Psychopharmacological characterisation of the successive negative contrast effect in rats.

RATIONALE: Successive negative contrast (SNC) describes a change in the behaviour of an animal following a downshift in the quantitative or qualitative value of an expected reward. This behavioural response has been hypothesised to be linked to affective state, with negative states associated with larger and/or prolonged shifts in behaviour. OBJECTIVE: This study has investigated whether different psychopharmacological treatments have dissociable actions on the SNC effect in rats and related these findings to their actions on different neurotransmitter systems and affective state. METHODS: Animals were trained to perform a nose-poke response to obtain a high-value food reward (four pellets). SNC was quantified during devalue sessions in which the reward was reduced to one pellet. Using a within-subject study design, the effects of acute treatment with anxiolytic, anxiogenic, antidepressant and dopaminergic drugs were investigated during both baseline (four pellets) or devalue sessions (one pellet). RESULTS: The indirect dopamine agonist, amphetamine, attenuated the SNC effect whilst the D1/D2 antagonist, alpha-flupenthixol, potentiated it. The antidepressant citalopram, anxiolytic buspirone and anxiogenic FG7142 had no specific effects on SNC, although FG7142 induced general impairments at higher doses. The α2-adrenoceptor antagonist, yohimbine, increased premature responding but had no specific effect on SNC. Results for the anxiolytic diazepam were mixed with one group showing an attenuation of the SNC effect whilst the other showed no effect. CONCLUSIONS: These data suggest that the SNC effect is mediated, at least in part, by dopamine signalling. The SNC effect may also be attenuated by benzodiazepine anxiolytics.

Children's responses to overt and relational aggression.

Investigated children's responses for coping with overt and relational aggression. Children in Grades 3 through 6 (N = 491) in a rural Midwestern public school district completed a survey designed to assess how students cope when they are the targets of peer aggression. Children endorsed greater use of internalizing and distancing strategies for coping with relational aggression and greater use of externalizing strategies for coping with overt aggression. In addition, older children reported greater use of externalizing and less use of internalizing and distancing strategies than younger children. Significant differences were also found between boys and girls. Regardless of type of aggression, girls endorsed greater use of problem-solving and support strategies and less use of externalizing strategies than boys. Coping of high target children and of children who frequently received prosocial treatment from peers were also examined.

The cost-effectiveness of magnetic resonance imaging for patients with equivocal neurological symptoms.

OBJECTIVE: To determine the incremental cost-effectiveness of magnetic resonance imaging (MRI) and computed tomography (CT) in young adults presenting with equivocal neurological signs and symptoms. DESIGNS AND METHODS: A decision analysis of long-term survival using accuracy data from a diagnostic technology assessment of MRI and CT in patients with suspected multiple sclerosis, information from the medical literature, and clinical assumptions. MAIN RESULTS: In the baseline analysis, at 30% likelihood of an underlying neurologic disease, MRI use has an incremental cost of $101,670 for each additional quality-adjusted life-year saved compared with $20,290 for CT use. As the probability of disease increases, further MRI use becomes a cost-effective alternative costing $30,000 for each quality-adjusted life-year saved. If a negative MRI result provides reassurance, the incremental costs of immediate MRI use decreases and falls below $25,000 for each quality-adjusted life-year saved no matter the likelihood of disease. CONCLUSIONS: For most individuals with neurological symptoms or signs, CT imaging is cost-effective while MR imaging is not. The cost-effectiveness of MRI use, however, improves as the likelihood of an underlying neurological disease increases. For selected patients who highly value diagnostic information, MRI is a reasonable and cost-effective use of medical resources when even the likelihood of disease is quite low (5%).

Good technologies gone bad: how and why the cost-effectiveness of a medical intervention changes for different populations.

Cost-effectiveness (CE) ratios vary considerably, not only across interventions, but within single interventions. Using a simple decision-tree model of the treat-vs no-treat decision to organize the analysis, four potential errors leading to these within-treatment differences in CE ratios are identified. These errors arise from estimates relating to 1) prior probabilities of disease; 2) treatment efficacies; 3) costs of treatment; and 4) patient preferences. Systematic biases, where present, suggest overuse of medical interventions. For diagnostic tests, two additional potential sources of error are considered (using a simple decision tree incorporating both test and treat decisions). These involve 5) sensitivity and specificity of the diagnostic test and 6) inappropriate choice of "cutoff" to determine abnormal patients, in part arising from errors in estimating prior probability of disease.

Economic foundations of cost-effectiveness analysis.

To address controversies in the applications of cost-effectiveness analysis, we investigate the principles underlying the technique and discuss the implications for the evaluation of medical interventions. Using a standard von Neumann-Morgenstern utility framework, we show how a cost-effectiveness criterion can be derived to guide resource allocation decisions, and how it varies with age, gender, income level, and risk aversion. Although cost-effectiveness analysis can be a useful and powerful tool for resource allocation decisions, a uniform cost-effectiveness criterion that is applied to a heterogeneous population level is unlikely to yield Pareto-optimal resource allocations.

Perspectives in health economics.

This paper, originally presented at the Institute d'Etudes Politiques de Paris, October 12, 1993, provides a perspective on envisioned changes in the practice of health economics. Foreseen changes include: (1) Study of more homogeneous units of analysis; (2) More original data gathering; (3) Increased attention to uncertainty and the supply of and demand for information; (4) Increased attention to institutional structures and their effects on economic behaviour; (5) Expansion of relevant tools for studying economic issues in health care; and (6) Continuing breakdown of disciplinary barriers between health economics and other disciplines. Of these, the two overriding features will be increased emphasis on understanding the many roles of uncertainty in economic behaviour, institutions, and outcomes in health care, and in the use of more and more 'micro' data to study these issues.

Estimating diagnostic test accuracy using a "fuzzy gold standard".

This study uses Monte Carlo methods to analyze the consequences of having a criterion standard ("gold standard") that contains some error when analyzing the accuracy of a diagnostic test using ROC curves. Two phenomena emerge: 1) When diagnostic test errors are statistically independent from inaccurate ("fuzzy") gold standard (FGS) errors, estimated test accuracy declines. 2) When the test and the FGS have statistically dependent errors, test accuracy can become overstated. Two methods are proposed to eliminate the first of these errors, exploring the risk of exacerbating the second. Both require a probabilistic (rather than binary) gold-standard statement (e.g., probability that each case is abnormal). The more promising of these, the "two-truth" method, selectively eliminates those cases where the gold standard is most ambiguous (probability near 0.5). When diagnostic test and FGS errors are independent, this approach can eliminate much of the downward bias caused by FGS error, without meaningful risk of overstating test accuracy. When the test and FGS have dependent errors, the resultant upward bias can cause test accuracy to be overstated, in the most extreme cases, even before the offsetting "two-truth" approach is employed.

Cost-effectiveness of screening for hereditary hemochromatosis.

BACKGROUND: Recent studies have estimated the prevalence of hereditary hemochromatosis to be 3 to 8 per 1000. Early detection and treatment can prevent disease manifestations and normalize life expectancy. We used decision analysis techniques to determine whether screening the population at large for hereditary hemochromatosis would be cost-effective. METHODS: We constructed a model to compare the cost and outcome of a strategy of performing screening transferrin saturation tests on cohorts of 30-year old men with that of awaiting symptomatic disease. Baseline estimates of disease prevalence and complication rates were based on the published literature. Costs of treatment were estimated based on prevailing local costs. Sensitivity analyses were then conducted to determine which variables had the most significant impact on the decision to screen. RESULTS: At our baseline estimates, the decision to screen was found to be a dominant strategy and resulted in cost saving. Sensitivity analysis showed that four variables had the most significant impact on the decision to screen: (1) the prevalence of hereditary hemochromatosis, (2) the probability of developing disease manifestations, (3) the cost of the screening test, and (4) the discount rate. Screening was a dominant strategy for asymptomatic men provided that the prevalence of hereditary hemochromatosis was at least 3 per 1000, the probability of developing disease manifestations was greater than 0.4, the test cost was less than $12, and the discount rate was less than 3%. Using more pessimistic estimates, the cost per life year saved was still less than that considered acceptable for many common medical interventions. CONCLUSION: Screening for hereditary hemochromatosis has a favorable cost-effectiveness ratio over a wide range of assumptions. We recommend that practitioners consider including a serum transferrin saturation test in their routine screening for asymptomatic white men.

The value of diagnostic information to patients with suspected multiple sclerosis. Rochester-Toronto MRI Study Group.

OBJECTIVE: To determine the value of diagnostic information to patients with suspected multiple sclerosis (MS). Because treatment choices would be only minimally affected by earlier diagnosis for most patients with this clinical problem, this study assessed the "nondecisional" value of diagnosis. DESIGN: Prospective survey of patients before and after diagnostic workup, including imaging with magnetic resonance scanning. We assessed the effect of diagnostic information on patients' sense of well-being, as well as direct measures of the utility of information (using time trade-off and willingness-to-pay techniques). SETTING: Patients referred from primary care practices for diagnostic workup for suspected MS to neurology clinics and practices. PATIENTS: Sixty-eight individuals, mean age 37.5 years, 53 female and 15 male. Thirty-one patients were classified as having "probable MS," and 37 were classified as having "possible MS" by the examining neurologist before workup. MEASUREMENTS: Present and future health perception, uncertainty about diagnosis-prognosis, and level of anxiety. Willingness to pay for diagnostic information, quality of life as measured by the time trade-off technique, and psychological state of the patient before and after diagnosis. RESULTS: Diagnostic uncertainty fell significantly as a result of the diagnostic workup. Most patients (59/62) said that they were better off having received diagnostic information. Although anxiety seemed to be reduced by testing, overall anxiety levels did not decrease as much as anticipated. Patients also became less optimistic about their future health after testing. On average, patients were willing to forgo 4.5 quality-adjusted life days to receive an earlier diagnosis and their quality of life after diagnosis improved slightly. Subgroups of patients differed in their response to diagnostic information. Those in whom no definitive diagnosis emerged tend to be more anxious rather than being reassured by the "negative" workup. Individuals with "positive" workups became less anxious and expressed favorable feelings about the diagnostic workup even though they often faced a chronic disease. CONCLUSIONS: Overall, the diagnostic workup seemed to benefit patients and improve their sense of well-being. However, whether the effects were beneficial or not depended on the results of the diagnostic workup itself. In clinical practice the decision to undergo testing in situations in which definitive treatment is unavailable should be individualized. The potential for negative as well as positive consequences should be recognized.

Cystic fibrosis carrier screening: knowledge and attitudes of prenatal care providers.

We are conducting a trial of population carrier screening for cystic fibrosis (CF), targeting pregnant and nonpregnant patients of prenatal care providers. We first enlisted providers by presenting a description of the trial to the obstetrical staffs of the five Rochester, New York, hospitals having delivery services. Of the 124 prenatal care providers (111 obstetricians and 13 family practitioners) with delivery privileges at the five hospitals, only 81 (65%) attended one of our presentations. Providers who attended lacked knowledge about CF screening and counseling and expressed divergent attitudes about prenatal diagnosis for carrier women having test-negative partners. Of the 79 providers completing an attitude questionnaire, 68 (86%) were willing to offer carrier screening to all their patients if educational materials, testing, and counseling were all provided without charge. After visiting participating physicians' offices to orient their staff, we reached two additional conclusions. First, in considering whether to offer CF carrier screening to their patients, prenatal care providers are less concerned about imperfect test sensitivity, false reassurance of those testing negative, or discrimination against those testing positive than about time required to answer patients' questions if they screen and about legal liability if they do not. Second, some providers are more resistant to offering screening to nonpregnant patients than to pregnant patients, not because they believe that the timing is less appropriate, but because nonpregnant patients do not routinely receive an advance mailing, have phlebotomy, or return for follow-up. Our experience raises concerns about the willingness and capability of prenatal care providers to translate advances in molecular medicine into prenatal screening services.

The accuracy of magnetic resonance imaging in patients with suspected multiple sclerosis. The Rochester-Toronto Magnetic Resonance Imaging Study Group.

OBJECTIVE: To design and implement a methodologically rigorous study to examine the accuracy of magnetic resonance imaging (MRI) in a patient population clinically suspected of having multiple sclerosis (MS). DESIGN AND SETTING: Three hundred three patients, who were referred to two university medical centers because of the suspicion of MS, underwent MRI of the head and double-dose, contrast-enhanced computed tomography (CT) of the head. The images were read by two observers individually and without knowledge of the clinical course or final diagnosis. Patients were followed up for at least 6 months and reevaluated clinically with subsequent neurological examination. Final diagnosis (MS or not MS) was made by a panel of neurologists on the basis of the clinical findings at presentation, those that developed during follow-up, and other diagnostic tests. The results of the imaging procedures were excluded to avoid incorporation bias. Diagnostic accuracy was assessed using receiver-operating characteristic analysis and likelihood ratios. RESULTS: Magnetic resonance imaging of the head was considerably more accurate than CT in diagnosing MS. The area under the receiver-operating characteristic curve for MS was 0.82 (compared with 0.52 for CT) indicating that MRI was a good but not definitively accurate test for MS. A "definite MS" reading on an MRI of the head was specific for MS (likelihood ratio, 24.9) and essentially established the diagnosis, especially in patients clinically designated as "probable MS" before testing. However, MRI of the head was negative for MS in 25% and equivocal in 40% of the patients considered to have MS by the diagnostic review committee (sensitivity, 58%). CONCLUSIONS: Magnetic resonance imaging of the head provided assistance in the diagnosis of MS when lesions were visualized. Its ability far exceeded imaging with double-contrast CT. The sensitivity and, therefore, the predictive value of a negative MRI result for MS were, however, not sufficiently high for a normal MRI to be used to conclusively exclude the diagnosis of MS.

The association between interdisciplinary collaboration and patient outcomes in a medical intensive care unit.

We prospectively studied the relationship between interdisciplinary collaboration and patient outcomes in the medical intensive care unit (MICU) using nurses' and residents' reports of amount of collaboration involved in making decisions about transferring patients from the MICU to a unit with a less intense level of care. Either readmission to the MICU or death was considered a negative patient outcome. Nurses' reports of collaboration were significantly (p = 0.02) and positively associated with patient outcome, controlling for severity of illness. Patient predicted risk of negative outcome decreased from 16%, when the nurse reported no collaboration in decision making, to 5% when the process was fully collaborative. There was an interaction of collaboration with availability of alternative choices in the transfer decision-making situation. When alternatives were available, collaboration was more strongly associated with patient outcome. There was no significant relationship between residents' reports of collaboration and patient outcomes. The correlation between amount of collaboration reported by nurses and residents about the same decisions was quite low (r = 0.10).

On the (near) equivalence of cost-effectiveness and cost-benefit analyses.

Many people believe that cost-effectiveness (CE) and cost-benefit (CB) analyses require different assumptions. However, when CE analysis supports decisions to use medical resources, it makes the same assumptions that CB analysis requires. They are mathematically equivalent. Differences between CE and CB hinge more on reporting style than on fundamental assumptions.