Technology of dynamic follow-up of patients in an urban polyclinic]

The procedure of follow-up of patients with chronic socially important diseases within an urban outpatient department is a closed cycle of ++medico-technological processes with constant involvement of new population groups. The study of traditional follow-up procedure revealed its inadequate efficiency. It also revealed a strong association between the dynamics of health status and strict observance of follow-up procedure (K = 0.652; p less than 0.05). The realization of the functional model of follow-up procedure suggested by the authors for patients with chronic socially important diseases would allow its efficiency to be increased under conditions of an urban out-patient department.     

Group testing in mediation analysis

We consider the scenario where there is an exposure, multiple biologically defined sets of biomarkers, and an outcome. We propose a new two-step procedure that tests if any of the sets of biomarkers mediate the exposure/outcome relationship, while maintaining a prespecified familywise error rate. The first step of the proposed procedure is a screening step that removes all groups that are unlikely to be strongly associated with both the exposure and the outcome. The second step adapts recent advances in postselection inference to test if there are true mediators in each of the remaining candidate sets. We use simulation to show that this simple two-step procedure has higher statistical power to detect true mediating sets when compared with existing procedures. We then use our two-step procedure to identify a set of Lysine-related metabolites that potentially mediate the known relationship between increased body mass index and the increased risk of estrogen-receptor positive breast cancer in postmenopausal women.     

Experiences with arthrotomy of the knee in day care]

A retrospective study was performed of patients who had undergone an open knee procedure treated as day cases at the Regional Hospital of Zevenaar. An analysis was made of the rate of complications, whether complications were treated adequately, and how patients experienced an arthrotomy of the knee as a day-case procedure. Eighty-seven healthy patients aged 15 to 50 years underwent an arthrotomy of one knee as a day-case procedure, secondary to a diagnostic arthroscopy. The mean follow-up period was 8 months. Patients were reviewed by questionnaire, after which the knee was examined. The number of complications (6) was comparable with those reported in the literature. Complications within a few days after operation were reported to the GPs, who either treated themselves, or referred patients to the hospital. Of the patients 76% preferred this procedure to an operation in a clinical setting. The amount of pain suffered appears to be of great influence on the preference of the patient. The results of this study demonstrate that an arthrotomy of the knee is feasible as a day-care procedure, although extensive pre- and postoperative instructions to the patients may be improved.     

The benefit method: fitting hearing aids in noise

The most common complaint among individuals with hearing impairment is the inability to follow a conversation when several people are talking simultaneously, a noisy listening situation which is completely different from the quiet surrounding of the conventional pure tone audiometry used as basis for the hearing aid settings. The purpose of this report was to present important characteristics of the BeneFit Method (BFM), a procedure that fits the hearing aid under simulated conditions of competing speech and also a clinical pilot evaluation study comparing the BFM to the NAL-R recommendations and also to the Logic procedure, a GN resound proprietary fitting algorithm representing a modern digital hearing aid fitting procedure. Speech recognition scores in noise (SRSN) using monosyllabic words presented under different background noise levels were evaluated on 21 randomly selected subjects with hearing impairment. The subjects were fitted with the same type of hearing aid Danalogic 163D according to the BFM procedure as well as the logic procedure, the latter developed and recommended by the manufacturer. A comparison of the SRSN when using the subjects' current hearing aid fitted according to the NAL-R procedure was also made. Only the BFM procedure provided a significant SRSN improvement compared to the unaided condition (P< 0.01) in a signal/speech-noise level of 75/65 dB corresponding to a normal cocktail party condition. Moreover, patients performed significantly higher SRSN when fitted according to the BFM, than when fitted according the Logic or NAL-R procedures. The BFM procedure, which is based on individual and functional detection of hearing thresholds in noise levels corresponding to a cocktail party condition, can improve SRSN significantly. Hearing aids should be fitted under conditions similar to those when the hearing disability is perceived the most, i.e, in an environment with background noise.     

Dunnett-type inference in the frailty Cox model with covariates

A frequent objective in medical research is the investigation of differences in patient survival between several experimental treatments and one standard treatment. In order to assess these differences statistically, we have to apply adjustments for multiple comparisons to prevent an increased number of false-positive findings. The most prominent procedure of this type is the Bonferroni correction, which maintains the error level but leads to conservative results. On the basis of a general statistical framework for simultaneous inference, we propose a new statistical procedure for many-to-one comparisons of treatments with adjustment for covariates for clustered survival data modeled by a frailty Cox model. In contrast to the Bonferroni method, dependencies between estimated effects are taken into account. The resulting simultaneous confidence intervals for the hazard ratios of the experimental treatments compared with a control can be interpreted in terms of both statistical significance and clinical importance. The quality of the new procedure is judged by the coverage probability for the simultaneous confidence intervals. Simulation results show an acceptable performance in balanced and various unbalanced designs. The practical merits are demonstrated by a reanalysis of a chronic myelogeneous leukemia clinical trial. The procedure presented here works well for multiple comparisons with a control with adjustment for covariates for survival data from multicenter clinical trials.     

On the use of logrank scores in the analysis of litter-matched data on time to tumour appearance

Previously, Mantel and Ciminera introduced an application of the Mantel-Haenszel procedure to litter-matched time-to-tumour data on treated and control animals with a device for recovering 'interlitter information' from non-informative litters. An example is given here to show that the Mantel-Ciminera procedure can confound litter effect and treatment effect; their procedure is shown to produce a large chi-square value on contrived data containing no information on the treatment effect on time to tumour. An alternative procedure is described which completely adjusts for litter effect. This procedure is adaptable to any scoring system. As an illustration, it is carried out with logrank scores to reanalyse the data of Mantel and Ciminera.     

Multiple comparisons with a control in families with both one-sided and two-sided hypotheses

Comparing several treatments with a control is a common objective of clinical studies. However, existing procedures mainly deal with particular families of inferences in which all hypotheses are either one- or two-sided. In this article, we seek to develop a procedure which copes with a more general testing environment in which the family of inferences is composed of a mixture of one- and two-sided hypotheses. The proposed procedure provides a more flexible and powerful tool than the existing method. The superiority of this method is also substantiated by a simulation study of average power. Selected critical values are tabulated for the implementation of the proposed procedure. Finally, we provide an illustrative example with sample data extracted from a medical experiment.     

Test for qualitative interaction in equivalence trials when the number of centres is large

We propose a generalized testing procedure to test for qualitative interaction in equivalence trails when the number of centres is large. The proposed testing procedure allows for an adaptable definition of qualitative interaction that can take into account the total number of centres. A tuning parameter k (k > or = 0) is introduced to quantify qualitative interaction. The testing procedure is proposed for equivalence trials with symmetric or asymmetric margins. In addition to the test procedure, we also provide explicit formulae for the power calculation. The proposed test is relatively easy to implement using any statistical software. Examples for detecting qualitative interaction are given to illustrate the method.     

A survival-adjusted quantal-response test for analysis of tumor incidence rates in animal carcinogenicity studies

In rodent cancer bioassays, groups of animals are exposed to different doses of a chemical of interest and followed for tumor occurrence. The resulting tumor rates are commonly analyzed using a survival-adjusted Cochran-Armitage (CA) trend test. The CA trend test has reasonable power when the tumor-response curve is linear in dose, but it may be underpowered for a nonlinear response. An alternative survival-adjusted test procedure based on isotonic regression methodology has previously been proposed. Although this alternative procedure performs well when the tumor response is nonlinear in dose, it has less power than the CA trend test when the response is linear in dose. Here, we introduce a new survival-adjusted test procedure that makes use of both the CA trend test and the isotonic regression-based trend test. Using a broad range of experimental conditions typical of National Toxicology Program (NTP) bioassays, we conducted extensive computer simulations to compare the false-positive error rate and power of the proposed procedure with the survival-adjusted CA trend test. The new procedure competes well with the survival-adjusted CA trend test when observed tumor rates are linear in dose and performs substantially better when observed tumor rates are nonlinear in dose. Further, the proposed trend test almost always has a smaller false-positive rate than does the survival-adjusted CA trend test. We also developed an order-restricted inference-based procedure for performing multiple pairwise comparisons between each of the dose groups and the control group. The trend test and the multiple pairwise comparisons test are demonstrated using an example from a study conducted by the NTP.     

Justice and Solidarity in Priority Setting in Health Care

During the last decade a "technical" approach has become increasingly influential in health care priority setting. The various country reports illustrate, however; that non-technical considerations cannot be avoided. As they often remain implicit in health care package decisions, this paper aims to make these normative judgements an explicit part of the procedure. More specifically, it aims to integrate different models of distributive justice as well as the principle of solidarity in four different phases of a decision-making procedure, and to identify important moral choices which present themselves. First four important justice models are discussed, then a justification is given for their inclusion in a four-step decision making procedure. This is followed by a discussion of different justice and solidarity problems--with their inherent conceptual difficulties in each of these stages. The paper concludes with a summary of the major moral choices that are to be made in health care package decisions.     

Tympanometry in middle ear disease.

Tympanometry is an objective procedure which can aid in the identification of middle ear disease and eustachian tube dysfunction. This paper reviews its rationale, operation, and applications. The test procedure is simple and can be performed by trained personnel. The test is valid and reliable and can be used with children without discomfort. The results of tympanometry are quantifiable, recordable, and easy to interpret. The routine use of tympanometry in the family physician's office would offer a valuable tool in the identification and management of middle ear problems.     

Reliability and credibility of an angoff standard setting procedure in progress testing using recent graduates as judges

INTRODUCTION: Progress testing is an assessment method that samples the complete domain of knowledge that is considered pertinent to undergraduate medical education. Because of the comprehensive nature of this test, it is very difficult to set a passing score. We obtained a progress test standard using an Angoff procedure with recent graduates as judges. This paper reports on the reliability and credibility of this approach. METHODS: The Angoff procedure was applied to a sample of 146 progress test items. The items were judged by a panel of eight recently graduated students. Generalizability theory was used to investigate the reliability as a function of the number of items and judges. Credibility was judged by comparing the pass/fail rates resulting from the standard arrived at by the Angoff procedure with those obtained using a relative and a fixed standard. RESULTS: The results indicate that an acceptable error score can be achieved, yielding a precision within one percentage on the scoring scale, by using 10 judges on a full-length progress test (i.e. 250 items). The pass/fail rates associated with the Angoff standard came closest to those of the relative standard, which takes variations in test difficulty into account. A high correlation was found between item-Angoff estimates and the item P-values. CONCLUSION: The results of this study suggest that the Angoff procedure, using recently graduated students as judges, is an appropriate standard setting method for a progress test.     

Parametric variable selection in generalized partially linear models with an application to assess condom use by HIV-infected patients

To study significant predictors of condom use in HIV-infected adults, we propose the use of generalized partially linear models and develop a variable selection procedure incorporating a least squares approximation. Local polynomial regression and spline smoothing techniques are used to estimate the baseline nonparametric function. The asymptotic normality of the resulting estimate is established. We further demonstrate that, with the proper choice of the penalty functions and the regularization parameter, the resulting estimate performs as well as an oracle procedure. Finite sample performance of the proposed inference procedure is assessed by Monte Carlo simulation studies. An application to assess condom use by HIV-infected patients gains some interesting results, which cannot be obtained when an ordinary logistic model is used.     

Blinded continuous information monitoring of recurrent event endpoints with time trends in clinical trials

Blinded sample size re-estimation and information monitoring based on blinded data has been suggested to mitigate risks due to planning uncertainties regarding nuisance parameters. Motivated by a randomized controlled trial in pediatric multiple sclerosis (MS), a continuous monitoring procedure for overdispersed count data was proposed recently. However, this procedure assumed constant event rates, an assumption often not met in practice. Here we extend the procedure to accommodate time trends in the event rates considering two blinded approaches: (a) the mixture approach modeling the number of events by a mixture of two negative binomial distributions and (b) the lumping approach approximating the marginal distribution of the event counts by a negative binomial distribution. Through simulations the operating characteristics of the proposed procedures are investigated under decreasing event rates. We find that the type I error rate is not inflated relevantly by either of the monitoring procedures, with the exception of strong time dependencies where the procedure assuming constant rates exhibits some inflation. Furthermore, the procedure accommodating time trends has generally favorable power properties compared with the procedure based on constant rates which stops often too late. The proposed method is illustrated by the clinical trial in pediatric MS.     

The use of the artificial kidney in the treatment of uremia

Summary Certain of the uremic states respond with gratifying clinical improvement to dialysis with the artificial kidney. In acute renal insufficiency, the procedure, if properly employed, may be a valuable adjunct to conservative management and occasionally in acute spontaneous potassium intoxication have a distinct advantage over other methods of treatment. The chronic uremic patient whose debility is due primarily to retention of metabolite may improve dramatically though temporarily following the procedure. Where the clinical situation is not in large part due to these derangements, hemodialysis should be expected to have very little effect upon the clinical course. In any consideration of the benefits to be achieved by this procedure, an understanding of the lack of indication and the contraindications are of utmost importance. Presented at The Stated Meeting of The New York Academy of Medicine, December 6, 1951.     

Bias of two one-sided tests procedures in assessment of bioequivalence

The current applications of Schuirmann's two one-sided tests procedure for the original scale ignore the variability of the least squares mean of the reference formulation when it substitutes for the unknown reference average of pharmacokinetic responses. We propose a modified two one-sided tests procedure that takes into account the variability of the least squares mean of the reference formulation. The non-parametric version of the modified procedure is also available. We conducted a simulation study to examine the true level of significance and empirical power of four current parametric and non-parametric two one-sided tests procedures under a 2 × 2 crossover design with different combinations of sample size, intrasubject variability, and correlation between the two responses from a subject. Both theoretical results and empirical evidence show that the true level of significance of the current two one-sided tests procedures converges to 0·5 when the correlation of the two responses approaches 1. However, not only is the modified two one-sided tests procedure a test of size α, but empirical evidence indicates it is also an unbiased test. The modified non-parametric procedure also controls the size of the tests and is competitive even under normality assumption.     

Protein homeostasis in chronic hemodialysis patients

PURPOSE OF REVIEW: Nutritional status is an important predictor of clinical outcome in chronic hemodialysis patients, as uremic malnutrition is strongly associated with an increased risk of death and hospitalization events. Decreased muscle mass is the most significant predictor of morbidity and mortality in these patients. Several factors that influence protein metabolism predispose chronic hemodialysis patients to increased catabolism and the loss of lean body mass. The purpose of this review is to discuss recent advances in the understanding of abnormalities in protein homeostasis in chronic hemodialysis patients. RECENT FINDINGS: It has long been suspected that the hemodialysis procedure is a net catabolic event. Recent studies have indeed shown that the hemodialysis procedure induces a net protein catabolic state at the whole-body level as well as in skeletal muscle. There is evidence to suggest that these undesirable effects are caused by decreased protein synthesis and increased proteolysis. The provision of nutrients, either in the form of intradialytic parenteral nutrition or oral feeding during hemodialysis, can adequately compensate the catabolic effects of the hemodialysis procedure. Whereas the mechanisms of these effects have not been studied in detail, changes in extracellular amino acid concentrations and certain anabolic hormones such as insulin are important mediators of these actions. SUMMARY: There is now indisputable evidence to suggest that the hemodialysis procedure leads to a highly catabolic state. Despite this, chronic hemodialysis patients can still achieve anabolism when given adequate protein supplementation to meet the metabolic requirements of hemodialysis, and when adequate insulin is present.     

A visual graphic/haptic rendering model for hysteroscopic procedures

Hysteroscopy is an extensively popular option in evaluating and treating women with infertility. The procedure utilises an endoscope, inserted through the vagina and cervix to examine the intra-uterine cavity via a monitor. The difficulty of hysteroscopy from the surgeon's perspective is the visual spatial perception of interpreting 3D images on a 2D monitor, and the associated psychomotor skills in overcoming the fulcrum-effect. Despite the widespread use of this procedure, current qualified hysteroscopy surgeons have not been trained the fundamentals through an organised curriculum. The emergence of virtual reality as an educational tool for this procedure, and for other endoscopic procedures, has undoubtedly raised interests. The ultimate objective is for the inclusion of virtual reality training as a mandatory component for gynaecologic endoscopy training. Part of this process involves the design of a simulator, encompassing the technical difficulties and complications associated with the procedure. The proposed research examines fundamental hysteroscopy factors, current training and accreditation, and proposes a hysteroscopic simulator design that is suitable for educating and training.     

A permutation test sensitive to differences in areas for comparing ROC curves from a paired design

The area under the receiver operating characteristic (ROC) curve (AUC) is a widely accepted summary index of the overall performance of diagnostic procedures and the difference between AUCs is often used when comparing two diagnostic systems. We developed an exact non-parametric statistical procedure for comparing two ROC curves in paired design settings. The test which is based on all permutations of the subject specific rank ratings is formally a test for equality of ROC curves that is sensitive to the alternatives of AUC difference. The operating characteristics of the proposed test were evaluated using extensive simulations over a wide range of parameters.The proposed procedure can be easily implemented in experimental ROC data sets. For small samples and for underlying parameters that are common in experimental studies in diagnostic imaging the test possesses good operating characteristics and is more powerful than the conventional non-parametric procedure for AUC comparisons.We also derived an asymptotic version of the test which uses an exact estimate of the variance in the permutation space and provides a good approximation even when the sample sizes are small. This asymptotic procedure is a simple and precise approximation to the exact test and is useful for large sample sizes where the exact test may be computationally burdensome.