Active-control trials: how would a new agent compare with placebo? A method illustrated with clopidogrel, aspirin, and placebo.

BACKGROUND: In an active-control trial with a new treatment and a comparator that has placebo-controlled trials, how might the effect of the new therapy versus placebo be estimated? For many diseases it is not ethically justified to use a placebo-control trial, yet in the United States regulatory efficacy is conceptually defined in comparison with placebo. METHODS: By use of the logarithm of the odds ratio for the active-control trial and for the placebo-controlled trials of the active-control, we estimated the effect of the new agent versus placebo. This "putative placebo" estimate assumes that the odds ratio in the active-control versus placebo trials is the same as would have been obtained had a placebo arm been possible in the trial with the new agent. A formula is given for sample size calculation in such a setting. RESULTS: Clopidogrel, an adenosine diphosphate (ADP) receptor antagonist, and aspirin were compared in the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) Study of patients with recent myocardial infarction, recent ischemic stroke, or symptomatic peripheral arterial disease. The 40 trials comparing aspirin with placebo are summarized by the Antiplatelet Trialists' Collaboration. For the outcome cluster of stroke, myocardial infarction, or vascular mortality, the estimated odds ratio for clopidogrel versus placebo is 0.70 (95% confidence interval 0.64-0.78, P<.000001). The relative risk reduction of approximately 30% represents a clinically meaningful benefit. CONCLUSIONS: For active-control trials use of prior trials of the active-control versus placebo may be usefully used to estimate the effect of the new therapy versus a putative placebo.

Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.

BACKGROUND: Both lipid-modifying therapy and antioxidant vitamins are thought to have benefit in patients with coronary disease. We studied simvastatin-niacin and antioxidant-vitamin therapy, alone and together, for cardiovascular protection in patients with coronary disease and low plasma levels of HDL. METHODS: In a three-year, double-blind trial, 160 patients with coronary disease, low HDL cholesterol levels and normal LDL cholesterol levels were randomly assigned to receive one of four regimens: simvastatin plus niacin, vitamins, simvastatin-niacin plus antioxidants; or placebos. The end points were arteriographic evidence of a change in coronary stenosis and the occurrence of a first cardiovascular event (death, myocardial infarction, stroke, or revascularization). RESULTS: The mean levels of LDL and HDL cholesterol were unaltered in the antioxidant group and the placebo group; these levels changed substantially (by -42 percent and +26 percent, respectively) in the simvastatin-niacin group. The protective increase in HDL2 with simvastatin plus niacin was attenuated by concurrent therapy with antioxidants. The average stenosis progressed by 3.9 percent with placebos, 1.8 percent with antioxidants (P=0.16 for the comparison with the placebo group), and 0.7 percent with simvastatin-niacin plus antioxidants (P=0.004) and regressed by 0.4 percent with simvastatin-niacin alone (P<0.001). The frequency of the clinical end point was 24 percent with placebos; 3 percent with simvastatin-niacin alone; 21 percent in the antioxidant-therapy group; and 14 percent in the simvastatin-niacin-plus-antioxidants group. CONCLUSIONS: Simvastatin plus niacin provides marked clinical and angiographically measurable benefits in patients with coronary disease and low HDL levels. The use of antioxidant vitamins in this setting must be questioned.

Comparative reliability and validity of chronic pain intensity measures.

Reliable and valid measures of pain are essential for conducting research on chronic pain. The purpose of this longitudinal study was to compare the reliability and validity of several measures of pain intensity. One hundred twenty-three patients with chronic pain were administered telephone interview versions of 0-10 scales of current, worst, least and average pain, immediately prior to beginning a multidisciplinary treatment program. The measures were administered again to these subjects 2 weeks (n=108), 1 month (n=106) and 2 months (n=105) after the end of treatment. The validity (defined as ability to detect changes in pain intensity over the course of treatment up to the 2-month follow-up assessment) and reliability (defined as stability over time in the 2 months after treatment) of these four measures and of composite combinations of these measures were examined. Contrary to prediction, the composite measures did not show a statistically significant superiority to the individual ratings in terms of their ability to detect change in pain intensity from pre-treatment to various points after treatment. The composite scores did, however, show greater stability than did the individual ratings after treatment. The practical conclusions of this study are; (1), individual 0-10 pain intensity ratings have sufficient psychometric strengths to be used in chronic pain research, especially research that involves group comparison designs with relatively large sample sizes, but, (2), composites of 0-10 ratings may be more useful when maximal reliability is necessary, (e.g. in studies with relatively small sample sizes, or in clinical settings where monitoring of changes in pain intensity in individuals is needed).

Advances in clinical trials in the twentieth century.

This article considers the rise of the randomized clinical trial during the twentieth century. Before such development could begin, probability and statistics needed to merge. Sir RA Fisher introduced randomization in the 1920s and, beginning in the 1930s and 1940s, randomized clinical trials in humans were being performed by using the statistical-hypothesis-testing paradigm. Randomization gave unbiased comparisons and a way to perform hypothesis testing without model assumptions. To preserve the benefits of randomization, a type of analysis called intent-to-treat analysis is appropriate. Needed development has occurred and is occurring in refining ethical standards, monitoring trials of serious irreversible endpoints while preserving type-I error, and instituting independent data- and safety-monitoring boards. Recent methodology has also been concerned with the appropriateness of using surrogate endpoints. A current area of debate is the appropriateness of using Bayesian statistical methods in this context.

Time-dependent covariates in the Cox proportional-hazards regression model.

The Cox proportional-hazards regression model has achieved widespread use in the analysis of time-to-event data with censoring and covariates. The covariates may change their values over time. This article discusses the use of such time-dependent covariates, which offer additional opportunities but must be used with caution. The interrelationships between the outcome and variable over time can lead to bias unless the relationships are well understood. The form of a time-dependent covariate is much more complex than in Cox models with fixed (non-time-dependent) covariates. It involves constructing a function of time. Further, the model does not have some of the properties of the fixed-covariate model; it cannot usually be used to predict the survival (time-to-event) curve over time. The estimated probability of an event over time is not related to the hazard function in the usual fashion. An appendix summarizes the mathematics of time-dependent covariates.

Carvedilol and the Food and Drug Administration approval process: an introduction.

We discuss briefly the new drug carvedilol (Coreg), a beta-blocker, alpha-blocker, and antioxidant. This drug was developed for congestive heart failure in a series of trials, four in the United States and one in Australia and New Zealand, briefly summarized in this document. We also summarize the classical paradigm of the U.S. Food and Drug Administration (FDA) for drug approval and the FDA's use of advisory committees. This document serves as background to the discussion of carvedilol's approval.

Carvedilol and the Food and Drug Administration (FDA) approval process: the FDA paradigm and reflections on hypothesis testing.

Carvedilol (Coreg), a beta- and alpha-blocker and an antioxidant drug, was evaluated for moderate to severe heart failure patients in a program containing four United States and one Australia/New Zealand study. The data were evaluated twice by the Cardiovascular and Renal Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA). These meetings resulted in opposite decisions by the advisory committee. The crux of the argumentation was the two-positive-trial FDA paradigm. Carvedilol did not meet the usual paradigm because an exercise end point was not statistically different from placebo in three U.S. trials. Most other end points were highly significant, and death, which was monitored across the U.S. program, was different with p < 0.0001. Here we argue that the usual paradigm is very useful but not an absolute principle, that the usual paradigm can sometimes miss the strength of evidence even in the primary end points, and that rational decision making requires on occasion that other evidence must lead to approval. Control of the type I error rate should be taken very seriously, should rarely be violated, and serves the biomedical community well. It is not an absolute principle, however, but rather must be considered in context.

Analysis of arrhythmias in the Circadian Antiischemia Program in Europe (CAPE) study.

The aim of this study was to analyze whether, in patients with long-standing (>4 years) coronary artery disease (CAD), the addition of the long-acting calcium channel blocker (CCB) amlodipine to conventional treatment [beta-blockers (BBLs) and nitrates] during anginal attacks would have a proarrhythmic effect. This was tested by analyzing data from patients who had taken part in the Circadian Anti-ischemia Program in Europe (CAPE) trial. After a 2-week, single-blind, run-in period (Phase 1), patients were randomized to amlodipine, 5 mg/day (first 4 weeks) and 10 mg/day (second 4 weeks), or placebo for 8 weeks (Phase 2). The 48-h Holter data were analyzed for 167 amlodipine-treated patients and 83 placebo patients based on a 2:1 randomization scheme. Sixty-three per cent of amlodipine patients and 67% of placebo patients were receiving concomitant BBLs, and >90% had taken sublingual nitrates during anginal attacks, as basic antiischemic therapy. After 7 weeks of therapy, when 48-h Holter monitoring was repeated, there were no significant changes in the frequency of ventricular arrhythmias in the placebo or amlodipine groups for all patients or subgroups of patients with or without BBLs. Also, between-group comparisons showed no significant differences in arrhythmias between amlodipine and placebo patients. In summary, amlodipine (5-10 mg/day) given to patients with severe, chronic CAD receiving conventional antiischemic therapy, did not produce any proarrhythmic effects.

Self-designing clinical trials.

I present a method of sequential analysis for randomized clinical trials that allows use of all prior data in a trial to determine the use and weighting of subsequent observations. One continues to assign subjects until one has 'used up' all the variance of the test statistic. There are many strategies to determine the weights including Bayesian methods (though the proposal is a frequentist design). I explore further the self-designing aspect of the randomized trial to note that in some cases it makes good sense (i) to change the weighting on components of a multivariate endpoint, (ii) to add or drop treatment arms (especially in a parallel group dose ranging/efficacy/safety trial), (iii) to select sites to use as the trial goes on, (iv) to change the test statistic and (v) even to rethink the whole drug development paradigm to shorten drug development time while keeping current standards for the level of evidence necessary for approval.

Lipid altering or antioxidant vitamins for patients with coronary disease and very low HDL cholesterol? The HDL-Atherosclerosis Treatment Study Design.

Evidence supports the idea that substantial benefits may derive from treatments that increase high density lipoprotein (HDL) cholesterol (HDL-C), apolipoprotein (apo) A-I, HDL2 (or 2b) or the size of HDL particles with, or without, apo A-II. HDL3 appears to be neutral in terms of coronary artery disease risk, and apo A-II appears to be adverse. Because HDL particles serve as antioxidants in vitro, the hypothesis that low HDL-C reflects an antioxidant deficiency state appears tenable. Based on these observations, a three-year angiographic study was proposed and received funding. Enrollment began in January 1995 and was completed in January 1997.

Assessment of pain during medical procedures: a comparison of three scales.

OBJECTIVE: Pain assessment is crucial to pain research. Knowledge about the strengths and weaknesses of pain measures is important to the continued advancement of our understanding of pain. The purpose of the present study was to compare the validity and utility of three measures of pain intensity during a medical procedure known to produce pain: an abortion. DESIGN: Assignment to one of three pain intensity assessment instruments, which were subsequently used to assess pain during an abortion procedure. Comparison of the relative sensitivity of the measures to assess changes in pain using a series of repeated measures analyses of variance. The relative utility of the measures was compared by examining the rates of accurate responses to each. SUBJECTS: Fifty-eight women presenting for a first-trimester abortion. MEASURES: Visual analog scale (VAS), the verbal 11-point Box Scale (Verbal BS-11), and the 21-point Box Scale (BS-21). RESULTS: All three pain intensity measures detected changes in pain during the abortion procedure. Rates of incorrect responses were higher for the Verbal BS-11 and the VAS than for the BS-21. CONCLUSIONS: The results supported the validity of each of the three measures used, although some superiority for the BS-21 over the Verbal BS- 11 and VAS exists. Patients had some difficulty completing the paper-and-pencil VAS during the procedure. In addition and consistent with previous research, some patients treated the Verbal BS-11 as a 21-point scale by responding with numbers between two whole numbers on the 0-10 measure. Overall, practical issues led us to conclude that the BS-21 is an excellent choice for assessing real-time abortion pain.

Lifetime exercise and disk degeneration: an MRI study of monozygotic twins.

Participation in some competitive sports has been shown to increase disk degeneration; however, the long-term effects of recreational physical activities are unclear. We investigated the effects of endurance exercise and power sports on disk degeneration in monozygotic male twins with contrasting lifetime exercise histories. The effects of endurance exercise were studied in 22 discordant twin pairs (mean lifetime frequencies of 3.9 vs 1.1 times/wk), and the effects of power sports were investigated in 12 discordant pairs (2,300 vs 200 h of weightlifting). The age range of the twins was from 35 to 69 yr. No differences in MRI findings between co-twins discordant for endurance exercise were found at any of the spinal regions. Subjects with more power sport involvement had greater disk degeneration in the T6-T12 region (P < 0.03), but similar findings were not present in the lumbar spine. Controlling for recalled back injuries, occupational loading, smoking, and driving did not significantly affect the results. No signs of beneficial or harmful effects of lifetime endurance exercise on disk degeneration were seen. Increased power sport participation was associated with slightly greater disk degeneration in the lower thoracic spine, but not in the lumbar spine.

Cardiovascular effects of equipotent isoflurane and alfentanil/isoflurane minimum alveolar concentration multiple in cats.

OBJECTIVE: To determine whether administration of opioids to anesthetized cats induced less cardiovascular depression than that induced by an equivalent amount of anesthetic alone, and to measure endocrine responses to a noxious stimulus. ANIMALS: 6 healthy female cats. PROCEDURE: Anesthesia was induced with isoflurane and was maintained for 60 minutes at 1.3 isoflurane MAC. Blood gas tensions, pH, and plasma alfentanil and hormone concentrations, blood pressures, and cardiac output were measured. A noxious stimulus was applied for 5 minutes, while blood acquisition and measurements were repeated. Alfentanil was administered i.v. to achieve estimated plasma concentration of 500 ng/ml, and end-tidal isoflurane concentration was reduced by 35%. After another 60 minutes, blood was obtained and measurements were taken, then a second 5-minute noxious stimulus was applied while blood acquisition and measurements were retaken. RESULTS: Alfentanil administration and reduction of isoflurane concentration significantly increased body temperature, heart rate, mean arterial pressure, mean pulmonary arterial pressure, stroke index, cardiac index, hemoglobin, oxygen delivery index, PvO2 and PvCO2, dopamine, epinephrine (EPI), norepinephrine (NOREPI), and cortisol values, and significantly decreased arterial and venous pH. Application of a noxious stimulus significantly increased heart rate, stroke index, cardiac index, PaO2, oxygen delivery index, arterial and venous pH, and NOREPI values, and decreased bicarbonate, PaCO2, PvCO2, and EPI values. Alfentanil administration blunted cardiac index, PaCO2, oxygen delivery index, arterial pH, PaO2, and EPI, and NOREPI responses to a noxious stimulus. CONCLUSIONS: Compared with isoflurane alone, alfentanil administration and reduction of isoflurane MAC improved cardiovascular variables, and blunted respiratory, hormonal, and most hemodynamic responses to a noxious stimulus in cats. CLINICAL RELEVANCE: Use of the balanced opioid anesthesia regimen induced some beneficial effects in healthy cats; effects were similar to, although greater in nature, than effects induced by a noxious stimulus.

Effect of alfentanil on the minimum alveolar concentration of isoflurane in cats.

OBJECTIVE: To evaluate effect of incremental doses of alfentanil on isoflurane minimum alveolar concentration (MAC) in cats to determine whether alfentanil reduces isoflurane MAC and, if so, maximal isoflurane MAC reduction. ANIMALS: 6 healthy spayed female cats. PROCEDURE: Cats were anesthetized with isoflurane and instrumented to allow collection of arterial blood for measurement of gas tensions, pH, and plasma alfentanil concentration and to measure arterial blood pressure. Isoflurane MAC was determined in triplicate, and alfentanil was administered i.v., using a computer-driven syringe pump to achieve estimated plasma alfentanil concentrations of 50, 100, 250, 500, 750, and 1,000 ng/ml; isoflurane MAC was determined at each alfentanil concentration. Cats were allowed to recover, and the process was graded as poor, good, or excellent. RESULTS: Alfentanil had a significant dose effect on isoflurane MAC reduction. Significant regression was found for normalized isoflurane MAC versus estimated plasma alfentanil concentration. A quadratic term was necessary to fit the model and, using this curve, MAC reduction (35.0 +/- 6.6%) was estimated to be maximal at a plasma alfentanil concentration of 500 ng/ml. Significant differences were evident in rectal temperature, bicarbonate concentration, base deficit, arterial carbon dioxide and oxygen tensions, and arterial pH between isoflurane alone and some plasma alfentanil concentration and the corresponding reduction in isoflurane concentration. CONCLUSIONS: Infusion of alfentanil resulted in maximal MAC reduction midway between that reported for horses and dogs. At such plasma alfentanil concentration, adverse effects were minimal, but included increase in rectal temperature, metabolic acidosis, and decrease in PaO2. Provided cats were not handled during the recovery period, recovery was smooth and quiet. CLINICAL RELEVANCE: Infusion of alfentanil decreases the need for potent inhalant anesthetics in cats and could potentially be a clinically useful anesthetic regimen in sick cats.

High HIV prevalence, low condom use and gender differences in sexual behaviour among patients with STD-related complaints at a Nairobi primary health care clinic.

Of 22,274 patients > or = 12 years old attending a Nairobi primary health care (PHC) clinic, 1076 (4.8%) had STD-related complaints, of whom 980 underwent assessment of risk factors for human immunodeficiency virus (HIV) infection and infrequent condom use. Gonorrhoea, chancroid, syphilis seroactivity, trichomoniasis, or objective signs of STD were found in 78%, and HIV seropositivity in 15% of men and 19% of women. Most women were married, living with a spouse; while most men were single, or married, but living separated from a spouse. Among married men, last sex was with a female sex worker (FSW) or casual partner for 60% not living with a spouse and 26% living with a spouse (P<0.005). Two or more partners during the past year were reported by 82% of men and 25% of women (P <0.001), and 55% of men and 11% of women reported the last partner was high risk. HIV seropositivity among both genders was associated with numbers of partners, and among women, with being widowed or divorced. Only 3% reported use of a condom with the last partner. Among men whose last sex was with a FSW, 74% said the reason for not using a condom was not having one. Thus, infrequent condom use, low condom availability, and gender differences in behaviour necessitate modifying development policies that separate families; and better coordination between family planning, PHC, and AIDS/STD programmes, with improved supply, social marketing and community-based distribution of condoms in high-risk settings for STD/HIV prevention.

Mortality hazard functions as related to neutropenia at different times after marrow transplantation.

We characterized the relationship between severe neutropenia and risk of death in 2,276 patients after marrow transplantation to define objective and clinically relevant criteria that could be used to judge the timing and potential value of interventions designed to improve survival in patients with delayed initial engraftment. Proportional hazard models were used to estimate the relative risk of death before day 100 among patients alive on any given day with an absolute neutrophil count (ANC) less than 100/microL compared with those alive on the same day with an ANC > or = 100/microL. Between day 10 and 14, the risk ratio remained close to 1.0, indicating that the risk of death before day 100 for patients with an ANC less than 100/microL was similar to that for patients with an ANC > or = 100/microL. Between day 15, when 38% of patients had an ANC less than 100/microL, and day 26, when 3.8% of patients had an ANC less than 100/microL, the risk ratio showed an overall upward trend, indicating that patients with an ANC less than 100/microL had a higher risk of death before day 100 than those with an ANC > or = 100/microL. Thereafter, the risk ratio fluctuated between 2.01 and 5.78, indicating consistently higher risks of mortality in patients with severe neutropenia. However, allogeneic and autologous transplant recipients each had distinctive risk ratio patterns. These results could be helpful in deciding the appropriate timing for treatment given to improve graft function after marrow transplantation.

Presumptive specific clinical diagnosis of genital ulcer disease (GUD) in a primary health care setting in Nairobi.

Of 22,274 patients 12 years of age or older attending a primary health care clinic in Nairobi, 1076 (4.8%) complained of symptoms suggesting a sexually transmitted disease (STD). Of these, 518 females and 462 males underwent complete clinical evaluation, and 78% had objective microbiologic or clinical evidence of STD, including 168 (17.1%) with genital ulcer disease (GUD). Presumptive specific clinical diagnoses on initial physical examination in cases of GUD were chancroid (131 patients), syphilis (25), genital herpes (15) and lymphogranuloma venereum (LGV) (1). Clinical diagnoses correlated only weakly with microbiological and serological diagnoses. Haemophilus ducreyi was isolated from 51 (41%) of the 125 with a clinical diagnosis of chancroid, and 4 (22%) of 18 with a diagnosis of syphilis, herpes, or LGV (P = 0.13). The rapid plasma reagin (RPR) test was reactive in 6 (24%) of 25 with a clinical diagnosis of syphilis, 18 (12.3%) of 146 with a diagnosis of chancroid or herpes, and 37 (4.7%) of 786 without a genital ulcer (P < 0.001, GUD vs no GUD). Sensitivity, specificity, and positive predictive value for presumptive clinical diagnosis of chancroid, relative to H. ducreyi isolation, were 93%, 16%, and 41%; and for diagnosis of syphilis, relative to reactive RPR, were 25%, 88% and 25%. Specific treatment based on presumptive specific clinical diagnosis frequently was inadequate for syphilis among patients with GUD and reactive RPR test. Syndromic treatment of GUD with antimicrobial combinations active against both chancroid and syphilis would be preferable to treatment with single drugs based on presumptive specific clinical diagnoses for this population.

PIP: During a 12-month period in 1990-1991 in Kenya, 1076 of 22,274 patients (4.8% of all patients over 12 years of age) presented at the Langata Health Center in Nairobi with symptoms of a sexually transmitted disease (STD). Researchers analyzed data on 980 of these patients whose records had complete data to assess the use of presumptive specific clinical diagnosis in the management of STDs in a primary health clinic. 17.1% (168) had genital ulcer disease (GUD). Men were more likely to have a GUD than women (24.7% vs. 10.4%). Haemophilus ducreyi, the etiologic agent of chancroid, was isolated in the cultures of 40% of the patients with a presumptive specific clinical diagnosis of chancroid compared with 17% of those with a presumptive specific clinical diagnosis of syphilis, herpes, or lymphogranuloma venereum (LGV) (p = 0.02). The clinical diagnoses of these two GUDs had only a weak correlation with microbiological and serological diagnoses (p = 0.13). 24% of patients with a presumptive specific clinical diagnosis of syphilis, 31% of those with a presumptive specific clinical diagnosis of chancroid, 6% of those with a specific clinical diagnosis of genital herpes or LGV, and 4.7% of those who had no GUD disease tested positive for syphilis (p 0.001, GUD vs. no GUD). Among patients with syndromic diagnosis of GUD, the presumptive specific clinical diagnosis of chancroid had a high sensitivity (91%), low specificity (24%), and low positive predictive value (40%). Among patients with syndromic diagnosis of syphilis, the presumptive specific clinical diagnosis of syphilis had a low sensitivity (25%), higher specificity (87%), and low positive predictive value (24%). 13% of patients with positive cultures for H. ducreyi did not receive a recommended or effective drug for chancroid. 82% of patients who tested positive for syphilis did not receive a recommended drug for syphilis. Based on these findings, the researchers conclude that syndromic treatment of GUD with use of antimicrobial combinations active against both chancroid and syphilis is a better course of treatment than use of single drugs based on presumptive specific clinical diagnoses for this population.

1995 Volvo Award in clinical sciences. Determinants of lumbar disc degeneration. A study relating lifetime exposures and magnetic resonance imaging findings in identical twins.

STUDY DESIGN: Retrospective cohort. OBJECTIVES: To investigate the effects of lifetime exposure to commonly suspected risk factors on disc degeneration using magnetic resonance imaging, and to estimate the effects of these suspected risk factors relative to age and familial aggregation, reflecting genetic and shared environmental influences. SUMMARY OF BACKGROUND DATA: Structural and biochemical changes associated with disc degeneration are suspected as the underlying conditions of many back-related symptoms. Little is known about the determinants of disc degeneration. METHODS: Based on lifetime discordance in suspected environmental risk factors for disc degeneration, 115 male identical twin pairs were selected. An in-depth interview was conducted of occupational and leisure time physical loading, driving, and smoking. Disc degeneration was evaluated using observational and digital magnetic resonance imaging assessment methods. RESULTS: Heavier lifetime occupational and leisure physical loading was associated with greater disc degeneration in the upper lumbar levels (P = 0.055 - 0.001), whereas sedentary work was associated with lesser degeneration (P = 0.006). These univariate associations did not reach statistical significance in the lower lumbar region. In multivariate analyses of the upper lumbar levels, the mean job code explained 7% of the variability in observational disc degeneration scores; the addition of age explained 16%, and familial aggregation improved the model such that 77% of the variability was explained. In the lower lumbar levels, leisure time physical loading entered the multivariate model, explaining 2% of the variability. Adding age explained 9%, and familial aggregation raised the variability in disc degeneration scores explained to 43%. CONCLUSIONS: The present study findings suggest that disc degeneration may be explained primarily by genetic influences and by unidentified factors, which may include complex, unpredictable interactions. The particular environmental factors studied, which have been among those most widely suspected of accelerating disc degeneration, had very modest effects.

Similarities in degenerative findings on magnetic resonance images of the lumbar spines of identical twins.

Although the etiology of most degenerative changes in the lumbar spine is unclear, genetic factors may play an important role. To investigate this link, we reviewed magnetic resonance images of the lumbar spines of identical twins to assess the degree of similarities in degenerative findings in the discs. Observers who were blinded to twinship evaluated sagittal T1-weighted and T2-weighted magnetic resonance images of the lumbar spines of forty male identical twins (twenty pairs) with respect to changes in the end plates, desiccation of the discs, bulging or herniated discs, and decrease in the height of the disc space. Similarities between co-twins were significantly greater than would be expected by chance. Whereas smoking status and age explained 0 to 15 per cent of the variability in the various degenerative findings in the discs, 26 to 72 per cent of the variability was explained with the addition of a variable representing co-twin status. These findings are compatible with a marked genetic influence and warrant further investigation.