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Biomedical subjects

D B Rubin

Publications and source records attributed to D B Rubin.

At least 19 recordsLinked to original sources
PubMed1999

Intermittent degradation in performance in schizophrenia.

In a series of repeated trials, schizophrenic patients often fluctuate in performance. Our data suggest that it may be useful, not just to report an increased variance relative to nonschizophrenics, but to model these fluctuations concretely as transitions between a relatively normal and an abnormal cognitive state - an intermittent degradation in performance that may be related to transient abnormalities in CNS functioning. We define 'dialipsis' as a temporary substitution of a less efficient process of task performance. This phenomenon is mentioned in the literature, but the descriptions of dialipsis are heuristic rather than based on a statistical model. We present a mixture model in which the ordinary and degraded states are described by distinct ANOVA structures, each with its own task, subject and interaction effects, with transitions between them occurring at random times. We discuss ways of detecting dialipsis and comparing the mixture model statistically with alternative models.

Analysis of Variance↗
PubMed1998

More powerful randomization-based p-values in double-blind trials with non-compliance.

Standard randomization-based tests of sharp null hypotheses in randomized clinical trials, that is, intent-to-treat analyses, are valid without extraneous assumptions, but generally can be appropriately powerful only with alternative hypotheses that involve treatment assignment having an effect on outcome. In the context of clinical trials with non-compliance, other alternative hypotheses can be more natural. In particular, when a trial is double-blind, it is often reasonable for the alternative hypothesis to exclude any effect of treatment assignment on outcome for a unit unless the assignment affected which treatment that unit actually received. Bayesian analysis under this alternative 'exclusion' hypothesis leads to new estimates of the effect of receipt of treatment, and to a new randomization-based procedure that has frequentist validity yet can be substantially more powerful than the standard intent-to-treat procedure. The key idea is to obtain a p-value using a posterior predictive check distribution, which includes a model for non-compliance behaviour, although only under the standard sharp null hypothesis of no effect of assignment (or receipt) of treatment on outcome. It is important to note that these new procedures are distinctly different from 'as treated' and 'per protocol' analyses, which are not only badly biased in general, but generally have very low power.

Data Interpretation, Statistical↗
PubMed1998

Aminothiols protect endothelial cell proliferation against inhibition by lipopolysaccharide.

Lipopolysaccharide (LPS) is a primary agent of sepsis that damages the vascular endothelium. Endothelial cell proliferation is key to the repair of damaged endothelium, and drugs that counteract the antiproliferative impact of LPS on endothelial cells should be beneficial. Because LPS exerts much of its cytotoxicity by generating reactive oxygen and nitrogen intermediates, it would be helpful to know whether therapeutic antioxidant thiols maintain cell proliferation in injured endothelium. In this study, it was found that LPS inhibited bovine aortic endothelial cell proliferation by inducing apoptosis and by decreasing DNA synthesis. Because of its benefit to irradiated endothelial cells, we then treated the cells with a radio- and chemoprotective aminothiol, WR-1065 ([N-2-mecaptoethyl]-1-3-diaminopropane, the active form of Amifostine/Ethyol). WR-1065 attenuated the inhibition of DNA synthesis caused by LPS exposure. The disulfide of WR-1065, WR-33278, was tested and shown to both promote DNA synthesis and inhibit apoptosis. The effectiveness of the disulfide suggests that the reduction of cytotoxicity does not necessarily result from the scavenging of free radicals. These findings demonstrate a novel role for aminothiols in promoting DNA synthesis and lowering apoptosis in endothelium injured with LPS.

Animals↗
PubMed1998

Aminothiol WR-1065 protects endothelial cell morphology against alterations induced by lipopolysaccharide.

In septic patients, lipopolysaccharide (LPS) damages the vascular endothelium, which manifests as tissue edema and impaired healing. This pathology occurs when LPS distorts endothelial cell morphology partly by generating free radicals. A radioprotector that scavenges free radicals, the aminothiol WR-1065 ([N-2-mercaptoethyl]-1-3-diaminopropane) was found in a prior study to normalize the morphology of irradiated endothelial cells (Mooteri SN, Podolski JL, Drab EA, et al: Radiat Res 145:217-224, 1996). The aim of this study was to determine whether WR-1065 also normalized endothelial cell morphology following exposure to LPS. For this aim, portions of bovine aortic endothelial cell cultures were denuded and exposed to LPS at 1 ng/mL. After 30 min, the apical membrane expressed increased integrin receptor to fibronectin, alpha5beta1. After 5 h, the morphology of the cells at the leading edge was distorted, and cell-cell contact was lessened. Also, filamentous actin-containing stress fibers were dissipated; however, filamentous actin content per cell was unchanged. Treatment with 2 mM WR-1065 for 2 h prior to LPS exposure attenuated the increased expression of alpha5beta1 and promoted cell-cell contact in the migrating endothelial cells. WR-1065 also promoted the retention of stress fibers and actin cytoskeletal shape in cells treated with LPS. Thus, LPS distorted endothelial cell morphology after increasing apical membrane expression of alpha5beta1 and dissipating stress fibers, effects prevented by WR-1065.

Actins↗
PubMed1997

Estimating causal effects from large data sets using propensity scores.

The aim of many analyses of large databases is to draw causal inferences about the effects of actions, treatments, or interventions. Examples include the effects of various options available to a physician for treating a particular patient, the relative efficacies of various health care providers, and the consequences of implementing a new national health care policy. A complication of using large databases to achieve such aims is that their data are almost always observational rather than experimental. That is, the data in most large data sets are not based on the results of carefully conducted randomized clinical trials, but rather represent data collected through the observation of systems as they operate in normal practice without any interventions implemented by randomized assignment rules. Such data are relatively inexpensive to obtain, however, and often do represent the spectrum of medical practice better than the settings of randomized experiments. Consequently, it is sensible to try to estimate the effects of treatments from such large data sets, even if only to help design a new randomized experiment or shed light on the generalizability of results from existing randomized experiments. However, standard methods of analysis using available statistical software (such as linear or logistic regression) can be deceptive for these objectives because they provide no warnings about their propriety. Propensity score methods are more reliable tools for addressing such objectives because the assumptions needed to make their answers appropriate are more assessable and transparent to the investigator.

Breast Neoplasms↗
PubMed1997

Modeling schizophrenic behavior using general mixture components.

This article proposes a novel and general mixture component model, the features of which include a hierarchical structure with random effects, mixture components characterized by ANOVA-like linear regressions, and mixing mechanisms governed by logistic regressions. The model was developed as a consequence of attending to long-standing psychological theory about schizophrenic behavior. Scientifically revealing results are obtained by fitting the model to a data set concerning nonschizophrenic and schizophrenic eye-tracking behavior under different conditions. Included are descriptions of the algorithms for model fitting, specifically the ECM/SECM algorithms for large sample modal inference, and the Gibbs sampler for simulating the posterior distribution. For guidance on model comparison and selection, we use posterior predictive check distributions to obtain posterior predictive p-values for likelihood ratio statistics, which do not have asymptotic chi 2 reference distributions. These posterior predictive p-values suggest that all the mixture components in our model are necessary. The final model is selected using a combination of scientific parsimony, the posterior predictive p-values, and the posterior distributions of relevant parameters.

Algorithms↗
PubMed1996

[Delayed effects of prenatal exposure to phenobarbital on intelligence--Phenemal].

Two double-blind studies were conducted on two independent samples of adult men prenatally exposed to phenobarbital and matched control samples using two different measures of general intelligence (WAIS and a draft board test (BPP)). The two studies included 33 and 81 exposed adult men respectively, and the two control groups included 52 and 101 unexposed men matched on a wide spectrum of maternal variables recorded pre- and perinatally. Based on data from control subjects, regression models were built relating intelligence scores to relevant pre-exposure matching variables. Models generated predicted scores for each exposed subject. Men exposed prenatally to phenobarbital had significantly lower verbal intelligence scores than predicted. Lower socioeconomic status and being the offspring of an unwanted pregnancy increased the magnitude of the negative effects. Exposure which includes the last trimester was the most detrimental. Physicians are urged to use increased caution in prescribing such medications during pregnancy or to premature neonates.

Adult↗
PubMed1996

Tumor angiogenesis in pheochromocytomas and paragangliomas.

BACKGROUND: Angiogenesis correlates with growth and likely metastases in several tumors. To determine whether it has a similar role in pheochromocytomas, immunohistochemical staining of factor VIII was done on the tumor tissue of 42 patients. METHODS: Formalin-fixed, paraffin-embedded tissue was obtained from 29 women and 13 men with 24 primary adrenal and 18 extraadrenal pheochromocytomas. Patients were divided into two groups. Group 1 included 32 patients with benign pheochromocytomas, and group 2 included 10 patients with malignant tumors evidenced by capsular or vascular invasion (six), liver metastases (three), or periaortic lymph node metastases (one). Blood vessels highlighted by factor VIII staining of endothelial cells with labeled streptavidin-biotin were counted under light microscopy. Mean vessel count within a 10 mm2 micrometer disk was calculated under x100, x200, and x400 magnification fields. RESULTS: There were no significant differences in patient age or clinical symptoms between the groups. The mean tumor size in group 2 of 8.8 +/- 5.3 cm was larger than the mean of 4.8 +/- 2.8 cm in group 1 (p < 0.005). The mean counts of vessels in the x100, x200, and x400 magnification fields were 102 +/- 48, 40 +/- 18, and 19 +/- 9 in group 1, and 203 +/- 77, 73 +/- 28, and 37 +/- 15 in group 2. The number of blood vessels in group 2 was significantly higher than in group 1 (p < 0.001) in each studied field. CONCLUSIONS: In this study the number of tumor blood vessels correlated with the invasive behavior of pheochromocytomas. Tumor angiogenesis may be useful in determining the likelihood of malignant behavior in pheochromocytomas.

Adolescent↗
PubMed1996

Markov chain Monte Carlo methods in biostatistics.

Appropriate models in biostatistics are often quite complicated. Such models are typically most easily fit using Bayesian methods, which can often be implemented using simulation techniques. Markov chain Monte Carlo (MCMC) methods are an important set of tools for such simulations. We give an overview and references of this rapidly emerging technology along with a relatively simple example. MCMC techniques can be viewed as extensions of iterative maximization techniques, but with random jumps rather than maximizations at each step. Special care is needed when implementing iterative maximization procedures rather than closed-form methods, and even more care is needed with iterative simulation procedures: it is substantially more difficult to monitor convergence to a distribution than to a point. The most reliable implementations of MCMC build upon results from simpler models fit using combinations of maximization algorithms and noniterative simulations, so that the user has a rough idea of the location and scale of the posterior distribution of the quantities of interest under the more complicated model. These concerns with implementation, however, should not deter the biostatistician from using MCMC methods, but rather help to ensure wise use of these powerful techniques.

Algorithms↗
PubMed1996

WR-1065 and radioprotection of vascular endothelial cells. I. Cell proliferation, DNA synthesis and damage.

Normal tissue toxicity limits radiation therapy and could depend on the extent of damage to the vascular endothelium Aminothiols such as WR-1065 [N-(2-mercaptoethyl)-1,3-diaminopropane] provide radioprotection for normal tissues, but little is known about how the aminothiols specifically affect the endothelium. Bovine aortic endothelial cells in culture were exposed to WR-1065 for 2 h before irradiation (137Cs gamma rays, 1 Gy/min). Alone, WR-1065 demonstrated an antiproliferative effect that was related to dose (0.5-4 mM) and was evident by lowered counts of adherent cells 48 h after exposure. WR-1065 was clearly radioprotective when assessed by colony formation and incorporation of [3H]thymidine. However, when the number of adherent cells was evaluated, radioprotection appeared to be slight and evident only in logarithmically growing cells. WR-1065 at 2 mM suppressed single-strand DNA breaks after 3 Gy by 22% and double-strand breaks after 9 Gy by 47%. Also in the irradiated cells, WR-1065 more than doubled the rate of progression of cells from G1 to S phase. WR-1065 pretreatment elevated cellular glutathione (GSH) content more than twofold. Although pretreatment with buthionine sulfoximine inhibited the elevation of GSH, the radioprotective impact of WR-1065 on total DNA strand breaks and colony formation was unaffected. These results suggest that WR-1065 may enable tissue recovery from irradiation by promoting the replication of endothelial cells, possibly by mechanisms independent of GSH.

Animals↗
PubMed1996

WR-1065 and radioprotection of vascular endothelial cells. II. Morphology.

Although the aminothiol WR-1065 protects normal tissues, its direct effect on the damage and restoration of the vascular endothelium is not clear. In endothelial cells, WR-1065 attenuates both the DNA damage and the G1-phase arrest induced by radiation. After the destruction of nearby endothelial cells, the survivors rearrange their cytoskeleton, migrate and replicate. To determine the effect of radiation on morphology and migration, portions of bovine aortic endothelial cell cultures were denuded with a pipette tip and irradiated (137Cs gamma rays). The following observations were noted after 5 Gy: within 10 min, there was increased formation of protein-mixed disulfides including actin-mixed disulfide; after 30-min, alpha 5 beta 1, the integrin receptor for fibronectin, was up-regulated on the apical membrane surface. Within 5 h, actin-containing stress fibers reorganized, although there was no change in the total filamentous (F-)actin content within the cells. Compared to controls after 24 h, the irradiated cells had migrated 15% farther (P < 0.01), and at the leading edge covered twice the surface area (P < 0.0001). The addition of 2 mM WR-1065 for 2 h before 5 Gy inhibited the increased expression of alpha 5 beta 1, promoted retention of stress fibers and prevented the enhanced cell migration and spreading. These results indicate that WR-1065 prevents radiation-induced morphological responses. This effect appears to be mediated by an impact on both adhesion molecule expression and cytoskeletal reorganization.

Actin Cytoskeleton↗
PubMed1996

Matching using estimated propensity scores: relating theory to practice.

Matched sampling is a standard technique in the evaluation of treatments in observational studies. Matching on estimated propensity scores comprises an important class of procedures when there are numerous matching variables. Recent theoretical work (Rubin, D. B. and Thomas, N., 1992, The Annals of Statistics 20, 1079-1093) on affinely invariant matching methods with ellipsoidal distributions provides a general framework for evaluating the operating characteristics of such methods. Moreover, Rubin and Thomas (1992, Biometrika 79, 797-809) uses this framework to derive several analytic approximations under normality for the distribution of the first two moments of the matching variables in samples obtained by matching on estimated linear propensity scores. Here we provide a bridge between these theoretical approximations and actual practice. First, we complete and refine the nomal-based analytic approximations, thereby making it possible to apply these results to practice. Second, we perform Monte Carlo evaluations of the analytic results under normal and nonnormal ellipsoidal distributions, which confirm the accuracy of the analytic approximations, and demonstrate the predictable ways in which the approximations deviate from simulation results when normal assumptions are violated within the ellipsoidal family. Third, we apply the analytic approximations to real data with clearly nonellipsoidal distributions, and show that the theoretical expressions, although derived under artificial distributional conditions, produce useful guidance for practice. Our results delineate the wide range of settings in which matching on estimated linear propensity scores performs well, thereby providing useful information for the design of matching studies. When matching with a particular data set, our theoretical approximations provide benchmarks for expected performance under favorable conditions, thereby identifying matching variables requiring special treatment. After matching is complete and data analysis is at hand, our results provide the variances required to compute valid standard errors for common estimators.

Analysis of Variance↗
PubMed1995

In utero exposure to phenobarbital and intelligence deficits in adult men.

OBJECTIVE: To test whether exposure to phenobarbital in utero is associated with deficits in intelligence scores in adult men and whether the magnitude of the postnatal effect is mediated by exposure parameters and/or postnatal environmental factors. DESIGN: Two double-blind studies were conducted on independent samples of adult men prenatally exposed to phenobarbital and matched control samples using different measures of general intelligence. Based on data from control subjects, regression models were built relating intelligence scores to relevant pre-exposure matching variables and age at testing. Models generated predicted scores for each exposed subject. Group mean differences between the individually predicted and observed scores estimated exposure effects. SETTING: Copenhagen, Denmark. PARTICIPANTS: Exposed subjects were adult men born at the largest hospital in Copenhagen between 1959 and 1961 who were exposed to phenobarbital during gestation via maternal medical treatment and whose mothers had no history of a central nervous system disorder and no treatment during pregnancy with any other psychopharmacological drug. Study 1 included 33 men and study 2, 81 men. Controls were unexposed members of the same birth cohort matched on a wide spectrum of maternal variables recorded prenatally and perinatally. Controls for studies 1 and 2 included 52 and 101 men, respectively. MAIN OUTCOME MEASURES: In study 1: Wechsler Adult Intelligence Scale (Danish version); in study 2: Danish Military Draft Board Intelligence Test (Børge Priens Prøve). RESULT: Men exposed prenatally to phenobarbital had significantly lower verbal intelligence scores (approximately 0.5 SD) than predicted. Lower socioeconomic status and being the offspring of an "unwanted" pregnancy increased the magnitude of the negative effects. Exposure that included the last trimester was the most detrimental. CONCLUSION: Phenobarbital exposure during early development can have long-term deleterious effects on cognitive performance. Detrimental environmental conditions can interact with prenatal biological insult to magnify negative outcomes. Physicians are urged to use increased caution in prescribing such medications during pregnancy.

Adult↗
PubMed1995

The analysis of repeated-measures data on schizophrenic reaction times using mixture models.

Reaction times for schizophrenic individuals in a simple visual tracking experiment can be substantially more variable than for non-schizophrenic individuals. Current psychological theory suggests that at least some of this extra variability arises from an attentional lapse that delays some, but not all, of each schizophrenic's reaction times. Based on this theory, we pursue models in which measurements from non-schizophrenics arise from a normal linear model with a separate mean for each individual, whereas measurements from schizophrenics arise from a mixture of (i) a component analogous to the distribution of response times for non-schizophrenics and (ii) a mean-shifted component. We fit four mixture models within this framework, where the distinctions between models arise from assumptions about the variance of the shifted observations and the exchangeability of schizophrenic individuals. Some of these models can be fit by maximum likelihood using the EM algorithm, and all can be fit using the ECM algorithm, where the covariance matrices associated with the parameters are calculated by the SEM and SECM algorithms, respectively. Bayesian model monitoring using posterior predictive checks is invoked to discard models that fail to reproduce certain observed features of the data and to stimulate the development of better models.

Algorithms↗
PubMed1995

Bismuth subsalicylate toxicity as a cause of prolonged encephalopathy with myoclonus.

Bismuth subsalicylate preparations are over-the-counter products for gastrointestinal complaints. Bismuth toxicity causes delirium, psychosis, ataxia, myoclonus, and seizures and is reversible over several weeks or months, when bismuth intake is stopped. We report a 54-year-old man with a 6-week history of progressive confusion and memory difficulty and a 2-3-week history of involuntary movements and gait impairment. His encephalopathy was further characterized by marked multifocal myoclonic jerks, coarse postural tremors, postural instability, and gait ataxia. He gradually improved. Extensive toxic, metabolic, and infectious workup demonstrated bismuth toxicity. Spinal tap and brain magnetic resonance scan were normal. Electroencephalography showed bihemispheric slowing. As his encephalopathy cleared, he reported using bismuth subsalicylate long term (daily intake of 8 oz). Bismuth levels 5 weeks after cessation of bismuth were elevated and normalized after 12 weeks. He followed a typical course for bismuth toxicity with subacute progressive encephalopathy and gradual recovery. Creutzfeldt-Jakob was strongly considered due to his rapidly progressive encephalopathy, multifocal myoclonus, and ataxia. Due to its rarity, bismuth toxicity is often overlooked. We hope this presentation will increase recognition of bismuth toxicity. We believe more detailed labeling of bismuth products is needed to avoid similar toxicity from this readily available product.

Bismuth↗
PubMed1995

Tumor angiogenesis as a predictor of recurrence and survival in patients with node-negative colon cancer.

OBJECTIVE: The authors' objective was to quantitatively assess angiogenesis or neovascularity within node-negative colon cancers and to determine if increased angiogenesis correlated with higher recurrence and lower survival rates. SUMMARY BACKGROUND DATA: Neovascularization promotes rapid tumor growth by facilitating nutrient and metabolite exchange. Recent work with breast and nonsmall cell lung cancers has shown that low angiogenic activity imparts a lower risk of recurrence and metastasis. Although adjuvant therapy is beneficial for patients with node-positive colon cancers, no such benefit has been demonstrated for patients with node-negative lesions. Nevertheless, up to 30% of this latter group will experience recurrence. We sought to identify a subset of patients with node-negative colon cancers at high risk for recurrence who might benefit from such therapy. METHODS: One hundred five node-negative colon cancers were immunostained for endothelial cell factor VIII-related antigen. Blood vessels within three microscopic fields at 100X magnification were counted, the mean calculated, and an angiogenesis score assigned. A subjective angiogenesis grade (1-4) was assigned after each slide was surveyed in its entirety. Score and grade were then assessed with respect to cancer recurrence and patient survival. RESULTS: Mean patient age was 71 years (range, 41-90 years) and mean tumor size, 5.6 cm (range, 2-12 cm). Mean follow-up was 6.5 years; mean angiogenesis score, 27.9 (range, 4-50); and mean grade, 2.0 (range, 1-4). Patients living 5 years had significantly lower angiogenesis scores than did nonsurvivors (22.8 vs. 43.2, p = 0.0004). Each 10-vessel increase in score imparted a 2.0-fold greater hazard of death and a 2.7-fold greater hazard of recurrence. The probability of surviving 5 years is estimated by: [formula: see text] and the probability of recurrence is estimated by: [formula: see text] CONCLUSIONS: Angiogenesis within colon cancer is an important predictor of tumor behavior and may identify patients at higher risk for recurrence and early death.

Adenocarcinoma↗