The effect of dropout on the efficiency of D-optimal designs of linear mixed models.

Dropout is often encountered in longitudinal data. Optimal designs will usually not remain optimal in the presence of dropout. In this paper, we study D-optimal designs for linear mixed models where dropout is encountered. Moreover, we estimate the efficiency loss in cases where a D-optimal design for complete data is chosen instead of that for data with dropout. Two types of monotonically decreasing response probability functions are investigated to describe dropout. Our results show that the location of D-optimal design points for the dropout case will shift with respect to that for the complete and uncorrelated data case. Owing to this shift, the information collected at the D-optimal design points for the complete data case does not correspond to the smallest variance. We show that the size of the displacement of the time points depends on the linear mixed model and that the efficiency loss is moderate.

Local influence to detect influential data structures for generalized linear mixed models.

This article discusses the generalization of the local influence measures for normally distributed responses to local influence measures for generalized linear models with random effects. For these models, it is shown that the subject-oriented influence measure is a special case of the proposed observation-oriented influence measure. A two-step diagnostic procedure is proposed. The first step is to search for influential subjects. A search for influential observations is proposed as the second step. An illustration of a two-treatment, multiple-period crossover trial demonstrates the practical importance of the detection of influential observations in addition to the detection of influential subjects.

[Roaming through methodology. XXI. How to arrive at a weighed total score of separate items of a questionnaire]. / Dwalingen in de methodologie. XXI. Hoe te komen tot een gewogen totaalscore van afzonderlijke scores op een vragenlijst.

In medical research the responses of patients to a number of items are often combined into a summary measure or total score for a more general patient characteristic, such as mobility. Clinical and statistical criteria exist for determining the weight of each question in the total score. The choice of weights may affect the differences between patients. The total score is often analysed statistically as if it had interval level of measurement, thereby allowing conclusions about the size of differences between patients, but it has merely an ordinal level. The incorrectness of the interval assumption may also affect differences between patients or patient groups. Finally, differences between patients are less dependent on the weighting of the items and on the assumption of an interval scale as the total score is based on more homogeneous items. Standard statistical software contains statistical methods for determining the homogeneity as well as the weights.

Detection of microemboli in patients with artificial heart valves using transcranial Doppler: preliminary observations.

Embolic events, particularly involving the central nervous system, represent one of the important hazards associated with the implantation of mechanical valves. The use of the transcranial Doppler to insonate the middle cerebral artery has allowed us to detect microembolic events in some of these patients. Patients with long term implantation and frequent microemboli appear to be more prone to transient ischemic attacks or stroke. Evaluation of 26 patients with mechanical valves revealed 14 with detectable microemboli, four of whom experienced central nervous system symptoms. Modifications in the medical or anticoagulant regimes have not been successful in decreasing or eliminating these microemboli. As the transcranial Doppler is a non-invasive means of quantifying these microemboli, it may become a useful tool in identifying those patients in need of a new type of antithrombotic regimen, or even a valve replacement. Transcranial Doppler could thus provide advance warning before a catastrophic cerebral embolism occurs.

A novel randomized iterative strategy for aligning multiple protein sequences.

The rigorous alignment of multiple protein sequences becomes impractical even with a modest number of sequences, since computer memory and time requirements increase as the product of the lengths of the sequences. We have devised a strategy to approach such an optimal alignment, which modifies the intensive computer storage and time requirements of dynamic programming. Our algorithm randomly divides a group of unaligned sequences into two subgroups, between which an optimal alignment is then obtained by a Needleman-Wunsch style of algorithm. Our algorithm uses a matrix with dimensions corresponding to the lengths of the two aligned sequence subgroups. The pairwise alignment process is repeated using different random divisions of the whole group into two subgroups. Compared with the rigorous approach of solving the n-dimensional lattice by dynamic programming, our iterative algorithm results in alignments that match or are close to the optimal solution, on a limited set of test problems. We have implemented this algorithm in a computer program that runs on the IBM PC class of machines, together with a user-friendly environment for interactively selecting sequences or groups of sequences to be aligned either simultaneously or progressively.

A pharmacodynamic approach to optimizing insulin therapy.

We have developed a program for simulation and optimization of insulin therapy in patients with insulin-dependent diabetes. The program, denoted GLUCOJECT, is based on a physiologic model of minimal complexity, which describes the pharmacokinetics of absorption and clearance of subcutaneous insulin and the dynamics of glucose utilization as dependent on both prevailing glucose and insulin levels. With self-monitored glucose values and insulin doses collected with one of several commercially available memory meters, GLUCOJECT reconstructs an average or 'typical' daily plasma glucose and insulin profile and displays them in a graph. The program then calculates the expected rate of glucose utilization, which permits calculation of the rate of glucose entry into plasma from both endogenous (hepatic) and exogenous (dietary) sources. In turn, this allows one to calculate an 'ideal' plasma insulin profile required to maintain a relatively constant 'ideal' plasma glucose level. GLUCOJECT can evaluate several different insulin regimens involving various combinations of short-, intermediate- and long-acting insulins, and select the one(s) most closely approximating the ideal or optimal insulin profile, using a least-squares criterion. For any optimized insulin regimen, GLUCOJECT calculates and displays the predicted time course of plasma glucose. These features make the program attractive as an educational tool for both patients and health care professionals and could potentially assist in the management of patients with insulin-dependent diabetes.

Empirical Comparison Between Factor Analysis and Multidimensional Item Response Models.

Many factor analysis and multidimensional item response models for dichotomous variables have been proposed in literature. The models and various methods for estimating the item parameters are reviewed briefly. In a simulation study these methods are compared with respect to their estimates of the item parameters both in terms of an item response theory formulation and in terms of a factor analysis formulation. It is concluded that for multidimensional data a common factor analysis on the matrix of tetrachoric correlations performs at least as well as the theoretically appropriate multidimensional item response models.

Combining statistical, rule-based, and physiologic model-based methods to assist in the management of diabetes mellitus.

Self-monitoring of capillary blood glucose is used by most patients with insulin-dependent diabetes mellitus as a means of assessing metabolic control. Therapeutic interventions are based on retrospective analysis of glycemic response to various factors, with insulin and diet playing the key roles. We describe a computer system being developed for intelligent automated analysis and interpretation of data relevant to glycemic control. CADMO (Computer-Assisted Diabetes Monitor) is intended to assist health care professionals with the management of patients with insulin-dependent diabetes. It takes as input glucose values and insulin doses collected via a memory meter by the patient over a period of several weeks. Rule-based logic, statistical methods, and a physiologic model of insulin pharmacokinetics and glucose dynamics are used to help detect meaningful patterns and trends in glucose and insulin data and to suggest approaches for optimizing insulin regimens.

Chromosomes in Ewing's sarcoma. I. An evaluation of 85 cases of remarkable consistency of t(11;22)(q24;q12).

Since our initial reports on chromosomal studies in eight Ewing's sarcomas (ES), we have carried out similar investigations on 23 additional ES specimens following short-term culture of tumor cells (16 cases), and established in vitro cell lines (three cases) and on xenografted tumors in nude mice (four cases). We demonstrated the presence of the reciprocal t(11;22)(q24;q12) in every case except one that exhibited a complex t(11;22;14)(q24;q12;q11). On the basis of results from these additional 23 cases, we confirm the consistency of the t(11;22)(q24;q12) in ES. Moreover, we reviewed 54 ES cases reported by other investigators; when added to our 31 cases, this brings the total number to 85 unrelated cases of ES available for an evaluation of the frequency of involvement of bands 11q24 and 22q12 in translocations in ES. The standard t(11;22)(q24;q12) proved to be a remarkably consistent event, present in 83% of the cases. Five percent of the cases exhibited complex translocations involving a third chromosome in addition to chromosomes #11 and #22. In 4% of the cases variant translocations involved 22q12 but with a chromosome(s) other than #11. The breakpoint on chromosome 22q12 appears to be the most consistently observed event in 92% of the cases, whereas, the breakpoint at chromosome 11q24 was observed in 88% of the cases.

Effects of disodium cromoglycate and beclomethasone dipropionate on the asthmatic response to allergen challenge I. Immediate response (IAR).

This study deals with comparative investigation of the protective effects of disodium cromoglycate (DSCG, Lomudal, Intal) and beclomethasone dipropionate aerosol (BDA, Aldecin, Becotide, Beclovent) on 103 immediate asthmatic responses (IARs) to allergen challenge recorded in 103 patients with an allergic bronchial asthma. Disodium cromoglycate demonstrated highly significant protective effects on the IAR in patients investigated (P less than .01). The protective effects of BDA on the IAR were found to be non-significant (P greater than .01). It is suggested that DSCG should be the first choice in controlling allergic bronchial asthma when the immediate asthmatic response to allergen plays the predominant role.

The immediate asthmatic response to allergen challenge.

One hundred and three bronchial asthma patients with a suspected allergic component developed 133 positive immediate asthmatic (bronchus-obstructive) responses (IARs) to bronchial challenge with allergen (BP). The onset of IAR was within 10 minutes, the maximum within 45 minutes, and the resolution of the response within 120 minutes after the challenge. All IARs were highly significant in comparison with the control test (p less than .01). The association of IAR with other diagnostic parameters was the following: positive disease history in 82 IAR cases (= 62%); positive immediate skin response in 91 IAR cases (= 68%); increased total serum IgE in 54 IAR cases (= 41%); positive specific IgE in the serum in 59 IAR cases (= 44%); increased serum concentration of IgG in 36 IAR cases (= 27%), of IgM in 17 (= 13%), and of IgA in 3 IAR cases (= 2%); increased blood eosinophilia in 36 (= 27%) and blood leukocytosis in 19 IAR cases (= 14%); increased bronchial reactivity to histamine in 74 of 103 patients with IAR (= 72%); body temperature increased during nine IAR cases (= 7%); and 131 IAR cases (= 98%) were accompanied by bronchial and 62 (= 47%) by general malaise complaints. The IAR showed a very good reproducibility and significant dose-response relationship (P less than .01). In conclusion, the IAR is an important diagnostic parameter for the allergic component due to immediate hypersensitivity in the bronchial tree. The correlation of other diagnostic parameters with IAR was not satisfactory. They should therefore be regarded as diagnostic supplement only.(ABSTRACT TRUNCATED AT 250 WORDS)

Movement related slow potentials. II. A contrast between finger and foot movements in left-handed subjects.

Finger and foot movement related potentials (MRPs) were recorded over the frontal, central and parietal areas of both hemispheres in 20 left-handed subjects. A unilateral flexion of the index finger and a plantar flexion of the foot were studied on either side. MRPs were larger preceding foot movements than preceding finger movements, their onset being earlier also. Prior to a finger flexion amplitudes were larger over the hemisphere contralateral to the movement than over the ipsilateral hemisphere. Preceding a foot movement, however, amplitudes were larger over the ipsilateral hemisphere. These results indicate differently localized sources of the MRPs in the two kinds of movement, in accordance with data obtained in right-handed subjects. No indication of a hemisphere effect, possibly related to motor dominance, was found in left-handers. This is in contrast to a slight hemisphere effect found with foot movements in right-handed subjects in the former study.

Chromosome study of Ewing's sarcoma (ES) cell lines. Consistency of a reciprocal translocation t(11;22)(q24;q12).

A detailed banded chromosome analysis was performed in five established Ewing's sarcoma (ES) cell lines originating from four unrelated patients in relapse. Of various numerical and structural abnormalities, a reciprocal translocation between chromosomes #11 and #22, t(11;22)(q24;q12), was observed in four of the lines. The t(11;22) was seen in every cell in three lines; in the fourth, it was seen in only 21% of the cells considered stemline, but the der(22) was present in the remaining 79% of cells. These results suggest that t(11;22)(q24;q12) is a chromosomal change specific to ES cells, in which the rearrangement of chromosome #22 could be the consistent karyotypic feature and the crucial step in terms of cell proliferation. Other, nonrandom chromosomal changes were found: monosomies 2p11----2pter, 10q25----10qter, and 17pter----17q11, and partial trisomies 1q21----1q31 and 8q24.1----8q24.2. The role of the therapeutic regimen received by these patients must be evaluated with regard to the formation of a wide variety of homogeneously staining regions, which were observed in every cell line, particularly on the short arm of chromosome #7, which was observed in three of the five cell lines.

[Chromosomal translocation (11; 22) in cell lines of Ewing's sarcoma]. / Translocation chromosomique (11; 22) dans des lignées cellulaires de sarcomes d'Ewing.

Chromosome studies were performed on 5 Ewing sarcoma cell lines. An identical reciprocal translocation t(11; 22) (q24; q12) was found in 4 cell lines established from 3 different tumors. These results, associated with those obtained at the same time and independently from fresh tumor cells, suggest that the translocation t(11; 22)(q24; q12) may be a chromosomal marker characteristic of Ewing sarcoma cells. This translocation involves the chromosome 22 on which the H-c-sis oncogene has been located; it could be used as a new tool for exploring the role of genetic transposition in the malignant cell transformation.

On Covariance Adjustment In The Analysis Of Time-Structured Data.

Covariance adjustment in the analysis of time-structured data may increase the efficiency of the estimates. The selection of an adequate set of covariates depends on the pattern of the unknown population covariance matrix, and Grizzle and Allen (1969) and Rao (1966) proposed selection on the basis of the correlations between the variates and covariates. This article uses heuristic arguments to propose a measure for covariate selection and demonstrates its effectiveness using data given by Grizzle and Allen and data generated from a population with a simplex and a circumplex covariance pattern.

Congenital bladder diverticula in adult twins.

We present two cases of apparent congenital bladder diverticula in adult twins associated with progressive hearing loss.

Pathophysiologic mechanisms of hydrocephalus.

Hydrocephalus is caused by a disequilibrium of forces at the ventricular-cerebral interface and may be progressive either due to a continued disequilibrium of forces or due to continued progressive periventricular ischemic injury. Treatment is indicated in all patients with progressive neurological deficit associated with progressive ventricular enlargement. Whenever possible, treatment should be directed toward the cause of the hydrocephalus (e.g., removal of tumors obstructing CSF flow) or the specifically abnormal force vector (e.g., shunting for increased intraventricular pulse waves due to an ectatic basilar artery). When it is not possible to treat the cause or the specifically abnormal force vector, treatment should be guided by the basic mechanisms--reduction of the intraventricular force (Fo), augmentation of the inward brain force (Fi), and improvement of nutrition and oxygenation of ischemic periventricular tissue.