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Statistical issues in long-term followup studies.

The thesis of this article is that since followup studies of patients with schizophrenia have provided a rich body of informative knowledge, emphasis should now be on hypothesis testing in future studies. The consumer of research needs to have a general appreciation of statistical thinking, design, and methods to make an informed synthesis of results presented. This article presents a brief discussion of relevant statistics and statistical issues, as free of jargon as possible. Given the multivariable nature of psychiatric research, the natural focus is on multivariate statistics. A strong background in statistics is not required to understand the methods described and how and why they might be applied. Reference material for more detailed discussions is provided. It is a truism to say that the highest quality scientific work is dependent on an intimate collaboration with the expert in statistics and the expert in clinical methods, and this merits repeating only because it is so often ignored.

Follow-Up Studies↗

Responses of primate cortical neurons to unitary and binary taste stimuli.

1. The responses of 126 neurons in primary gustatory cortices of two rhesus monkeys were recorded during sapid stimulation of the tongue with 18 taste stimuli. Ten of these stimuli were dissolved in distilled water (DW): 1.0 M sucrose (Suc), 0.1 M and 0.03 M sodium chloride (NaCl), 0.003 M hydrochloric acid (HCl), 0.001 M quinine hydrochloride (QHCl), 0.03 M monosodium glutamate (MSG), 0.03 M polycose, 0.3 M glycine, 0.1 M proline, and 0.1 M malic acid. Seven other stimuli were dissolved in 0.03 M MSG; the last stimulus was a mixture of 1.0 M Suc and 0.03 M NaCl. 2. The average spontaneous rate (2.2 +/- 0.2 spikes/s, mean +/- SE) and response to DW (2.5 +/- 0.2) of these 126 neurons was low but within the range previously reported for neurons in primate taste cortex. Suc was the most effective stimulus for 24.1% of the neurons tested followed by NaCl (15.7%), QHCl (14.8%), HCl (11.1%), MSG (10.2%), and other miscellaneous unitary gustatory stimuli (8.3%). Binary taste mixtures were the most effective stimuli for 15.7% of the sample. The net responses (corrected for DW, in spikes/s) for Suc-best (3.3), NaCl-best (4.3), HCl-best (3.4), QHCl-best (2.3), and MSG-best (4.1) were sluggish, but comparable with that reported previously. 3. The response breadth of the 82 neurons that responded best to either Suc, NaCl, HCl, or QHCl measured with the entropy coefficient indicated a moderate response breadth for these neurons (mean = 0.79; range = 0.30-0.98). According to the response criteria adopted in this experiment (water response +/- 1.96 SD), however, 81 of these 82 neurons (98.1%) responded to only one or two of the four basic taste stimuli. The disparity between the entropy- and criterion-based measures of response derive from the nature of the two statistics. Adjustments that would make the entropy statistic less inclusive and the definition of a response according to statistical criteria less exclusive would increase their concordance. 4. Three multivariate statistics (cluster, principal axis factor, and multidimensional analysis) were used to analyze the data. Cluster analysis enabled us to divide the 82 taste neurons into groups on the basis of response similarity. Each of the four largest groups was dominated by neurons that responded best to one of the four basic taste stimuli: Suc, NaCl, QHCl, and HCl (ranked in descending order); the fifth largest cluster contained neurons that responded best to MSG. Principal axis factor analysis demonstrated that 80.8% of the total variance could be accounted for by three factors. Neurons responding best to Suc, NaCl, and QHCl each were closely associated with one of those three factors, but the loadings of the HCl-best neurons were evenly distributed across all three factors. The communality coefficient of these three factors was > 80% for the Suc-, NaCl-, HCl-, and QHCl-best neurons; the MSG-best neurons, by comparison, had very few high loadings on any of these three factors and a correspondingly low communality coefficient of 40.4%, a difference that was statistically significant from the other four groups. Thus the three factors related to Suc-, NaCl-, HCl-, and QHCl-best neurons are not relevant to MSG-best neurons. We used multidimensional analysis to arrange the neurons that responded best to Suc, NaCl, HCl, QHCl, and MSG into five loosely arranged and partially overlapping clusters. A multidimensional space based on stimulus similarity showed that MSG was as different from the four basic taste stimuli as they were from one another. 5. Mixture suppression, a common observation in human psychophysical experiments, was examined at the neurophysiological level by including binary tastants in the stimulus battery. The average response of 19 Suc-best neurons to 1.0 M Suc (4.1 spikes/s) decreased to near 0 when the solvent was changed from DW to either 0.03 M MSG or 0.03 M NaCl. Similar decrements were observed in NaCl- and MSG-best neurons tested with Suc/NaCl mixtures.

Animals↗

Incidence and prediction of stone recurrence after lithotripsy in idiopathic calcium stone patients: a multivariate approach.

In order to evaluate the recurrence of calcium kidney stones, 520 patients (275 males and 245 females), aged 14-79 years, previously treated with lithotripsy were followed up for 23 months on average (median = 24 months; range = 12-48 months), and 101 relapses (10%/year) were recorded. Among the possible predictors of recurrence, measured at the beginning of the follow-up and analyzed in univariate and multivariate statistical ways, age was inversely related with occurrence of event (multivariate t value = -2.12) whereas urinary calcium (UC; t = 2.78), alkaline phosphatase (AP; t = 3.55) and history of previous relapses (t = 2.07) were directly related to the recurrence. The levels of UC were not correlated to those of AP (linear correlation coefficient r = 0.0032), but the combination of their high levels increased the risk of recurrences. The contribution of the other considered factors to stone formation were not significant (sex, family history of stone disease, gallstone, renal failure, serum calcium, phosphate, uric acid, sodium and proteins, urinary phosphate, sodium, magnesium and uric acid.

Adolescent↗

[Methodological premises of statistical analysis of the data].

Most psychic disorders, such as anxiety, agitation and dementia are difficult to measure objectively since the scale of measure--psychometric tests--are often liable to subjective judgment--especially of clinicians or patients during self-rating scales. It become therefore necessary to use a complex way of measuring--a battery of tests--from which the results should be analyzed through multivariate statistic models. During this polycentric it was believed suitable to use the repeated multivariate analysis of variance, an instrument largely used in the data analysis of rating scale thanks to the flexibility of the generalized east squares methods. In this article the characteristics of this method and how to read its results will be discussed.

Acetylcarnitine↗

Asteroid hyalosis in an autopsy population: The University of California at Los Angeles (UCLA) experience.

OBJECTIVES: To study the prevalence and associations of asteroid hyalosis (AH) in a series of autopsy eyes. METHODS: Retrospective review of the University of California at Los Angeles (UCLA) autopsy eye database from 1965 to 2000 yielded 10,801 patients. The patients' medical histories were reviewed for evidence of diabetes mellitus, hypertension, hyperlipidemia, alcohol abuse, hypercalcemia, hypothyroidism, and chronic renal failure. Autopsy records were searched for evidence of optic atrophy, macular degeneration, posterior vitreous detachment, atherosclerosis, and chronic renal failure. Asteroid hyalosis was diagnosed by examination of the autopsy eyes. Univariate and multivariate statistical methods were used to analyze our data. RESULTS: The prevalence of AH was 1.96% in this autopsy population. By chi(2) analysis, AH was significantly correlated with age (P<.001), male sex (P = .006), age-related macular degeneration (P = .02), hypertension (P = .03), atherosclerosis (P<.001), and posterior vitreous attachment (P<.001). After adjusting for age in a multivariate logistic regression analysis, statistical significance was found only for posterior vitreous attachment (P = .002) and male sex (P = .046). No statistically significant association was found with diabetes mellitus or alcohol abuse by univariate or multivariate analysis. Analysis of the odds ratio showed a strong age effect that increased from 5.0 (95% confidence interval, 2.2-11.3) in age group 41 to 50 years, compared with 25.4 (95% Wald confidence interval, 8.2-77.9) in the age group of patients older than 90 years. CONCLUSIONS: A unique epidemiological autopsy cohort study of AH and its systemic associations yielded a higher prevalence of AH than previous studies. Asteroid hyalosis was strongly correlated with age and inversely correlated with posterior vitreous detachment. Unlike some previous reports, we found no statistically significant correlation between AH and diabetes mellitus.

Academic Medical Centers↗

[Latex allergy in children with myelomeningocele. Incidence and associated factors].

RATIONALE: The purpose of our work is to know the prevalence of allergies to latex in patients with myelomeningocele (MMC) and to evaluate any potential factors influencing its development. METHODS: The study included 100 children with mean age 7.5 +/- 4.8 years, diagnosed with MMC by skin tests and total and latex-specific IgE determination. The results were compared to those obtained in three "control" groups: atopic patients, patients undergoing their first operation and multi-operated patients. The relationship between the different variables analyzed was assessed using univariant and multivariant statistical studies. RESULTS: 29 were sensitized (15 symptomatic and 14 asymptomatic) and 8 doubtful. Results showed statistically significant (p < 0.05) differences for atopic and first operation groups and non significant differences for the multi-operation group. The multivariant study selected the followed as the most relevant variables: number of surgical interventions, total IgE levels in z units, ventricle-peritoneal by-pass carriers and atopy background. Also in the multivariant study, the following showed statistically significant results: age, Cums' number, inclusion in intermittent catheterism program and total IgE levels. Neither sex or familial background of atopy showed statistical significance. CONCLUSIONS: Allergy to latex in MMC patients is related to multiple antigen contacts, the numerous manipulations and operations undertaken throughout the patient's life plus a personal propensity to allergies. It is essential that this group should adopt certain standards to minimize contact with the antigen and undergo an allergological study so as to detect those who are sensitized, which in nearly half our series has not yet exhibited symptomatology in contact with latex utensils. All diagnostic and therapeutical procedures should be conducted in latex-free environments.

Adolescent↗

Statistical analysis of in vivo tumor growth experiments.

We review and compare statistical methods for the analysis of in vivo tumor growth experiments. The methods most commonly used are deficient in that they have either low power or misleading type I error rates. We propose a set of multivariate statistical modeling methods that correct these problems, illustrating their application with data from a study of the effect of alpha-difluoromethylornithine on growth of the BT-20 human breast tumor in nude mice. All the methods find significant differences between the alpha-difluoromethylornithine dose groups, but recommended sample sizes for a subsequent study are much smaller with the multivariate methods. We conclude that the multivariate methods are preferable and present guidelines for their use.

Animals↗

A statistical model predicting the seizure threshold for right unilateral ECT in 106 patients.

Titration of the electroconvulsive therapy (ECT) stimulus to the patient's convulsive threshold is the only way to directly assess the patient's seizure threshold. This technique is presently practiced by 39% of ECT providers, according to a recent survey. Because multiple variables influence the seizure threshold in patients, multivariate statistical methods may provide a useful strategy to determine which variables exert the most influence on convulsive threshold. A multivariate ordinal logistic model of seizure threshold was developed on an experimental group of 66 consecutive patients undergoing titrated right unilateral (RUL) ECT for major depression. The accuracy of the model was cross-validated on a second group of 40 patients undergoing similar RUL ECT procedures. The final multivariate ordinal logistic regression model for the seizure threshold level (STL) was significant (Likelihood ratio chi 2 = 54.115; p < 0.0001:R2 = 0.313). Increasing age, African-American race, and longer inion-nasion distances (p < 0.06) predicted higher STL. Female gender was associated with a lower STL. The ability of the final model to accurately predict STL for the validation group was fair (pairwise correlation was 0.576; p < 0.001). The model did well for predicting lower STL, but fared poorly for higher STL. In conclusion, modeling STL may help establish the relative contribution of variables thought to be important to seizure threshold. However, STL models remain impractical for clinical applications in estimating seizure threshold at this time, and empirical stimulus titration should be used.

Adult↗

Determinants of the autopsy decision: a statistical analysis.

Our goal was to use cross-sectional national mortality data to provide a multivariable statistical analysis of the factors that contribute to the decision of whether an autopsy will be performed. The identification of determinants of the autopsy is an important prerequisite for finding cost-effective alternatives for arresting or reversing the decline of autopsy rates in the circumstances in which the autopsy can continue to make a crucial contribution to clinical medicine and public health. The source of the data was 1986 National Center for Health Statistics (Washington, DC) mortality data tapes for Kentucky, Maryland, Minnesota, and Washington for the 1986 calendar year. Separate multiple logistic regressions were conducted on these data on a state-by-state basis, with a total of 139,063 individual mortality records as the unit of analysis. The dependent variable in all models was autopsy (yes/no). Odds ratios for selected explanatory variables were estimated for all four states, and the relative contribution of each explanatory variable was studied in a detailed analysis of one state. In general, the following independent variables had a statistically significant positive relationship with whether an autopsy will be performed: male sex; nonwhite ethnicity; death due to ill-defined or unknown cause; death due to accident, suicide, or homicide; presence of a nationally recognized medical center in the county of death; and death occurring in a standard metropolitan statistical area. In general, the following independent variables had a statistically significant negative relationship with whether an autopsy will be performed: older age at death; higher income level of the decedent; death in a nursing home; death at home; and residency in the county of death. The two most important variables influencing the autopsy decision were age at death (especially old age) and death due to accident, homicide, or suicide.

Adolescent↗

Autoantibodies in patients with glaucoma: a comparison of IgG serum antibodies against retinal, optic nerve, and optic nerve head antigens.

PURPOSE: The aim of this study was to analyze and compare the entire IgG autoantibody patterns against different ocular antigens (retina, optic nerve, and optic nerve head) in sera of glaucoma patients and healthy subjects. METHODS: Sixty-six patients were included in this study: healthy volunteers without any ocular disorders (CO, n=30), patients with primary open-angle glaucoma (POAG, n=19), and patients with normal-tension glaucoma (NTG, n=17). The sera were tested for antibodies against retinal, optic nerve, and optic nerve head tissues. Immunodetection was performed using 4-chloro-1-naphthol staining. The autoantibody patterns were digitized and subsequently analyzed by multivariate statistical techniques. RESULTS: All patients showed a complex repertoire of IgG antibodies against retinal, optic nerve, and optic nerve head antigens. The analysis of discriminance revealed a statistically significant differences between the patterns of all three groups. Our multivariate approach could quantify the differences in immunoreactivities of patient sera against the three antigens. The POAG group had the most significant difference against retinal antigens (P=0.0021) compared with the other antigens. In the NTG group the highest reactivity appeared against optic nerve head (P=0.00053) and optic nerve (P=0.0025). CONCLUSIONS: All groups showed different and complex antibody patterns against the three ocular tissues. These autoantibodies are highly specific for each patient group. The analysis of these patterns could provide further information about possible autoimmune mechanisms in the pathogenesis of glaucoma.

Aged↗

Logistic regression models in obstetrics and gynecology literature.

OBJECTIVE: To evaluate the reporting of multivariable logistic regression analyses and assess variations in quality over time in the obstetrics and gynecology literature. METHODS: Methodologic criteria for reporting logistic regression analyses were developed to identify problems affecting accuracy, precision, and interpretation of this approach to multivariable statistical analysis. These criteria were applied to 193 articles that reported multivariable logistic regression in the issues of four generic obstetrics and gynecology journals in 1985, 1990, and 1995. Rates of compliance with the methodologic criteria and their time trends were analyzed. RESULTS: The proportion of articles using logistic regression analysis increased over time: 1.7% in 1985, 2.8% in 1990, and 6.5% in 1995 (P < .001 for trend). Violations and omissions of methodologic criteria for reporting logistic models were common. The research question, in terms of dependent and independent variables, was not clearly reported in 32.1%. The process of variable selection was inadequately described in 51.8% of the articles. Among articles with ranked independent variables, 85.1% did not report assessment of conformity to linear gradient. Tests for goodness of fit were not given in 93.2% of articles. The contribution of the independent variables could not be evaluated in 36.2% of the articles because of a lack of coding of the variables. Interactions between variables were not assessed in 86.4% of articles. Analysis of variations in the quality of logistic regression analyses over time showed no increase in reporting of the criteria concerning variable selection and goodness of fit. However, the proportion of articles reporting one quality criterion concerning interpretation of the substantive significance of independent variables showed a trend toward improvement: 42.3% in 1985, 73.6% in 1990, and 75.4% in 1995 (P = .004 for trend). CONCLUSION: The reporting of multivariable logistic regression models in the obstetrics and gynecology literature is poor, and the time trends of improvement in quality of reporting are not particularly encouraging.

Gynecology↗

An assessment of HIV/AIDS risk in higher education students in Yerevan, Armenia.

Armenia's current sociopolitical and economic instability and the alarming HIV incidence rates in neighboring countries amplify its risk for a national epidemic. The goals of this study were to assess HIV/AIDS knowledge and risk behaviors among higher education students in Yerevan. Knowledge of HIV transmission through sexual intercourse was markedly higher than that on intravenous transmission and prevailing myths; however, HIV/AIDS knowledge was not related to risk behaviors. Tobacco and alcohol prevalence was relatively high. Students reported risky sexual behaviors, including inconsistent condom use, casual sex, and multiple partners. In addition to descriptive statistics delineating gender differences across the target behavioral domains, bivariate and multivariate statistical analyses were used to understand factors that contributed to increased risk, including early age of initiation and the relationship between substance use and risky sexual activity. The study results provide much-needed information for the development of school- and community-based AIDS prevention programs in Armenia.

Acquired Immunodeficiency Syndrome↗

[Grouping of countries according to indicators of standard of living].

The position of 125 countries is studied on the basis of a collection of 26 basic, health, economic and educational indicators. Multivariate statistical methods were used, including Cluster Analysis, Principal Component Analysis and Multivariate Analysis of Variance. The most discriminating variables were life expectancy the child mortality rate, the mortality rate of children of less than five years of age, the birth and fertility rates and the high-school female matriculation rate. The first principal component was interpreted as a measure of the living standard which made it possible to place the countries in order. Five clusters of countries are suggested.

Global Health↗

[Early and late prognosis in acute myocardial infarct. A retrospective study in patients admitted to the coronary care unit in the past 10 years].

The prognostic evaluation of the patient with an acute myocardial infarction is one of the most interesting unanswered problems. This is both because of its complexity and its implications in terms of secondary prevention. Several clinical studies have emphasized the reliability of the prognostic evaluation based on data collected during the first 24 hours. We therefore evaluated the prognostic relevance of 26 variables measured in the coronary care unit in 1914 patients admitted to our Unit as a result of acute myocardial infarction during the past 10 years. Twenty-four patients were lost to follow-up so that the evaluation refers to 1,890 patients, 1,506 of whom are males aged between 22 and 99 years (mean 58.1) and 384 are females aged between 29 and 88 years (mean 67.1); thus there is a greater prevalence of males. The sex-related difference in the age distribution is statistically significant. In-hospital mortality was analyzed using univariate and multivariate statistical methods (chi-squared test, multiple logistic regression analysis). The prognostic relevance of the considered variables in relation to the survival was analysed using the logrank test and using Cox's model. The variables associated with a greater risk of in-hospital death were found to be: age, presence of diabetes, anterior location of the infarct, arterial hypotension at admission, Killip class III and IV and the presence of ventricular tachyarrhithmias. In contrast, smokers had a lower in-hospital death risk. As to mortality during the follow-up, there was an association with age, female sex, pre-existent coronary disease, presence of high heart rate on admission, low peripheral tissue perfusion, x-ray documented pulmonary congestion, supraventricular tachiarrhythmias and intraventricular block. In contrast, the presence of obesity was associated with a reduced death risk during the follow-up. During the follow-up the most frequent cause of death was re-infarction, followed by sudden death, death from non-cardiac causes and heart failure.

Adult↗

Esophagovisceral anastomotic leak. A prospective statistical study of predisposing factors.

An esophagovisceral anastomotic leak is a life-threatening postoperative complication, especially in the mediastinum. Of the 242 patients who underwent intrathoracic esophagogastric anastomosis for esophageal carcinoma (182 patients) and adenocarcinoma of the cardia (60 patients) between January 1980 and June 1985, 14 (5.8%) had esophageal anastomotic leakage and two died (0.8%). Various clinical and biologic parameters and aspects of operative technique were studied prospectively and analyzed statistically to identify possible factors responsible for leaks. Both bivariate and multivariate statistical analysis with logistic regression showed that the following clinical and biologic factors do not influence anastomotic leakage: tumor stage, the curative or palliative purpose of resection, neoplastic permeation of anastomotic margins, total protein concentration below 5 gm/dl, albumin concentration below 3 gm/dl, patient's age, diabetes, high blood pressure, cirrhosis of the liver, and cardiac, respiratory, or renal diseases. Technical factors, on the contrary, were statistically significant and of great clinical importance: manual as opposed to mechanical suturing (chi 2 = 8.8, p = 0.013) and single-layer as opposed to double-layer suturing (chi 2 = 9.9, p = 0.043). The level of the anastomosis was found to be a further statistically significant factor: The incidence of leakage was greater when the anastomosis was located between the azygos vein and the lower pulmonary vein (chi 2 = 15.5, p = 0.004) than above the azygos vein or below the lower pulmonary vein.

Adenocarcinoma↗

[Chronic myeloid leukemia: multivariant analysis of initial findings regarding its effect on mean life expectancy].

Clinical signs, complete blood counts and bone marrow differential counts at the time of diagnosis were investigated in 75 consecutive patients with chronic myelogenous leukemia in a study of prognostic parameters. All patients were followed until death (62 patients) or for a mean follow-up time of 69 months (13 patients). Clinical signs and hematological values were analyzed by univariate and multivariate statistical methods. The only parameter relevant to mean survival time in multivariate analysis is the percentage of bone marrow myeloblasts at diagnosis. Patients with less than 5% myeloblasts at diagnosis had a mean survival time of 48 months compared with 16 months for those with greater than or equal to 5% (p less than 0.01).

Analysis of Variance↗

Incidence and costs of accidents among attention-deficit/hyperactivity disorder patients.

PURPOSE: The purpose is to analyze the incidence and costs of accidents among Attention-Deficit/Hyperactivity Disorder (ADHD) patients. METHODS: The analysis relied on administrative medical, pharmaceutical, and disability claims for a national manufacturer's employees, spouses, dependents, and retirees (n > 100,000). Accidental injuries were identified using ICD-9 codes for injuries or poisoning treatment. ADHD sample consists of individuals with at least one claim for ADHD during 1996-98 (NADHD = 1308), which was compared with a matched control sample. In addition to descriptive statistics, multivariate analysis involving logistic regression was used to model the probability of having an accident claim in 1998. This probability was estimated for the whole population, for adults alone, for children (under age 12 years), and for adolescents (age 12-18 years). We also estimated a generalized estimation equation (GEE) model to account for the possibility of multiple accident claims for a single patient. RESULTS: ADHD patients had a greater probability of having at least one accident claim than their controls for children (28% vs. 18%), adolescents (32% vs. 23%), and adults (38% vs. 18%). Although ADHD patients' costs were greater than their controls for adults ($483 vs. $146), there was no difference for children or adolescents. However, among patients with accident claims, the average number of accident claims was similar for both groups (3.6 vs. 3.5) and costs were not statistically different. The multivariate analysis confirms this utilization pattern: the odds of having an accident for ADHD patients were 1.7 times greater than for controls. CONCLUSIONS: ADHD was a significant predictor of having an accident claim. However, for people with an accident claim, ADHD patients and controls had a similar number of accident claims and costs.

Accidents↗

Theoretical calculation and prediction of intestinal absorption of drugs in humans using MolSurf parametrization and PLS statistics.

A method for modeling and prediction of the intestinal absorption of drugs in humans using theoretically computed molecular descriptors and multivariate statistics has been investigated using 20 diverse drug-like compounds. The program MolSurf was used to compute theoretical molecular descriptors related to physicochemical properties such as lipophilicity, polarity, polarizability and hydrogen bonding. The multivariate Partial Least Squares Projections to Latent Structures (PLS) method was used to delineate the relationship between the intestinal absorption of drugs in humans and the theoretically computed molecular descriptors.Good statistical models were derived. Properties associated with hydrogen bonding had the largest impact on absorption and should be kept to a minimum to promote high absorption. High charge-transfer properties and the presence of surface electrons, i.e. valence electrons, which are not tightly bonded to the molecule, were also found to promote high absorption.

Computer Simulation↗