Beatrice A. Golomb

Logistic regression in the medical literature : Standards for use and reporting, with particular attention to one medical domain

Logistic regression (LR) is a widely used multivariable method for modeling dichotomous outcomes. This article examines use and reporting of LR in the medical literature by comprehensively assessing its use in a selected area of medical study. Medline, followed by bibliography searches, identified 15 peer-reviewed English-language articles with original data, employing LR, published between 1985 and 1999, pertaining to patient interest in genetic testing for cancer susceptibility. Articles were examined for each of 10 criteria for proper use and reporting of LR models. Substantial shortcomings were found in both use of LR and reporting of results. For many studies, the ratio of the number of outcome events to predictor variables (events per variable) was sufficiently small to call into question the accuracy of the regression model. Additionally, no studies reported validation analysis, regression diagnostics, or goodness-of-fit measures. It is recommended that authors, reviewers, and editors pay greater attention to guidelines concerning the use and reporting of LR models.

Statin Adverse Effects: A Review of the Literature and Evidence for a Mitochondrial Mechanism

HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications, have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many nonmuscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.

Peripheral Arterial Disease Morbidity and Mortality Implications

Atherosclerotic peripheral arterial disease (PAD) refers to a range of non-coronary arterial vascular syndromes with progressive stenosis, occlusion, or aneurysmal dilation, most commonly affecting the lower extremity. Lower extremity PAD involves occlusive disease of the aorta, iliac, femoral, and more distal arteries. Patients with PAD typically carry a substantial burden of systemic atherosclerotic disease. Like other manifestations of atherosclerosis, the prevalence of PAD is related to hyperlipidemia, diabetes mellitus, hypertension, tobacco smoking, age, gender, and heredity. Clinical manifestations associated with lower extremity PAD include decrements in functional capacity and quality of life, intermittent claudication, and possibly limb loss. In addition, patients with PAD face an increased risk of vascular events including myocardial infarction (MI), stroke, and mortality.

Cholesterol and Violence: Is There a Connection?

Violence, which was recently declared a public health emergency [1], is increasingly viewed as the province of the primary care practitioner [1-6]. It is a substantial source of morbidity and is the leading cause of death in persons younger than 44 years of age [7] and of years of life lost for persons of all ages [8]. Meanwhile, cholesterol screening and treatment remain the subject of vigorous debate [9-11], the outcome of which will influence medical care for millions of persons and annual health expenditures of billions of U.S. dollars. Arguments on both sides of the debate hinge on the costs, risks, and benefits of cholesterol level reduction [12]. One possible risk stems from a putative connection between low or lowered cholesterol levels and violent death in men. However, the presence of such a connection remains controversial. In this paper, the medical literature has been systematically evaluated for evidence of this relation, including observational and experimental evidence in humans and nonhuman primates. Methods The MEDLINE, PsycINFO, and Current Contents databases were searched for English-language peer-reviewed articles by using the keywords cholesterol and violence or cholesterol and suicide. Bibliographies from identified articles were also searched. Articles met the inclusion criteria if they presented original research, individual-level data, and single (lipid-only) or no interventions and included persons documented to be violent or used direct measures of violence (as opposed to mood or personality indices). Psychological measures, such as depression and nonbehavioral expressions of hostility, correlate poorly with measures of violent acts [13, 14]. The neurotransmitter serotonin has been implicated in the control of violent behaviors. It is postulated that lowered cholesterol levels may lead to lowered brain serotonin activity; this may, in turn, lead to increased violence. Thus, additional searches were performed to relate brain serotonin to cholesterol and serotonin to violence. No randomized, controlled trials have been designed to evaluate a causal connection between low or lowered cholesterol levels and violence in humans, but criteria that permit a causal connection to be evaluated in the absence of direct experimental evidence have been developed. The following seven criteria, set forth by Hill [15], are used to guide presentation of the results: strength of association, consistency of association, temporality (cause precedes effect), biological gradient, biological plausibility, coherence with preexisting knowledge, and specific association. Results One hundred sixty-three articles that linked cholesterol and violence were identified. Of these, 32 met the inclusion criteria: 9 community cohort analyses (1 of which summarized 18 studies), 6 studies in criminal populations, 6 studies of suicide in psychiatric populations, 8 meta-analyses of randomized trials, 1 mixed-design study, and 2 controlled trials in nonhuman primates. The results of individual randomized trials reporting violent outcomes have in no case been statistically significant, and these results are not presented individually. In community cohorts and meta-analyses of randomized trials, violence was defined as death by homicide, suicide, or accident; in other types of study, violence was defined as noted in the text. Studies relating cholesterol to serotonin and serotonin to violence are briefly reviewed. Hills Criteria for a Causal Connection Strength and Consistency of Association The evidence for an association between cholesterol and violence in humans derives from community cohort studies, observational studies in violent populations, and meta-analyses of randomized trials of cholesterol-lowering therapy. A meta-analysis of 18 community cohort studies by Jacobs and colleagues [16] (Table 1) found 50% more violent deaths in men with cholesterol levels less than 160 mg/dL (4.14 mmol/L) than in the group with the highest cholesterol levels. Results of 8 additional studies are also shown [17-24]; 1 of these studies examined only death by suicide [23]. Although the number of violent deaths in all of these studies totaled only half of that in the meta-analysis by Jacobs and colleagues [16], 4 of the 8 studies (including the 2 largest studies) independently showed a statistically significant association between low cholesterol levels and violent death. Findings presented are for men, except in the study [24] where data were not segregated by sex. Few studies reported results for women separately, and although the largest of these studies showed a trend toward increased violent death with low cholesterol levels in women [18], the increased risk was less than that in men. In no study was the association of low cholesterol levels with violence significant for women when they were studied separately. Although this may be the result of inadequate power to test the association in this group, women are at substantially lower risk for violence and violent death; therefore, even a similar relative risk would confer comparatively modest absolute risk and clinical importance. Table 1. Association of Violent Death and Low Cholesterol Level in Cohort Studies In large community cohort analyses in which suicide was investigated separately, the relative risk for suicide with low cholesterol levels was greater than that for violence overall [17, 18], although one moderate-sized study found a significant positive association between suicide and cholesterol level [20]. One meta-analysis found significantly increased violent death with low cholesterol levels only in community cohorts and not in cohorts confined to employed persons [25]. However, a recent French cohort study of 6393 employed men with repeated cholesterol level measurements found that a low average cholesterol level was linked to subsequent death by suicide (relative risk, 3.16; P = 0.007), and the connection between a decrease in cholesterol level of more than 5 mg/dL per year and subsequent suicide was marginal (relative risk, 2.17; P = 0.056) [23]. One study of nonhuman primates [26] noted a relation between low baseline cholesterol level and agonistic behaviors. However, multiple measures of association were examined, and the significant relation to aggression could have arisen by chance. Because violence is rare, studies targeting populations with high rates of violence may show an association between cholesterol level and violence more efficiently. Several cross-sectional, retrospective, cohort, casecontrol, and mixed-design observational studies have investigated the relation between cholesterol levels and suicide attempts in psychiatric populations or between cholesterol levels and violence in criminally violent persons and controls. Substantially lower cholesterol levels were seen in the parasuicide group (suicide attempts or ideation) in 2 studies [27, 28] and in the violent group in 3 of 4 studies [29-32] (Table 2). Another study found that among children with psychiatric diagnoses, patients who had the diagnosis with which the most suicide attempts were associated also had the lowest average cholesterol levels [33]. Two of 3 analyses reported significantly more suicide attempts among persons with low cholesterol levels [34, 35] (Table 3); the third analysis [34] showed a nonsignificant relation in women. One study reported a higher frequency of violence [36, 37]. These psychiatric and criminal data support criteria of strong association and, in conjunction with community cohort data, show consistency of effect. Table 2. Difference in Mean Cholesterol Level between Suicidal or Violent Group and Control Group Table 3. Suicide Attempts and Violence in Patients with Low Cholesterol Levels Compared with Patients with High Cholesterol Levels An apparent increase in violent deaths was noted in several randomized, primary prevention trials of cholesterol lowering, including the well-designed Lipid Research Clinics and Helsinki Heart trials [38-40]. This increase was statistically significant in one trial that included both a cholesterol and a blood pressure intervention [41], but the number of violent deaths in most studies is small, and the excess of violent deaths has not reached statistical significance in any unifactorial intervention trial. To overcome the problem of small numbers of violent deaths, several meta-analyses have been performed. Table 4 presents results from meta-analyses of unifactorial studies, isolating primary prevention measures and men for cases in which data were separately available [25, 42-46]. Overlap exists in the trials that were included; therefore, analyses are not independent. Substantially more violent deaths were found among groups randomly allocated to receive cholesterol-lowering treatment in several meta-analyses; no study found significantly fewer violent deaths. Indeed, for all meta-analyses and for all subject categories (including additional subanalyses [43, 45]), any trend was toward an increased number of violent deaths with reduction of cholesterol level, whether for men or women, primary prevention or secondary prevention, or long trials or all trials. The absolute increase in violent death was similar to the absolute reduction in cardiac death and was statistically more significant than the latter in one meta-analysis that examined both [45] for all but secondary prevention trials. For secondary prevention trials, the trend toward increase in violent death was minimal and the benefit from reduction of cardiac deaths was substantial. Table 4. Meta-Analyses of Randomized Trials in Humans: Violent Death in Persons Who Received Cholesterol-Lowering Treatment Compared with Controls More recent trials of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have also failed to show a marked increase in violent deaths associated with treatment in populations that received secondary prevention measures. The Choleste

Statin‐Associated Adverse Cognitive Effects: Survey Results from 171 Patients

Study Objective. To characterize the adverse cognitive effects of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins). Design. Patient survey‐based analysis.

Effects of Statins on Energy and Fatigue With Exertion: Results From a Randomized Controlled Trial

No drug is without adverse effect potential, and fatigue and exertional intolerance are adverse effects reported by patients receiving statins.1,2 Little direct information is available regarding the typical or average impact of statins on energy or exertional fatigue.

Reduction in blood pressure with statins: results from the UCSD Statin Study, a randomized trial.

BACKGROUND Some studies have suggested reductions in blood pressure (BP)with statin treatment, particularly in persons with hypertension. Randomized trial evidence is limited. METHODS We performed a randomized, double-blind, placebo-controlled trial with equal allocation to simvastatin, 20 mg; pravastatin sodium,40 mg; or placebo for 6 months. Nine hundred seventy-three men and women without known cardiovascular disease or diabetes mellitus, with low-density lipoprotein cholesterol screening levels of 115 to 190 mg/dL, had assessment of systolic and diastolic BP (SBP and DBP, respectively). Blood pressure values were compared for placebo vs statins by intention-to-treat (ITT) analysis. Additional analyses were performed that (1) were confined to subjects with neither high baseline BP (SBP>140 mm Hg or DBP>90 mm Hg) nor receiving BP medications, to exclude groups in whom BP medications or medication changes may have influenced results, and (2) separately evaluated simvastatin and pravastatin (vs placebo). The time course of BP changes after statin initiation and the effect of stopping statins on BP were examined. RESULTS Statins modestly but significantly reduced BP relative to placebo,by 2.2 mm Hg for SBP (P=.02) and 2.4 mm Hg for DBP (P<.001) in ITT analysis. Blood pressure reductions ranged from 2.4 to 2.8 mm Hg for both SBP and DBP with both simvastatin and pravastatin, in those subjects with full follow-up, and without potential for influence by BP medications (ie, neither receiving nor meriting BP medications). CONCLUSIONS Reductions in SBP and DBP occurred with hydrophilic and lipophilic statins and extended to normotensive subjects. These modest effects may contribute to the reduced risk of stroke and cardiovascular events reported on statins. Trial Registration clinicaltrials.gov Identifier: NCT00330980.

Acetylcholinesterase inhibitors and Gulf War illnesses.

Increasing evidence suggests excess illness in Persian Gulf War veterans (GWV) can be explained in part by exposure of GWV to organophosphate and carbamate acetylcholinesterase inhibitors (AChEis), including pyridostigmine bromide (PB), pesticides, and nerve agents. Evidence germane to the relation of AChEis to illness in GWV was assessed. Many epidemiological studies reported a link between AChEi exposure and chronic symptoms in GWV. The link is buttressed by a dose–response relation of PB pill number to chronic symptoms in GWV and by a relation between avidity of AChEi clearance and illness, based on genotypes, concentrations, and activity levels of enzymes that detoxify AChEis. Triangulating evidence derives from studies linking occupational exposure to AChEis to chronic health symptoms that mirror those of ill GWV. Illness is again linked to lower activity of AChEi detoxifying enzymes and genotypes conferring less-avid AChEi detoxification. AChEi exposure satisfies Hills presumptive criteria for causality, suggesting this exposure may be causally linked to excess health problems in GWV.

Physician response to patient reports of adverse drug effects: implications for patient-targeted adverse effect surveillance.

AbstractObjective: Using a patient targeted survey, we sought to assess patient representations of how physicians responded when patients presented with possible adverse drug reactions (ADRs). As a demonstration case, we took one widely prescribed drug class, the HMG-CoA reductase inhibitors (‘statins’). This information was used to assess whether a patient-targeted ADR surveillance approach may complement provider reporting, potentially fostering identification of additional patients with possible or probable ADRs. Methods: A total of 650 adult patients taking statins with self-reported ADRs completed a survey. Depending on the problems reported, some patients completed additional surveys specific to the most commonly cited statin ADRs: muscle, cognitive or neuropathy related. Patients were asked to report drug, dose, ADR character, time course of onset with drug, recovery with discontinuation, recurrence with rechallenge, quality-of-life impact, and interactions with their physician in relation to the perceived ADR. This paper focuses on patients’ representation of the doctor-patient interaction and physicians’ attribution, when patients report perceived ADRs. Results: Eighty-seven percent of patients reportedly spoke to their physician about the possible connection between statin use and their symptom. Patients reported that they and not the doctor most commonly initiated the discussion regarding the possible connection of drug to symptom (98% vs 2% cognition survey, 96% vs 4% neuropathy survey, 86% vs 14% muscle survey; p < 10−8 for each). Physicians were reportedly more likely to deny than affirm the possibility of a connection. Rejection of a possible connection was reported to occur even for symptoms with strong literature support for a drug connection, and even in patients for whom the symptom met presumptive literature-based criteria for probable or definite drug-adverse effect causality. Assuming that physicians would not likely report ADRs in these instances, these patient-submitted ADR reports suggest that targeting patients may boost the yield of ADR reporting systems. Conclusions: Since low reporting rates are considered to contribute to delays in identification of ADRs, findings from this study suggest that additional putative cases may be identified by targeting patients as reporters, potentially speeding recognition of ADRs.

Low cholesterol and violent crime

BACKGROUND Community cohort studies and meta-analyses of randomized trials have shown a relation between low or lowered cholesterol and death by violence (homicide, suicide, accident); in primates, cholesterol reduction has been linked to increased behavioral acts of aggression (Kaplan J, Manuck S. The effects of fat and cholesterol on aggressive behaviour in monkeys. Psychosom. Med 1990;52:226-7; Kaplan J, Shively C, Fontenot D, Morgan T, Howell S, Manuck S et al. Demonstration of an association among dietary cholesterol, central serotonergic activity, and social behaviour in monkeys. Psychosom. Med 1994;56:479-84.). In this study we test for the first time whether cholesterol level is related to commission of violent crimes against others in a large community cohort. METHODS We merged one-time cholesterol measurements on 79,777 subjects enrolled in a health screening project in Varmland, Sweden with subsequent police records for arrests for violent crimes in men and women aged 24-70 at enrollment; and with information on covariates. We performed a nested case control comparison of cholesterol in violent criminals - defined as those with two or more crimes of violence against others - to cholesterol in nonoffenders matched on age, enrollment year, sex, education and alcohol, using variable-ratio matching, with a nonparametric sign test. RESULTS One hundred individuals met criteria for criminal violence. Low cholesterol (below the median) was strongly associated with criminal violence in unadjusted analysis (Men: risk ratio 1.94, P=0.002; all subjects risk ratio 2.32, P<0.001). Age emerged as a strong confounder. Adjusting for covariates using a matching procedure, violent criminals had significantly lower cholesterol than others identical in age, sex, alcohol indices and education, using a nonparametric sign test (P=0.012 all subjects; P=0.035 men). CONCLUSIONS Adjusting for other factors, low cholesterol is associated with increased subsequent criminal violence.