the 10,000 simulation steps resulted in savings of between DM69 500 and D94,600 per PYCDA after 3 years. CONCLUSIONS: Results from this evaluation show that ramipril offers enormous savings from the perspective of the SHI provider (third-party payer) in Germany when added to the conventional treatment of patients with non-diabetic nephropathy and hypertension.

Angiotensin-Converting Enzyme Inhibitors↗

On the existence and the role of chaotic processes in the nervous system.

Chaos theory is a rapidly growing field. As a technical term, "chaos" refers to deterministic but unpredictable processes being sensitively dependent upon initial conditions. Neurobiological models and experimental results are very complicated and some research groups have tried to pursue the "neuronal chaos". Babloyantz's group has studied the fractal dimension (d) of electroencephalograms (EEG) in various physiological and pathological states. From deep sleep (d = 4) to full awakening (d > 8), a hierarchy of "strange" attractors paralles the hierarchy of states of consciousness. In epilepsy (petit mal), despite the turbulent aspect of a seizure, the attractor dimension was near to 2. In Creutzfeld-Jacob disease, the regular EEG activity corresponded to an attractor dimension less than the one measured in deep sleep. Is it healthy to be chaotic? An "active desynchronisation" could be favourable to a physiological system. Rapp's group reported variations of fractal dimension according to particular tasks. During a mental arithmetic task, this dimension increased. In another task, a P300 fractal index decreased when a target was identified. It is clear that the EEG is not representing noise. Its underlying dynamics depends on only a few degrees of freedom despite yet it is difficult to compute accurately the relevant parameters. What is the cognitive role of such a chaotic dynamics? Freeman has studied the olfactory bulb in rabbits and rats for 15 years. Multi-electrode recordings of a few mm2 showed a chaotic hierarchy from deep anaesthesia to alert state. When an animal identified a previously learned odour, the fractal dimension of the dynamics dropped off (near limit cycles).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

The cost-effectiveness of air bags by seating position.

CONTEXT: Motor vehicle crashes continue to cause significant mortality and morbidity in the United States. Installation of air bags in new passenger vehicles is a major initiative in the field of injury prevention. OBJECTIVE: To assess the net health consequences and cost-effectiveness of driver's side and front passenger air bags from a societal perspective, taking into account the increased risk to children who occupy the front passenger seat and the diminished effectiveness for older adults. DESIGN: A deterministic state transition model tracked a hypothetical cohort of new vehicles over a 20-year period for 3 strategies: (1) installation of safety belts, (2) installation of driver's side air bags in addition to safety belts, and (3) installation of front passenger air bags in addition to safety belts and driver's side air bags. Changes in health outcomes, valued in terms of quality-adjusted life-years (QALYs) and costs (in 1993 dollars), were projected following the recommendations of the Panel on Cost-effectiveness in Health and Medicine. PARTICIPANTS: US population-based and convenience sample data were used. MAIN OUTCOME MEASURE: Incremental cost-effectiveness ratios. RESULTS: Safety belts are cost saving, even at 50% use. The addition of driver's side air bags to safety belts results in net health benefits at an incremental cost of $24000 per QALY saved. The further addition of front passenger air bags results in an incremental net benefit at a higher incremental cost of $61000 per QALY saved. Results were sensitive to the unit cost of air bag systems, their effectiveness, baseline fatality rates, the ratio of injuries to fatalities, and the real discount rate. CONCLUSIONS: Both air bag systems save life-years at costs that are comparable to many medical and public health practices. Immediate steps can be taken to enhance the cost-effectiveness of front passenger air bags, such as moving children to the rear seat.

Adult↗

Probabilistic code for DNA recognition by proteins of the EGR family.

A recognition code for protein-DNA interactions would allow for the prediction of binding sites based on protein sequence, and the identification of binding proteins for specific DNA targets. Crystallographic studies of protein-DNA complexes showed that a simple, deterministic recognition code does not exist. Here, we present a probabilistic recognition code (P-code) that assigns energies to all possible base-pair-amino acid interactions for the early growth response factor (EGR) family of zinc-finger transcription factors. The specific energy values are determined by a maximum likelihood method using examples from in vitro randomisation experiments (namely, SELEX and phage display) reported in the literature. The accuracy of the model is tested in several ways, including the ability to predict in vivo binding sites of EGR proteins and other non-EGR zinc-finger proteins, and the correlation between predicted and measured binding affinities of various EGR proteins to several different DNA sites. We also show that this model improves significantly upon the prediction capabilities of previous qualitative and quantitative models. The probabilistic code we develop uses information about the interacting positions between the protein and DNA, but we show that such information is not necessary, although it reduces the number of parameters to be determined. We also employ the assumption that the total binding energy is the sum of the energies of the individual contacts, but we describe how that assumption can be relaxed at the cost of additional parameters.

Algorithms↗

The development and mortality of the non-infective free-living stages of Ostertagia ostertagi in the field and in laboratory culture.

A deterministic model of the population biology of the non-infective free-living phase of Ostertagia ostertagi is described and tested. A comparison of field and laboratory studies indicates that the pre-infective larvae of O. ostertagi spend about twice as long in this phase in the field as in laboratory culture (13 days and 7 days respectively at 15 degrees C), and that the subsequent transition (i.e. second moult) to the infective phase also proceeds at a much slower rate (about 10 times less at 15 degrees C) in the field. Because of this discrepancy, estimates of model parameters are based entirely on measurements from field studies. A two-parameter model of pre-infective development in the field is derived. It describes egg and larval development as a direct non-linear function of air temperature. We also show that the mortality of the eggs and pre-infective larvae increases with temperature (although this relationship probably also subsumes a dependence on faecal moisture content). The model is shown to be a good mimic of the population dynamics of the non-infective free-living phase when tested against an independent data set, and is the basis of a larger model of the epidemiology of ostertagiasis.

Aging↗

Relation between weight matrix and substitution matrix: motif search by similarity.

MOTIVATION: The discovery of patterns shared by several sequences that differ greatly is a basic task in sequence analysis, and still a challenge. Several methods have been developed for detecting patterns. Methods commonly used for motif search include the Gibbs sampler, Expectation-Maximization (EM) algorithm and some intuitive greedy approaches. One cannot guarantee the optimality of the result produced by the Gibbs sampler in a single run. The deterministic EM methods tend to get trapped by local optima. Solutions found by greedy approaches are rarely sufficiently good. RESULTS: A simple model describing a motif or a portion of local multiple sequence alignment is the weight matrix model, in which a motif is characterized with position-specific probabilities. Two substitution matrices are proposed to relate the sequence similarity with the weight matrix. Combining the substitution matrix and weight matrix, we examine three typical sets of protein sequences with increasing complexity. At a low score threshold for pair similarity, sliding windows are compared with a seed window to find the score sum, which provides a measure of statistical significance for multiple sequence comparison. Such a similarity analysis reveals many aspects of motifs. Blocks determined by similarity can be used to deduce a primary weight matrix or an improved substitution matrix. The algorithm successfully obtains the optimal solution for the test sets by just greedy iteration.

Algorithms↗

Model validation for external doses due to environmental contaminations by the Chernobyl accident.

The objective of the present paper is to validate the deterministic JSP5 model for external exposures to population groups living in the areas contaminated with radionuclides after the Chernobyl accident. For this purpose inhabitants of contaminated areas wore TL-dosimeters for about 1 mo in the spring/summer periods of the years 1989 to 1994. External doses due to the Chernobyl accident were determined from the dosimeter readings by subtracting the natural background. 2,342 results for rural inhabitants and 420 results for inhabitants of the town Novozybkov passed reliability checks. These data show that the average dose in inhabitants of a rural settlement predicted by the model is in the range 0.69-1.55 of the measured values with a confidence level of 95%. Differences are attributed to settlement specific location factors, which are supported by the very good agreement of model and measurements in Novozybkov. In this case location factors of the model were obtained from Novozybkov directly.

Adult↗

A mixed-effects model for cognitive decline with non-monotone non-response from a two-phase longitudinal study of dementia.

Most longitudinal studies of elderly are characterized by substantial drop-out due to death and many other factors beyond the control of the investigators. In a two-phase longitudinal study of dementia, subjects with cognitive impairment skip the first phase survey in the next follow-up, leading to intermittent missing variables measured in that phase. In the context of analysing pre-dementia cognitive decline in an elderly population, both of the two causes of non-response can potentially be informative in the sense that the missingness is dependent on the unobserved outcome. To take these factors into account, mixed-effects models are constructed to allow the outcome and the multiple causes of missing values to share the same 'random parameter' or random effect. The crucial assumption of our model is that the random effects of the model for the outcome and that of the model for the missing-data indicators are linked in a deterministic manner. It can be thought of as an approximation of a more general and realistic situation, in which the two models have distinct, yet dependent, random effects. We conduct a simulation study to investigate possible deviations of the estimates under such a scenario. A second simulation illustrates the magnitude of the bias in estimating the difference of decline rate between two groups when the random effects are linked in different manners for the two groups.

Aged↗