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The effect of medicare health maintenance organizations on hospitalization rates for ambulatory care-sensitive conditions.

OBJECTIVE: The objective of this study was to estimate the effect of Medicare Health Maintenance Organization (HMO) enrollment on hospitalization rates and total inpatient days for ambulatory care-sensitive conditions (ACSCs) after controlling for selection. RESEARCH DESIGN: Simultaneous equations using a discrete factor selection model are used to estimate the probability of HMO enrollment, hospitalization rates, and total inpatient days for ACSCs. SUBJECTS: Enrollment data on Medicare beneficiaries in California were linked to hospital discharge data from the California Office of Statewide Health Planning and Development for January through December 1996. The following beneficiaries were excluded: 1) end-stage renal disease, 2) under 65 years of age, 3) not covered by both Medicare Part A and Part B, 4) switched between HMOs and fee-for-service (FFS), and 5) switched between HMOs. The sample was stratified by age, gender, race, county, disability, Medicaid eligibility, HMO status, and death. A 2% random sample from the 4 California counties with the largest Medicare enrollment yielded 10,448 HMO enrollees and 11,803 FFS beneficiaries. RESULTS: Using a discrete factor selection model, we estimated the rate of ACSC hospitalizations among FFS beneficiaries would decline from 51.2 to 44.2 per 1000 if all FFS beneficiaries joined an HMO. Similarly, the mean total inpatient days for ACSC hospitalizations would be reduced from 7.5 days to 5.1 days if all FFS beneficiaries joined an HMO. CONCLUSIONS: After controlling for selection, Medicare HMO enrollees have lower hospitalization rates and fewer total inpatient days for 15 ACSCs than Medicare FFS beneficiaries. These findings suggest selection of healthier beneficiaries into HMOs does not completely explain their lower rates of ACSC hospitalization.

Aged↗

Alternative methods for handling attrition: an illustration using data from the Fast Track evaluation.

Using data from the evaluation of the Fast Track intervention, this article illustrates three methods for handling attrition. Multiple imputation and ignorable maximum likelihood estimation produce estimates that are similar to those based on listwise-deleted data. A panel selection model that allows for selective dropout reveals that highly aggressive boys accumulate in the treatment group over time and produces a larger estimate of treatment effect. In contrast, this model produces a smaller treatment effect for girls. The article's conclusion discusses the strengths and weaknesses of the alternative approaches and outlines ways in which researchers might improve their handling of attrition.

Data Collection↗

Diagnostic and management procedures for compensable back injuries without serious associated injuries. Modeling of the 1991 injury cohort from a major Michigan compensation insurer.

STUDY DESIGN: A retrospective cohort of 2425 workers with compensated back conditions was created from the 1991 compensated cohort of the largest compensation insurer in Michigan by linking computerized information on social and demographic factors, diagnostic and management procedures, and cumulative missed worktime. OBJECTIVE: To describe medical care use from date of injury in 1991 to mid-1993 by type of back condition, to identify factors affecting this use, to determine the effect of alternative model selection strategies on identifying such factors, to investigate the timing of surgery and the use of diagnostic studies in patients with displaced or herniated discs with and without surgery, and to compare the use of medical care in the study group with that recommended by national expert panels. SUMMARY OF BACKGROUND DATA: Despite the enormous costs involved in medical care for patients with work-related back injuries, almost no information on the use of medical care is available for compensated back injuries by diagnostic and procedure code. METHODS: Use of medical care was grouped into 18 categories for tabulation. Factors affecting use of medical care were identified by logistic regression, supplemented by Cox analysis for time to first procedure. The Hosmer-Lemeshow chi-square statistic was compared with the Bayes Information Criterion for evaluating model fit. Overall model utility was evaluated by comparing receiver operating characteristic curves generated by the model. For patients with displaced or herniated discs, algorithms were used to identify the diagnostic procedures performed before and after the first surgery and the amount of time that passed before each procedure was performed. RESULTS: In patients with diagnoses of disc displacement or herniation or vertebrogenic neuritis, approximately 80% underwent radiography to obtain plain views of the spine, 75% underwent diagnostic imaging, 45% underwent electrodiagnostic procedures, and 24% underwent spinal surgery (29.3% had surgical procedures among those with disc conditions). In patients with diagnoses of back sprain or other symptomatic diagnoses, the percentages for the first three procedures are approximately 70%, 12%, and 12%, respectively. Diagnostic category, age, gender, and cumulative missed worktime predicted the receipt of diagnostic and treatment procedures. Women were 30% less likely to undergo computed axial tomography or magnetic resonance imaging and 50% less likely to undergo spinal surgery. Median time to spinal surgery was twice as long in the group that underwent diagnostic imaging and electrodiagnostic testing before surgery (134.5 days). Of the 622 patients with disc displacement/herniation, 510 (approximately 80%) had initial diagnostic imaging studies, and, of the 510, 162 (approximately 30%) had surgery. Thirteen (8%) were reoperated. Of the 162 patients who had surgery, 46 (approximately 30%) had follow-up diagnostic imaging, and, of the 46, nine (approximately 20%) were reoperated. Of the 348 managed conservatively, 96 (approximately 30%) had follow-up diagnostic imaging. CONCLUSIONS: The data suggest only modest differences in the use of medical care between this study group and noncompensated study populations from previous reports. The authors of this study estimate that 27% of diagnostic imaging studies and 43% of plain radiography of the spine could have been avoided if then available Canadian recommendations or current American, guidelines had been followed. The gender effect remains unexplained and needs to be investigated in additional studies. There was an increase of 6% in the use of surgery in compensated patients compared with the use of surgery in a recent American series involving traditional health insurance, but this may be associated with greater work disability in the compensated group. The results of the current study suggest that the use and reporting of model selection strategies and the use of receiver operati

Adolescent↗

An experimental model for selective inhibition of proliferating cells by chemotherapeutic agents.

Conditionally transformable cells of primate origin in which 'untransformed' and 'transformed' cells derived from the same source grow in culture, has been used as an experimental system for testing selective inhibition of proliferating cells by chemotherapeutic agents. The cytotoxic agents Adriamycin and Mitomycin C fail to recognise "tumour cells" in a heterogenous population and thus differ from the non-toxic and non-carcinogenic agent L-canavanine.

Animals↗

Theoretical proposal: allele dosage of MAP2K4/MKK4 could rationalize frequent 17p loss in diverse human cancers.

Although aneuploidy is a global genomic abnormality present in most human cancers, the clonal selection model best explains the action of select activating mutations in oncogenes and homozygous losses of tumor-suppressor genes. Simple gene dosage changes are difficult however, to incorporate into this model, in part due to negative feedback loops that govern major cancer mutational targets (e.g., TP53, PTCH, SMAD4) and essentially preclude a haploinsufficient phenotype. The 17p conundrum may offer a clue to reconciling this difficulty: In comparison to the moderate mutation rate of TP53, many tumors have a disproportionately high frequency of loss of 17p. This discrepancy, and similar discrepancies at other sites of LOH, has long been thought to be due to the presence of undiscovered yet frequently mutated tumor-suppressor genes. However, over 15 years of searching for this grail has distributed bountiful disappointment. It is perhaps time to seriously consider an alternative explanation. Located on 17p adjacent to the TP53 gene, MKK4 is one of the most consistently mutated genes across tumor types, and is located on one of the most frequently lost arms in the human genome. We theorized that a gene dosage-dependent phenotype of MKK4 could plausibly promote the emergence of 17p LOH and thereby the probability of evolving the biallelic inactivation of TP53. Using MKK4 somatic human knockout cancer cells, we observed the proof-of-principle in the downstream gene dosage-dependent phenotypes: heterozygous and homozygous knockouts were progressively deficient in Mkk4 protein, in stress-induced phosphorylation of Jnk, and the resultant upregulation of JUN mRNA. These observations highlight a lack of compensatory regulation when gene dosage changes perturb the Jnk-Jun relationship. Consideration of gene dosage changes specifically affecting members of positive feedback loops may permit integration of the aneuploidy process into a conventional model of clonal selection in tumorigenesis.

Cell Line, Tumor↗

MEG source localization under multiple constraints: an extended Bayesian framework.

To use Electroencephalography (EEG) and Magnetoencephalography (MEG) as functional brain 3D imaging techniques, identifiable distributed source models are required. The reconstruction of EEG/MEG sources rests on inverting these models and is ill-posed because the solution does not depend continuously on the data and there is no unique solution in the absence of prior information or constraints. We have described a general framework that can account for several priors in a common inverse solution. An empirical Bayesian framework based on hierarchical linear models was proposed for the analysis of functional neuroimaging data [Friston, K., Penny, W., Phillips, C., Kiebel, S., Hinton, G., Ashburner, J., 2002. Classical and Bayesian inference in neuroimaging: theory. NeuroImage 16, 465-483] and was evaluated recently in the context of EEG [Phillips, C., Mattout, J., Rugg, M.D., Maquet, P., Friston, K., 2005. An empirical Bayesian solution to the source reconstruction problem in EEG. NeuroImage 24, 997-1011]. The approach consists of estimating the expected source distribution and its conditional variance that is constrained by an empirically determined mixture of prior variance components. Estimation uses Expectation-Maximization (EM) to give the Restricted Maximum Likelihood (ReML) estimate of the variance components (in terms of hyperparameters) and the Maximum A Posteriori (MAP) estimate of the source parameters. In this paper, we extend the framework to compare different combinations of priors, using a second level of inference based on Bayesian model selection. Using Monte-Carlo simulations, ReML is first compared to a classic Weighted Minimum Norm (WMN) solution under a single constraint. Then, the ReML estimates are evaluated using various combinations of priors. Both standard criterion and ROC-based measures were used to assess localization and detection performance. The empirical Bayes approach proved useful as: (1) ReML was significantly better than WMN for single priors; (2) valid location priors improved ReML source localization; (3) invalid location priors did not significantly impair performance. Finally, we show how model selection, using the log-evidence, can be used to select the best combination of priors. This enables a global strategy for multiple prior-based regularization of the MEG/EEG source reconstruction.

Bayes Theorem↗

Bayesian shrinkage estimation of quantitative trait loci parameters.

Mapping multiple QTL is a typical problem of variable selection in an oversaturated model because the potential number of QTL can be substantially larger than the sample size. Currently, model selection is still the most effective approach to mapping multiple QTL, although further research is needed. An alternative approach to analyzing an oversaturated model is the shrinkage estimation in which all candidate variables are included in the model but their estimated effects are forced to shrink toward zero. In contrast to the usual shrinkage estimation where all model effects are shrunk by the same factor, we develop a Bayesian method that allows the shrinkage factor to vary across different effects. The new shrinkage method forces marker intervals that contain no QTL to have estimated effects close to zero whereas intervals containing notable QTL have estimated effects subject to virtually no shrinkage. We demonstrate the method using both simulated and real data for QTL mapping. A simulation experiment with 500 backcross (BC) individuals showed that the method can localize closely linked QTL and QTL with effects as small as 1% of the phenotypic variance of the trait. The method was also used to map QTL responsible for wound healing in a family of a (MRL/MPJ x SJL/J) cross with 633 F(2) mice derived from two inbred lines.

Animals↗

Estimating the effect of help-seeking on achieving recovery from alcohol dependence.

AIMS: To investigate the effect of help-seeking on the likelihood of recovery from Diagnostic and Statistical Manual version IV (DSM-IV) alcohol dependence, specifically examining the impact of model selection, factors that moderate the effect of help-seeking and distinctions between the effects of 12-Step participation and formal treatment. DESIGN: This analysis is based on data from the Wave 1 2001-02 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a cross-sectional, retrospective survey of a nationally representative sample of US adults 18 years of age and over. The analytical sample consisted of 4422 individuals with prior-to-past-year (PPY) onset of DSM-IV alcohol dependence. METHODS: Logistic regression, proportional hazards and time-dependent proportional hazards models were used to estimate the effects of help-seeking on three outcomes: (1) any recovery from alcohol dependence, which required full remission of all symptoms of alcohol abuse and dependence and excluded asymptomatic drinkers whose alcohol consumption exceeded low-risk drinking guidelines; (2) non-abstinent recovery (NR), representing low-risk asymptomatic drinkers; and (3) abstinent recovery (AR), representing abstainers. FINDINGS: Only one-quarter of individuals with PPY-onset alcohol dependence had ever sought help for alcohol problems, including 3.1% who had participated in 12-Step programs only, 5.4% who had received formal treatment only and 17.0% with both 12-Step and formal treatment. Based on the most appropriate model, help-seeking increased the likelihood of any recovery [hazard rate ratio (HRR) = 2.38], NR (HRR = 1.50) and AR (HRR = 4.01). The impact of help-seeking on AR did not show any significant variation across the exposure period but was modified by severity among other factors. Individuals who participated in 12-Step programs in addition to formal treatment had almost twice the chance of recovery and more than more than twice the chance of AR compared with those who received formal treatment alone. CONCLUSIONS: Help-seeking plays a significant role in the achievement of abstinent recovery from alcohol dependence, with 12-Step participation playing a major role. Appropriate model selection is critical to assessing the impact of help-seeking.

Adolescent↗

Effect of antidepressant therapy on health care utilization and costs in primary care.

OBJECTIVE: Four groups of patients receiving different antidepressant drugs in a primary care setting were compared in terms of duration of antidepressant therapy and health and mental health care utilization and costs. METHODS: A retrospective analysis of the medical and pharmacy claims of an employed population and their families was conducted. A total of 1,242 patients with a diagnosis of depression were included in the analyses. The four antidepressant cohorts were fluoxetine (N = 799), trazodone (N = 89), the tricyclics amitriptyline and imipramine (N = 104), and the secondary amine tricyclics desipramine and nortriptyline (N = 250). The primary outcome measures were total health care charges, total charges for mental health services, and the pattern of antidepressant use. Secondary measures included charges for outpatient care and pharmacy and the number of outpatient visits. Data analysis involved use of two-stage multivariate regression modeling known as sample selection models. RESULTS: Patients taking fluoxetine achieved higher rates of continuous use for at least six months compared with those taking the other drugs. After selection bias due to observed and unobserved characteristics and other confounding variables was adjusted for, no significant differences were found between drug cohorts in total medical charges. CONCLUSIONS: Improvements in the process of care at no apparent increase in total charges appear possible through appropriate medication therapy.

Adult↗

Identification of Staphylococcus aureus genes expressed during growth in milk: a useful model for selection of genes important in bovine mastitis?

Staphylococcus aureus is a major cause of bovine mastitis. Since gene expression of many bacteria is known to be regulated by the environment, milk may play an important role in the regulation of the early steps in the pathogenesis of bovine mastitis by S. aureus. To get insight into the response of S. aureus to the milk environment, a Tn917-lacZ mutant library was generated and screened for genes specifically expressed during growth in milk. Twenty-eight mutants were identified and analysed. Four groups of genes were found, involved in cell-wall synthesis, nucleotide synthesis, transcriptional regulation and carbohydrate metabolism. A fifth group contained genes with hypothetical or unknown functions. Many of the genes identified belonged to biosynthetic pathways of S. aureus and other bacterial species which have also been shown to play a role in vivo as determined in murine infection models. Therefore, growth on milk may be an attractive model for the identification of genes preferentially expressed during bovine mastitis.

Animals↗

A one-year mortality study of the most acutely ill patients in a medical-surgical intensive care unit: toward developing a model for selection of recipients of intensive care.

This study over a 1-year period of time in a medical-surgical ICU in a large metropolitan teaching hospital was conducted to determine the mortality rate among a select group of acutely ill patients. By operational definition the acutely ill patients included in this study were those who were admitted to the medical-surgical ICU and treated with at least two out of three of the following: MA-1 ventilator, flow-directed balloon-tipped catheter, and vasopressor(s). Of 158 patients in the study, 117 died during hospitalization. The personnel in this oversubscribed unit were constantly faced with the decision of who should and who should not be admitted and who should be transferred out. Statistics on intensive care management are converted into daily costs for intensive care for those who did and did not survive. Model building is discussed as a process necessary in determining who shall receive intensive care and who shall not. The basic premise for conducting the study was that decisions regarding who shall receive care that is expensive and in limited supply should be based on facts to the extent that they can be elucidated.

Adult↗

Simulation study of a multigene family, with special reference to the evolution of compensatory advantageous mutations.

We investigate the evolution of a multigene family incorporating the forces of drift, mutation, gene conversion, unequal crossing over and selection. The use of simulation studies is required due to the complexity of the model. Selection is modeled in two modes: positive selection as a function of the number of different beneficial alleles and negative selection against deleterious alleles. We assume that gene conversion is unbiased, and that all mutations are initially deleterious. Compensation between mutants creates beneficial and neutral alleles, and allowances are made for compensatory mutations either within or between the members of a multigene family. We find that gene conversion can enhance the rate of acquisition of compensatory advantageous mutations when genes are redundant.

Alleles↗

Random selection: a model for poliovirus infection of the central nervous system.

Mixed infections occur in the natural environment, and also result from the use of mixed live vaccines. Some recipients of the trivalent oral poliovirus vaccine develop vaccine-associated paralytic poliomyelitis (VAPP). Numerous serotypes and recombinant genotypes of vaccine-derived polioviruses may be found in stool samples from such cases. To investigate the relationship between the multiplication of various genotypes at the primary replication site in the gut and the infection outcome in the central nervous system (CNS), the viruses excreted on consecutive days by two patients with VAPP were compared with the viruses isolated from the CNS. The genotypes from stools were numerous and varied with time in both cases, suggesting a multiplication of the viruses in multiple foci in the gut. Where the CNS isolated virus clearly corresponded to one of the many viruses detected in stool, this virus was unexpectedly less neurovirulent than others isolated from stool. To assess the mechanism by which viruses with different degrees of neurovirulence are selected in the CNS, transgenic mice sensitive to poliovirus infection were inoculated extraneurally with mixtures of two phenotypically different viruses at different neuropathogenic doses. The virus(es) inducing neurological disease was then isolated from the CNS. At less than 100% input neuropathogenic dose of both inoculated viruses, individual mice were affected stochastically by the virus variants from the mixture. Extrapolated to humans, this selection pattern might explain the occurrence of CNS infections with less neurotropic viruses derived from an extraneural pool containing also highly neurotropic viruses.

Animals↗

Analysis and improvement of fitness exploitation in XCS: bounding models, tournament selection, and bilateral accuracy.

The evolutionary learning mechanism in XCS strongly depends on its accuracy-based fitness approach. The approach is meant to result in an evolutionary drive from classifiers of low accuracy to those of high accuracy. Since, given inaccuracy, lower specificity often corresponds to lower accuracy, fitness pressure most often also results in a pressure towards higher specificity. Moreover, fitness pressure should cause the evolutionary process to be innovative in that it combines low-order building blocks of lower accurate classifiers, to higher-order building blocks with higher accuracy. This paper investigates how, when, and where accuracy-based fitness results in successful rule evolution in XCS. Along the way, a weakness in the current proportionate selection method in XCS is identified. Several problem bounds are derived that need to be obeyed to enable proper evolutionary pressure. Moreover, a fitness dilemma is identified that causes accuracy-based fitness to be misleading. Improvements are introduced to XCS to make fitness pressure more robust and overcome the fitness dilemma. Specifically, (1) tournament selection results in a much better fitness-bias exploitation, and (2) bilateral accuracy prevents the fitness dilemma. While the improvements stand for themselves, we believe they also contribute to the ultimate goal of an evolutionary learning system that is able to solve decomposable machine-learning problems quickly, accurately,and reliably. The paper also contributes to the further understanding of XCS in general and the fitness approach in XCS in particular.

Algorithms↗

Ca2+-cardiolipin interaction in a model system. Selectivity and apparent high affinity.

The interaction of cardiolipin with Ca2+ was assessed by measuring the cardiolipin-mediated extraction of 45Ca2+ from an aqueous to an organic (methylene chloride) phase. Cardiolipin binds Ca2+ with high affinity [Kd(apparent) = 0.70 +/- 0.17 microM (S.D.)]. Cation-cardiolipin interactions are selective. Interaction of cardiolipin with Ca2+ is insensitive to Na+, but is inhibited by divalent cations with Mn2+ greater than Zn2+ greater than Mg2+. In addition La3+ and Ruthenium red are particularly potent inhibitors of Ca2+ binding by cardiolipin. Cardiolipin-mediated extraction of Ca2+ into an aqueous phase is also inhibited by phosphatidylcholine. Inhibition of Ca2+-cardiolipin interaction by phosphatidylcholine (a phospholipid known to stabilize the bilayer conformation) may implicate inverted, non-bilayer lipid structures in the binding.

Calcium↗

Rapid assessment of onchocerciasis prevalence and a model for selecting communities for ivermectin distribution in West Africa.

Analysis of the prevalence of onchocerciasis in an area of north-east Nigeria indicates that clinical symptoms are generally good predictors of the rate of onchocerciasis infection and of the mean microfilarial density in infected individuals. However, differences between regions and anomalous communities within regions make reliance on a single indicator dubious. Use of multivariate equations was tested, but offered little improvement over bivariate ones and an algorithmic approach, making use of local knowledge of factors which might complicate interpretation, is proposed instead. The framework is suggested as a basis for screening, although a larger database is required to produce definitive equations.

Algorithms↗

Chinchilla models of selective cochlear hair cell loss.

Although it is well known that ethacrynic acid (EA) can enhance gentamicin (GM) ototoxicity, there has been no systematic study of the relationship between dosing parameters and inner ear pathology. We examined the effects of two parameters, GM dose and time delay between GM and EA administration, on cochlear and vestibular hair cell loss in chinchillas. 'No delay' groups received one injection of GM (125, 40, 20, or 10 mg/kg i.m.) followed immediately by EA (40 mg/kg i.v.); 'delay' groups received GM (10 mg/kg i.m.) followed by EA 1 or 1.5 h later. Animals were sacrificed 7 days later for evaluation of hair cell loss in the cochlea and vestibular end organs (cristae, saccule and utricle). Vestibular function was assessed prior to sacrifice by measuring the duration of nystagmus induced by cold caloric stimulation. No delay groups had approximately 100% loss of outer hair cells and dose-dependent losses of inner hair cells, ranging from approximately 100% to 58%. In 1 and 1.5 h delay groups, inner hair cell losses were approximately 19% and 0%, outer hair cell losses were approximately 74% and 47%, and outer hair cell loss followed a typical base to apex gradient. Two results were remarkable. First, the three groups with partial inner hair cell loss showed an atypical lesion pattern in which losses were substantially greater in the apical half than in the basal half of the cochlea. Second, there was no vestibular pathology in any group. The results establish dosing parameters that can be used to produce animal models with defined patterns and magnitudes of cochlear hair cell damage, but normal vestibular function and morphology.

Animals↗

Mutational analysis of the endothelin type A receptor (ETA): interactions and model of selective ETA antagonist BMS-182874 with putative ETA receptor binding cavity.

Endothelin (ET) receptor antagonism is a potential therapeutic intervention in the treatment of vascular diseases. To elucidate the mechanism of antagonist-ET receptor complex formation, the interactions of four chemically distinct antagonists were investigated using a combination of genetic and biochemical approaches. By site-specific mutagenesis we previously demonstrated that Tyr129 in the second transmembrane domain was critical for high-affinity, subtype-selective binding to the A subtype of ET (ETA) receptors [Krystek et al. (1994) J. Biol. Chem. 269, 12383-12386]. Affinities of the constrained cyclic pentapeptide BQ-123, the pyrimidinylbenzenesulfonamide bosentan, the indancarboxlic acid SB 209670, and the naphthalenesulfonamide BMS-182874 were decreased 20-1000-fold in Tyr129Ala, Tyr129Ser, and Tyr129His ETA receptor mutants. Substitution of Tyr129 with Phe or Trp did not alter the high-affinity binding of BQ-123, bosentan, or SB 209670. BMS-182874 binding affinity was decreased 10-fold in Tyr129Phe and Tyr129trp ET receptors. These data indicate a role of aromatic interactions in the binding of these antagonists to ETA receptors an, in the case of BMS-182874, also suggested a hydrogen bond with the tyrosine hydroxyl. This hypothesis was supported by structure-activity data with analogs of BMS-182874 that varied the C-5 dimethylamino substituent on the naphthalene ring. Mutation of Asp126 and Asp133 also altered binding of BMS-182874 and C-5 analogs. In all cases, naphthalenesulfonamide binding was more severely affected by mutation of Asp133 than by mutation of Asp126. Phosphoinositide hydrolysis and extracellular acidification rate studies demonstrated the importance of Tyr129 to ETA-mediated signal transduction. On the basis of these data, two plausible models of the docked conformation of BMS-182874 in the ETA receptor are proposed as a starting point for further delineation of interactions that underlie antagonist-ETA receptor complex formation.

Amino Acid Sequence↗