Bias and prevalence effects on kappa viewed in terms of sensitivity and specificity.

Paradoxical effects of bias and prevalence on the kappa coefficient are examined using the concepts of sensitivity and specificity. Results that appear paradoxical when viewed as a 2 x 2 table of frequencies do not appear paradoxical when viewed as a pair of sensitivity and specificity measures where each observer is treated as a predictor of the other observer. An adjusted kappa value can be obtained from these sensitivity/specificity measures but simulation studies indicate that it would result in substantial overestimation of reliability when bias or prevalence effects are observed. It is suggested that investigators concentrate on obtaining populations with trait prevalence near 50% rather than searching for statistical indices to rescue or excuse inefficient experiments.

Interexaminer reliability of the palpation of trigger points in the trunk and lower limb muscles.

OBJECTIVES: To determine the interexaminer reliability of palpation of three characteristics of trigger points (taut band, local twitch response, and referred pain) in patients with subacute low back pain, to determine whether training in palpation would improve reliability, and whether there was a difference between the physiatric and chiropractic physicians. DESIGN: Reliability study. SETTING: Whittier Health Campus, Los Angeles College of Chiropractic. PARTICIPANTS: Twenty-six nonsymptomatic individuals and 26 individuals with subacute low back pain. INTERVENTION: Twenty muscles per individual were first palpated by an expert and then randomly by four physician examiners. MAIN OUTCOME MEASURES: Palpation findings. RESULTS: Kappa scores for palpation of taut bands, local twitch responses, and referred pain were .215, .123, and .342, respectively, between the expert and the trained examiners, and .050, .118, and .326, respectively, between the expert and the untrained examiners. Kappa scores for agreement for palpation of taut bands, twitch responses, and referred pain were .108, -.001, and .435, respectively, among the nonexpert, trained examiners, and -.019, .022, and .320, respectively, among the nonexpert, untrained examiners. CONCLUSIONS: Among nonexpert physicians, physiatric or chiropractic, trigger point palpation is not reliable for detecting taut band and local twitch response, and only marginally reliable for referred pain after training.

Sample size calculations when outcomes will be compared with an historical control.

The usual formulae for calculating sample size are not valid when a treated cohort will be compared with an historical control population. Methods appropriate for a single group study may greatly underestimate the required sample size because they, in effect, assume a control population of infinite size. Methods appropriate for a two-group study require specification of the proportions of patients in the two groups--a requirement that can not be met when the size of the historical control group is fixed. An easily programmed iterative solution is presented and simulations indicating the validity of the method are performed.

Reduction of serum lactate by sodium dichloroacetate, and human pharmacokinetic-pharmacodynamic relationships.

Sodium dichloroacetate (DCA) or placebo, two infusions 30 min in duration and 8 h apart, was administered to healthy subjects under double-blind conditions. The objectives were to characterize accurately the tolerability of DCA, its pharmacokinetics, and the reduction of resting serum lactate concentration by DCA. A hybrid, one-compartment pharmacokinetic model fitted best, with zero-order elimination mean of 27.9 micrograms/ml/h at concentrations above about 80 to 120 micrograms/ml, and with first-order elimination (mean kelim = 0.54) at lower serum concentrations of DCA. Resting serum lactate was dose-independently, maximally reduced within 15 min of the end of all active infusions. The duration of suppression of resting serum lactate was dose-dependent, from 4.5 h (30 mg/kg) to > 8 h (100 mg/kg). Second infusions (15-50 mg/kg) again promptly and maximally reduced resting serum lactate. Hysteresis loops were asymmetrical for all doses but exhibited change in shape that was dose-dependent; no good pharmacokinetic-pharmacodynamic model could be fitted that was consistent between doses. Infusions were well tolerated, 100 mg/kg + 50 mg/kg being the highest doses. Somnolence, the only dose-related adverse event, was reported by 3 of 37 subjects at times corresponding to the highest serum DCA concentrations. This study demonstrates the tolerability of i.v. DCA, proposes a simple pharmacokinetic model for its elimination, characterizes the dose-response relationship in terms of time course of effect, shows the dissociation between elimination of DCA and offset of response and will guide further studies of DCA in patients with head injury or stroke.

Exact power calculations when the dependent variable is a single proportion and the number of events is small.

This paper presents methods for calculating the exact power to reject the null hypothesis that an observed event rate is significantly lower than a clinically relevant alternative event rate or that the confidence interval is less than a specified range when the hypothesis will be tested using exact binomial confidence intervals. SAS programs that perform the calculations are presented and the results are compared with power calculations using the normal approximation. The method can be extended to studies involving paired comparisons but, in that case, it does not appear to provide a significant advantage over normal approximation methods.

Logistic equations in the analysis of S-shaped curves.

A version of the logistic equation that provides useful descriptive parameters for the asymptote, slope and inflection point of the curve is presented and is suggested for use in empirically fitting S-shaped curves to data. A short SAS program that easily calculates the parameter values is shown.

Management of hymenoptera sting anaphylaxis: a preventive medicine survey.

The evaluation of aftercare instructions given to patients suffering from hymenoptera sting anaphylaxis was the objective of the study. Part of this evaluation included asking the physicians questions to examine the knowledge on which they based their aftercare instructions. Survey questionnaires were completed by 124 of 174 (71%) physicians who worked in an emergency department or urgent care center. Fifty-eight percent of the physicians never provided written avoidance instructions, 24% provided or prescribed anaphylaxis ID bracelets, 44% referred all of their patients to an allergist for further evaluation, and 73% reported prescribing an Epi-pen or Ana-kit to all hymenoptera sting anaphylaxis victims. Twenty-four percent of physicians did not know where to obtain anaphylaxis identification bracelets. This survey demonstrates that a substantial number of physicians practicing emergency medicine are not providing appropriate aftercare instructions to patients, and substantiates the need for educational efforts to increase the awareness of physicians concerning the implications of hymenoptera allergy and the value of proper preventive measures.

Balancing allocation of subjects in biomedical research: a minimization strategy based on ranks.

A new method for ensuring the comparability of groups of experimental subjects is proposed. All subjects are ranked on each measured pretreatment variable and differences between groups in the means and the standard deviations of these ranks are minimized by systematically exchanging subjects when those exchanges yield less imbalance between groups. This method was designed for small studies in which pretreatment data from all subjects are known before the start of the experiment. A series of computer simulations suggests that this procedure is effective in balancing groups on several variables although the amount of computer time required becomes excessive as the number of subjects is increased.

Medical registers as historical controls: analysis of an open clinical trial of inosiplex in subacute sclerosing panencephalitis.

Clinical trials of treatments for rare or fatal diseases must often use historical rather than randomized concurrent controls. Randomized trials may not be possible if (1) the number of patients available is quite small, (2) ethical considerations discourage the assignment of patients to control treatments known to be ineffective or (3) some evidence suggests that the proposed new treatment is substantially more effective than the control. We suggest that, when randomization is not feasible, adequately maintained medical registers can serve as a source of control patients. Investigators must pay careful attention to prognostic factors that might bias the results. However, statistical techniques for controlling such bias exist and, if these are properly employed, registry-derived historical controls can be used to evaluate the effectiveness of treatment.

Psychological factors in the treatment of back pain by spinal manipulation.

Ninety patients with low back pain completed a short form of the Minnesota Multiphasic Personality Inventory (MMPI) and, subsequently, received spinal manipulative therapy. Most (84%) of the patients reported immediate relief following manipulation but the extent of that relief was not correlated with any psychological measure. However, several days after treatment, the percentage of patients reporting improvement was much lower (55%) and lack of improvement was associated with elevated scores on hypochondriasis (Hs), and functional low back pain (Lb). Unimproved patients also tended to report longer durations of back pain prior to treatment. Multiple regression analyses indicated that pain duration and the psychological factors were independent predictors of the response to treatment. It is suggested that, although a single manipulative treatment will often relieve the immediate cause of back pain, underlying psychosomatic factors may predispose the condition to recur.

Naloxone attenuates self-abusive behavior in developmentally disabled clients.

The opiate antagonist naloxone was effective in reducing self-abusive behavior in two mentally retarded clients with an extensive history of such behavior. Three doses of naloxone (0.1, 0.2, 0.4 mg) were compared with a vehicle solution in a double-blind, crossover design. Naloxone greatly attenuated self-abusive episodes in one client and eliminated them entirely in the second client. In addition, use of self-restraining behavior by one client was reduced. The findings suggested that some clients with self-injurious behavior may have disturbances of the endogenous opiate system. Maintenance of self-abuse by tonically elevated pain threshold and/or by the putative addictive characteristics of such behavior was discussed.

Isoprinosine and NPT 15392: immunomodulation and cancer.

These data demonstrate that both Isoprinosine and NPT 15392 are active nontoxic biological response modifiers that qualify for studies in cancer patients. Because of their immunomodulating properties, these agents are expected to be most appropriate in the treatment of immunosuppressed patients who are prone to infection or recurrence following cytoreductive therapy.

Instrumental avoidance conditioning of increased leg lowering in the spinal rat.

Five pairs of chronic spinal rats were trained to lower a hind leg and then were tested for retention using a counter-balanced instrumental avoidance paradigm in which one animal served as the experimental and the other as a yoked control subject. An additional three pairs of rats were used in this paradigm after their lumbosacral spinal cords had been removed by aspiration. The results indicate that the chronic spinal rat is capable of instrumental avoidance conditioning when leg lowering is the response, and that the lumbosacral spinal cord is essential for this phenomenon.

Attenuation of morphine analgesia by alpha-MSH, MIF-I, melatonin and naloxone in the rat.

In two experiments the effects of the pituitary peptide alpha-MSH, the hypothalamic tripeptide MIF-I (P-L-G-NH2) and the pineal hormone melatonin were investigated on the attenuation of morphine analgesia measured by a tail flick test. In Experiment 1, alpha-MSH had minimal effect on morphine analgesia, whereas, MIF-I and melatonin clearly delayed the onset of morphine analgesia, and melatonin also shortened the duration of analgesia. Experiment 2 was designed to investigate the possible synergistic effect of MIF-I and melatonin. The combined treatment of MIF-I and melatonin significantly delayed the onset of morphine analgesia, and melatonin alone shortened the duration of analgesia. The relationships among the pituitary, hypothalamus and the pineal for the modulation of pain and response to morphine were discussed.

Low back pain and its treatment by spinal manipulation: measures of flexibility and asymmetry.

Nineteen low back pain patients and eight patients not suffering from low back pain were given several tests of flexibility and asymmetry by two different examiners. Three criteria of reliability and validity were used: (1) significant agreement between independent observers, (2) significantly different scores in the groups with and without low back pain, and (3) significant improvement following a successful spinal manipulation. Tests of anterior flexion and asymmetry of foot eversion met only the first and second criteria while tests of hamstring tightness and asymmetry of voluntary straight leg raising met only the first and third criteria. Passive and voluntary straight leg raising tests were the only measures that met all three criteria. Therefore, of the objective tests investigated here, only passive or voluntary straight leg raising can be strongly recommended for use in the evaluation of spinal manipulative therapy for low back pain.

Habituation of the Hoffmann reflex.

The human monosynaptic H-reflex system was examined for the presence of several parametric features of habituation. Dishabituation was present, but there was no indication of an increasing rate or extent of habituation during repeated sessions, nor was there any apparent habituation of the dishabituating effect of an extraneous stimulus. Furthermore, there was only a very small effect of stochastic stimulation. There was, however, a substantial effect of voluntary activation: contraction of the soleus tended to prevent habituation, while stretch of the soleus produced sensitization during repetitive stimulation. We conclude that the H-reflex is an extremely simple response system with little or no long-term plasticity.

Spinal manipulation for low back pain.

A randomized clinical trial of rotational manipulation was conducted on 95 patients with low back pain selected for (1) the absence of any contraindications for vertebral manipulation, (2) the absence of any psychosocial problems that might affect the outcome of treatment, (3) the absence of any previous experience with manipulative therapy, and (4) the presence of palpatory cues indicating that manipulation might be successful. Patients were randomly assigned to one of two groups: an experimental group receiving manipulation therapy and a control group receiving soft-tissue massage. Comparison of the two groups indicated that (1) patients who received manipulative treatment were much more likely to report immediate relief after the first treatment, and (2) at discharge, there was no significant difference between the two groups because both showed substantial improvement.