Disease-modifying agents in the Sonya Slifka Longitudinal Multiple Sclerosis Study.

BACKGROUND: Although experts recommend that people with multiple sclerosis (MS) should begin treatment with disease-modifying agents (DMAs) as soon as possible after diagnosis and continue indefinitely, many do not use these agents or discontinue them prematurely. Since DMAs reduce relapse rates and slow disease progression, and since even benign relapses and course can lead to axonal damage and permanent neurologic impairment, it is important that all appropriate candidates have access to treatment. We used a population-based sample of people with MS to determine rates, predictors, and reasons for use, non-use, and discontinuation of DMAs. METHODS: We collected data from 2156 people with MS on their use of and experience with DMAs. We used chi-squared tests to compare current, past, and never users of any DMA and ever users of individual DMAs, and logistic regression to identify predictors of use. RESULTS: One-half of the participants were using a DMA at the time of the interview; 12.2% had used previously, but stopped. Reasons for never using and reasons for stopping were at odds with expert recommendations. Characterization of users, and of their experiences by type of DMA, was consistent with current knowledge of these agents. Seeing a neurologist for usual MS care was an important factor in starting and persisting with DMA therapy. CONCLUSIONS: Dissemination of expert opinion about, and management strategies for, use of DMAs to non-neurologic professionals and patients and their families might help more people who are appropriate candidates for DMA therapy to start and continue treatment.

Access to and utilization of neurologists by people with multiple sclerosis.

OBJECTIVE: This study examined access to and use of neurologists among a broad, national sample of people with multiple sclerosis (MS); identified demographic, economic, and clinical factors associated with access and use; and examined differences in treatment and management of MS. METHODS: We used computer-assisted telephone interviews to collect data from 2,156 people with MS on demographics, disease characteristics, and use of neurologists, other specialists, and disease-modifying agents (DMAs). We used chi(2) tests and logistic regressions to compare patients of neurologists and other providers and identify predictor variables and treatment factors associated with seeing neurologists. RESULTS: For their usual MS care, 72.2% of participants saw a neurologist. The probability of seeing a neurologist was significantly lower for people who lacked health insurance, were poor, lived in rural areas, or were African American; had been ill for more than 15 years; had difficulty walking but did not use an assistive device; or required a wheelchair/scooter or were confined to bed. People who reported one to two relapses in the preceding year and women were significantly more likely to see neurologists. Patients of neurologists were significantly more likely to take a DMA, attend an outpatient rehabilitation program, or see an occupational therapist, urologist, or physical therapist. CONCLUSIONS: People with multiple sclerosis who see neurologists are more likely than people who see other providers to receive treatment with disease-modifying agents and see rehabilitation specialists and urologists. While some people may choose other providers, economic, insurance, racial, and geographic factors appear to limit access to neurologists.

Access to health care for people with multiple sclerosis.

The Sonya Slifka Longitudinal Multiple Sclerosis (MS) Study follows a population-based cohort of approximately 2000 people with MS to study demographic and clinical characteristics, use and cost of health services, provider and treatment characteristics, neurological, economic, and psychosocial outcomes. We examined key indicators of access to health care and found that the majority of participants had health insurance, a usual source of care, and access to specialty care. Nevertheless, 3.8% did not have health insurance which, with application of sampling weights, corresponds to approximately 7000 people with MS in the US population. Even with insurance, population-based estimates indicated that substantial numbers of people with MS have plans that pay nothing toward prescription medication, limit their access to specialists, and restrict their choice of hospitals and providers. Some 9% of the sample, corresponding to 15,800 people with MS, did not have a usual source of MS care; 11.8% or 17,300 people did not have a usual source of general health care; and 31% or 57,400 people did not see the specialists that they or their physicians wanted them to see. Further, 10.5% or 19,400 people reported difficulty obtaining prescription medication, 4.1% or 7600 people encountered obstacles accessing medical care, and 2.4% or 4500 people could not obtain the mental health services they needed. Finally, out-of-pocket health care expenditures were twice those found for the general population. Two-thirds of study participants (representing almost 70,000 people) chose their MS care providers because they were neurologists or MS specialists, creating a demand that almost certainly exceeds current supply.

The Sonya Slifka Longitudinal Multiple Sclerosis Study: methods and sample characteristics.

The Sonya Slifka Longitudinal Multiple Sclerosis Study follows a population-based cohort of approximately 2000 people with multiple sclerosis (MS) to study demographic and clinical characteristics, course of illness, utilization and cost of health services, provider characteristics, use of MS specialists and disease modifying agents, and neurologic, economic and psychosocial outcomes. This report describes the study methodology, presents baseline demographic and clinical data, and evaluates the representativeness of the sample. A stratified random sample of persons with established and recently-diagnosed MS selected from the National Multiple Sclerosis Society (NMSS) mailing lists was supplemented with recently-diagnosed patients recruited through systematic nationwide outreach. Baseline data were collected by computer-assisted telephone interviews derived from standardized instruments; data collection continues at six-month intervals. The cohort was comparable to population-based and clinical samples with respect to demographics, course, relapse rate, symptoms, and severity of disability. Almost two-thirds of the cohort needed help with activities of daily living, three-quarters were limited in work or other activities, and half had emotional problems that compromised quality of life. The Slifka Study cohort is broadly representative of the MS population and the database can be used to address questions not answered by natural history studies, clinical databases, or population-based surveys.

Overview of the sampling design and statistical methods used in the National Immunization Survey.

Abstract: The National Immunization Survey (NIS) is a large federally funded survey designed to estimate vaccination coverage rates for children residing in the United States aged 19 to 35 months. In 1999, over 8 million telephone call attempts were made to obtain provider-reported vaccination histories on 22,521 children in the age range of interest.

An empirical Bayes approach to estimating the relation of mortality to exposure to particulate matter.

As part of its assessment of the health risks associated with exposure to particulate matter (PM), the U.S. Environmental Protection Agency analyzed the risks associated with current levels, and the risk reductions that might be achieved by attainment of alternative PM standards, in two locations in the United States, Philadelphia, and Los Angeles. The concentration-response function describing the relation between a health endpoint and ambient PM concentrations is an important component, and a source of substantial uncertainty, in such risk analyses. In the absence of location-specific estimates, the concentration-response functions necessary for risk assessments in Philadelphia and Los Angeles must be inferred from the available information in other locations. Although the functional form of the concentration-response relations is assumed to be the same everywhere, the value of the PM coefficient in that function may vary from one location to another. Under this model, a distribution describes the probability that the PM coefficient in a randomly selected location will lie in any range of interest. An empirical Bayes estimation technique was used to improve the estimation of location-specific concentration-response functions relating mortality to short-term exposure to particles of aerodynamic diameter less than or equal to 2.5 microm (PM-2.5), for which functions have previously been estimated in several locations. The empirical Bayes-adjusted parameter values and their SEs were used to derive an estimate of the distribution of PM-2.5 coefficients for mortality associated with short-term exposures. From this distribution, distributions of relative risks corresponding to different specified changes in PM-2.5 concentrations could be derived.

Meta-analysis of multiple outcomes by regression with random effects.

Earlier work showed how to perform fixed-effects meta-analysis of studies or trials when each provides results on more than one outcome per patient and these multiple outcomes are correlated. That fixed-effects generalized-least-squares approach analyzes the multiple outcomes jointly within a single model, and it can include covariates, such as duration of therapy or quality of trial, that may explain observed heterogeneity of results among the trials. Sometimes the covariates explain all the heterogeneity, and the fixed-effects regression model is appropriate. However, unexplained heterogeneity may often remain, even after taking into account known or suspected covariates. Because fixed-effects models do not make allowance for this remaining unexplained heterogeneity, the potential exists for bias in estimated coefficients, standard errors and p-values. We propose two random-effects approaches for the regression meta-analysis of multiple correlated outcomes. We compare their use with fixed-effects models and with separate-outcomes models in a meta-analysis of periodontal clinical trials. A simulation study shows the advantages of the random-effects approach. These methods also facilitate meta-analysis of trials that compare more than two treatments.

Cancer incidence and mortality: the priority of screening frequency and population coverage.

In addition to the usual measures of screening-test performance, it is important to consider testing frequency when evaluating a screening program. Data on which to base recommendations for the timing of screening tests are urgently needed. For example, in the cases of cervical and colon cancer, when the target is a precursor lesion, research indicates that less frequent screening may be appropriate. This finding may not apply, however, to screening for breast cancer by mammography, which requires currently recommended intervals for the early detection of malignancies. Resources now allocated to breast cancer might more effectively be applied to the construction of tests that would permit longer intervals between screenings. To achieve the National Cancer Institute's goal of reducing cancer mortality in the United States by the year 2000, it will be important to review the balance between population coverage and individual screening for each cancer and to emphasize prevention strategies that maximize population coverage while minimizing expenditures.

Simple robust procedures for combining risk differences in sets of 2 x 2 tables.

Meta-analyses often use a random-effects model to incorporate unexplained heterogeneity of study results. Trimmed versions of meta-analytic estimators for the risk difference, adapted from procedures designed for a random-effects analysis, can resist the impact of a few anomalous studies. A simulation study compared untrimmed and trimmed versions of four meta-analytic procedures that give weighted averages of risk differences. An adaptation of Winsorized estimates of components of variance gains some resistance to anomalous studies when estimating variability. The simulations found that a modified version of the DerSimonian-Laird estimator is attractive when risk differences reveal the added variability described by a random-effects model, and that a 20 per cent trimmed, weighted version of this procedure offers resistance against the impact of highly anomalous results. Among four trimmed procedures considered, the trimmed version of the modified DerSimonian-Laird estimator offers the best performance over a wide range of simulation designs and sample sizes. None of the methods, whether trimmed or untrimmed, is uniformly preferable. A published meta-analysis of a vaccination against TB provides data that serve to illustrate differences among the eight procedures.

Multiple-outcome meta-analysis of clinical trials.

When several clinical trials report multiple outcomes, meta-analyses ordinarily analyse each outcome separately. Instead, by applying generalized-least-squares (GLS) regression, Raudenbush et al. showed how to analyse the multiple outcomes jointly in a single model. A variant of their GLS approach, discussed here, can incorporate correlations among the outcomes within treatment groups and thus provide more accurate estimates. Also, it facilitates adjustment for covariates. In our approach, each study need not report all outcomes nor evaluate all treatments. For example, a meta-analysis may evaluate two or more treatments (one 'treatment' may be a control) and include all randomized controlled trials that report on any subset (of one or more) of the treatments of interest. The analysis omits other treatments that these trials evaluated but that are not of interest to the meta-analyst. In the proposed fixed-effects GLS regression model, study-level and treatment-arm-level covariates may be predictors of one or more of the outcomes. An analysis of rheumatoid arthritis data from trials of second-line drug treatments (used after initial standard therapies prove unsatisfactory for a patient) motivates and applies the method. Data from 44 randomized controlled trials were used to evaluate the effectiveness of injectable gold and auranofin on the three outcomes tender joint count, grip strength, and erythrocyte sedimentation rate. The covariates in the regression model were quality and duration of trial and baseline measures of the patients' disease severity and disease activity in each trial. The meta-analysis found that gold was significantly more effective than auranofin on all three treatment outcomes. For all estimated coefficients, the multiple-outcomes model produced moderate changes in their values and slightly smaller standard errors, to the three separate outcome models.

Multiple-outcomes meta-analysis of treatments for periodontal disease.

The results of periodontal therapy vary by disease severity, outcome measure, and method of data analysis. Several clinical trials and a subsequent meta-analysis have demonstrated that, for teeth with severe disease, surgery decreases probing depth (PD) and increases attachment level (AL) more than non-surgical treatment. For other disease levels, the choice of therapy depends on the outcome measure. When clinical trials use two or more outcome measures (such as PD and AL), investigators ordinarily analyze each outcome separately. When the correlations are incorporated among the outcomes, a meta-analysis can use generalized-least-squares (GLS) regression to analyze multiple outcomes jointly. We applied the GLS multiple-outcomes model in a meta-analysis of 5 trials comparing surgical and non-surgical periodontal treatments, each assessing the outcomes PD and AL one year after treatment. The clinical conclusions are similar to those reported earlier, but our estimates of the relative benefits of surgical and non-surgical treatment should be more accurate, because the GLS method takes into account correlation between AL and PD. When correlations between the two outcomes rise, as they do with increasing severity of disease, the GLS estimates depart from those derived from separate analyses of PD and AL.

A random-effects regression model for meta-analysis.

Many meta-analyses use a random-effects model to account for heterogeneity among study results, beyond the variation associated with fixed effects. A random-effects regression approach for the synthesis of 2 x 2 tables allows the inclusion of covariates that may explain heterogeneity. A simulation study found that the random-effects regression method performs well in the context of a meta-analysis of the efficacy of a vaccine for the prevention of tuberculosis, where certain factors are thought to modify vaccine efficacy. A smoothed estimator of the within-study variances produced less bias in the estimated regression coefficients. The method provided very good power for detecting a non-zero intercept term (representing overall treatment efficacy) but low power for detecting a weak covariate in a meta-analysis of 10 studies. We illustrate the model by exploring the relationship between vaccine efficacy and one factor thought to modify efficacy. The model also applies to the meta-analysis of continuous outcomes when covariates are present.

Can a survey influence quality of care in nursing homes? The impact of the New York Quality Assurance System on resident deterioration and adverse outcomes.

Data from a standardized administrative form, the Patient Review Instrument, were used to evaluate whether the New York Quality Assurance System (NYQAS) had an impact on deterioration in functional status or on the incidence of adverse outcomes among residents in New York's nursing homes. The NYQUAS approach evaluated nursing homes by using "triggers" suggestive of deficient quality of care. A random sample of nursing home facilities was selected from data encompassing 2 years before and 2 years after the implementation of NYQAS in 1988. Growth curve analysis and logistic regression were used to assess the influence of NYQAS on deterioration and on the probability of developing decubitus ulcers or contractures, or of being mechanically restrained. The functional status of most residents did not change significantly over time. After allowing statistically for differences in the resource needs of residents within the facilities, the implementation of NYQAS was associated with decreased deterioration in toileting and/or transferring, depending on the site of care. NYQAS was not associated with changes in incidence rates of decubitus, contractures, or the use of mechanical restraints.

Revising a display of multidimensional laboratory measurements to improve accuracy of perception.

To display multidimensional laboratory measurements, Hoeke et al. (1991) proposed a technique that uses plotting axes radiating from a point, assigns each test to a separate axis, and links the test results with line segments. A special nonlinear scaling ensures that a patient whose results all fall in the normal range is represented by a regular polygon of middle size, and colored zones emphasize more serious departures from the normal range. Results of research in graphical perception, however, point to potential difficulties in clinical applications. Those results also suggest a revision of the display that should overcome the difficulties. The new version plots the test results on parallel horizontal lines and links the points for adjacent tests by line segments, while retaining the special scaling and the colored bands.

The effect of selective drainage positions on oxygen saturation in obese patients after upper abdominal surgery.

The obese patients undergoing upper abdominal surgery are at particularly high risk to develop postoperative pulmonary complications, and hypoxemia is one of the most common ones reported. During the initial postoperative period, they are often advised to maintain a semi-sitting position to optimize oxygenation. Although chest physical therapy usually avoids a Trendelenburg position, no published data indicate this position as being able to induce desaturation in obese patients following upper abdominal surgery. We studied fifteen adult obese patients without cardiopulmonary disease undergoing upper abdominal surgery. All patients were tested for 5 minutes during the first 3 postoperative days in each of 3 positions: semi-sitting, bed-flat lateral decubitus, and 15 degrees of Trendelenburg lateral decubitus positions. A statistically significant difference in oxygen saturation related to position was found only on the first postoperative day between semi-sitting and bed-flat lateral decubitus positions. The difference in mean SaO2 value between these 2 positions, however, was only 0.88%; and no significant correlation between the magnitude of obesity and the mean SaO2 difference was found. Although arterial oxygen saturation demonstrated statistically significant daily improvement during the first 3 postoperative days, the mean SaO2 values for any 2 consecutive days differed by less than 0.78%. Thus, in obese patients following upper abdominal surgery, 15 degrees of Trendelenburg lateral decubitus and bed-flat lateral decubitus positions do not induce clinically significant desaturation and can be used if necessary and appropriate. In obese patients with borderline oxygenation, supplemental oxygen used postoperatively can maintain adequate oxygenation and allow aggressive positioning.

Leukotrienes, thromboxane A2, and prostaglandins during systemic anaphylaxis in sheep.

We investigated the roles of eicosanoid mediators in acute systemic anaphylaxis in anesthetized sheep. Sheep were sensitized with dinitrophenylated Ascaris suum extract and were challenged with an intravenous injection of dinitrophenylated bovine serum albumin. During anaphylaxis, cyclooxygenase inhibitors eliminated the elevation of arterial plasma levels of thromboxane B2 and 6-ketoprostaglandin F 1 alpha but markedly elevated the levels of leukotriene E4 in lung lymph without significantly eliminating elevation of plasma levels of histamine. Most of the measured physiological abnormalities accompanying anaphylaxis were aggravated by cyclooxygenase blockade. Enhancement of this anaphylactic mediator response was associated with an accentuated and prolonged increase of airway pressure (P less than 0.05, compared with sensitized, antigen-challenged but otherwise untreated sheep), a more intense hypoxemia (P less than 0.0001), and leukopenia (P less than 0.001), changes that were largely eliminated by pretreating with the sulfidopeptide leukotriene (SPLT) antagonist FPL 55712, suggesting that the SPLTs were important mediators of these responses. In contrast, the prolonged, but less severe, systemic vascular collapse and the reduced pulmonary hypertension induced by cyclooxygenase inhibitors were not influenced by the SPLT antagonist. These results demonstrate that in sheep cyclooxygenase metabolites are mainly involved in the acute, but transient, systemic and pulmonary vascular response of systemic anaphylaxis, whereas SPLTs are primarily implicated in the airway and secondary cardiovascular response. SPLT may act either directly or by potentiating the release of and reactivity to histamine and other mediators. Our data therefore suggest that a combination of cyclooxygenase and lipoxygenase inhibition will be necessary to more effectively protect against the consequences of an anaphylactic reaction.

Oxygenated cardioplegia: the metabolic and functional effects of glucose and insulin.

Reports differ as to the efficacy of glucose and insulin as cardioplegic additives. Although deliberate oxygenation of crystalloid cardioplegic solutions improves myocardial protection, little is known about the protection afforded by glucose and insulin in such oxygenated solutions. In the isolated working rat heart, we studied the addition of oxygen, glucose, and insulin, separately and together, to a cardioplegic solution. The solution was equilibrated with O2 or N2, with glucose added as a substrate or sucrose as a nonmetabolizable osmotic control, with or without insulin. Hearts were arrested for 2 hours at 8 degrees C by multidose infusions. Oxygenation decreased lactate production and improved high-energy phosphate and glycogen preservation during arrest, prevented ischemic contracture, and improved functional recovery. The addition of glucose to the oxygenated solution increased the level of adenosine triphosphate at end-arrest from 10.5 +/- 0.5 to 13.9 +/- 0.6 nmol/mg dry weight and glycogen stores from 18.7 +/- 2.5 to 35.7 +/- 5.5 nmol/mg dry weight. The further addition of insulin did not better preserve these metabolites. Improvements in functional recovery due to glucose or insulin in the oxygenated solution attained statistical significance when both additives were included. Glucose increased lactate production significantly only when the solution was nitrogenated. Insulin added to the nitrogenated glucose-containing solution increased adenosine triphosphate and glycogen levels after 1 hour of arrest; and, although insulin did not prevent ischemic contracture from developing during the latter part of arrest with profound depletion of these metabolites, functional recovery was improved. The mechanism of improved functional recovery by insulin is not clear.(ABSTRACT TRUNCATED AT 250 WORDS)

A brief introduction to influence diagnostics in regression.

Statistical analyses that involve regression methods often encounter data in which some observations have substantial influence. This article presents a nontechnical discussion of influence and of two techniques, based on leaving out each individual observation in turn, for diagnosing influential data. An example illustrates the techniques in an analysis of recurrence rates in endoscopic treatment of bleeding peptic ulcers.

An empirical study of the possible relation of treatment differences to quality scores in controlled randomized clinical trials.

Meta-analytic investigations sometimes use assessments of research quality according to a formal protocol as a tool for improving research synthesis. We asked whether a particular quality scoring system could have a direct use in adjusting the summary estimates of a treatment difference. In an empirical study of the relation of quality scores to treatment differences in published meta-analyses of 7 groups of controlled randomized clinical trials comprising 107 primary studies, we found no relation between treatment difference and overall quality score. We also found no relation between quality score and variation in treatment difference. The level of quality scores has increased at a rate of 9% per decade for three decades, averaging 0.51 on a scale of 0 to 1 for the 1980s, and leaving much room for improvement. Nevertheless, attention to quality of studies by editors, reviewers, and authors may be raising both the level of research done and quality of the reports.

Pulmonary vascular responses to hypercalcemia and hypocalcemia in the dog.

The pulmonary artery responses in the isolated whole-blood perfused canine lung to ionized calcium ([Ca++]) were quantified over a range of hypercalcemia and hypocalcemia values ([Ca++] = 0.23-1.88 mM) under conditions of controlled pulmonary blood flow and constant mean aortic and left atrial pressures. Calcium chloride, administered as bolus doses in the clinical range (5-15 mg.kg-1) at initial normocalcemia and without interventions producing vasoconstriction did not influence mean pulmonary artery pressure at constant pulmonary blood flow. Stable hypercalcemia ([Ca++] = 1.88 +/- 0.05 mM) did not influence the slope of the pulmonary artery pressure-flow plot. Because normal pulmonary vasomotor tone is low and cannot readily be lowered further, the possible vasodilator action of hypocalcemia was assessed by its ability to decrease the slope of the mean pulmonary artery pressure-flow plot, which had been first increased by alveolar hypoxia (AHX) or infusion of the prostaglandin endoperoxide analog U46619 (PG). During AHX (n = 5), a graded reduction from normocalcemia ([Ca++] = 1.08 +/- 0.02 mM) to moderate hypocalcemia ([Ca++] = 0.8 and 0.5 mM) did not alter the pulmonary artery pressure-flow plot, but severe hypocalcemia ([Ca++] = 0.26 +/- 0.01 mM) decreased the slope by 13 +/- 0.9 mmHg.l-1.min-1. The comparison of severe hypocalcemia ([Ca++] = 0.23-0.27 mM) versus a high dose of nifedipine (bolus of 10 micrograms/kg followed by continuous infusion at 40 micrograms.kg-1.h-1) on pulmonary vascular tone increased by either AHX or PG infusion indicated that both hypocalcemia and nifedipine decreased the slope of the relationship between mean pulmonary artery pressure and flow (during AHX: -16.1 +/- 1.38 and -23.3 +/- 1.73 mmHg.l-1.min-1, both P = 0.0001 vs. AHX alone, and during PG: -17.05 +/- 1.95 and -8.4 +/- 1.78 mmHg.l-1.min-1, P = 0.0001 vs. PG alone). Two principal conclusions emerge. First, the pulmonary vessels are minimally sensitive to changes in ionized calcium throughout the clinical hypercalcemia and hypocalcemia ranges; extreme hypocalcemia is required to produce vasodilation, which was reversed with calcium infusion. Second, whereas the pulmonary vasodilator effects of extreme hypocalcemia were independent of the intervention inducing pulmonary vasoconstriction (AHX vs. PG), those of nifedipine were much more pronounced with AHX.