Similarity-based modeling applied to signal detection in pharmacovigilance.

One of the main objectives in pharmacovigilance is the detection of adverse drug events (ADEs) through mining of healthcare databases, such as electronic health records or administrative claims data. Although different approaches have been shown to be of great value, research is still focusing on the enhancement of signal detection to gain efficiency in further assessment and follow-up. We applied similarity-based modeling techniques, using 2D and 3D molecular structure, ADE, target, and ATC (anatomical therapeutic chemical) similarity measures, to the candidate associations selected previously in a medication-wide association study for four ADE outcomes. Our results showed an improvement in the precision when we ranked the subset of ADE candidates using similarity scorings. This method is simple, useful to strengthen or prioritize signals generated from healthcare databases, and facilitates ADE detection through the identification of the most similar drugs for which ADE information is available.

Medication-wide association studies.

Undiscovered side effects of drugs can have a profound effect on the health of the nation, and electronic health-care databases offer opportunities to speed up the discovery of these side effects. We applied a "medication-wide association study" approach that combined multivariate analysis with exploratory visualization to study four health outcomes of interest in an administrative claims database of 46 million patients and a clinical database of 11 million patients. The technique had good predictive value, but there was no threshold high enough to eliminate false-positive findings. The visualization not only highlighted the class effects that strengthened the review of specific products but also underscored the challenges in confounding. These findings suggest that observational databases are useful for identifying potential associations that warrant further consideration but are unlikely to provide definitive evidence of causal effects.

Accounting for comorbidity in assessing the burden of epilepsy among US adults: results from the National Comorbidity Survey Replication (NCS-R).

Although epilepsy is associated with substantial role impairment, it is also highly comorbid with other physical and mental disorders, making unclear the extent to which impairments associated with epilepsy are actually due to comorbidities. This issue was explored in the National Comorbidity Survey Replication (NCS-R), a nationally representative household survey of 5692 US adults. Medically recognized epilepsy was ascertained with self-report, comorbid physical disorders with a chronic conditions checklist, and comorbid DSM-IV mental disorders with the Composite International Diagnostic Interview. Lifetime epilepsy prevalence was estimated at 1.8%. Epilepsy was comorbid with numerous neurological and general medical conditions and with a sporadic cluster of mental comorbidities (panic, PTSD, conduct disorder and substance use disorders). Although comorbid disorders explain part of the significant gross associations of epilepsy with impairment, epilepsy remains significantly associated with work disability, cognitive impairment and days of role impairment after controlling comorbidities. The net association of epilepsy with days of role impairment after controlling for comorbidities is equivalent to an annualized 89.4 million excess role impairment days among US adults with epilepsy, arguing that role impairment is a major component of the societal costs of epilepsy per se rather than merely due to disorders comorbid with epilepsy. This estimated burden is likely conservative as some parts of the effects of epilepsy are presumably mediated by secondary comorbid disorders.

The associations of migraines and other headaches with work performance: results from the National Comorbidity Survey Replication (NCS-R).

It is unknown if comorbid conditions account for the association between migraines and work performance. This issue was investigated in the National Comorbidity Survey Replication (n = 9282). Twelve-month severe or persistent migraines and other headaches were assessed with comorbid 12-month mental and physical disorders using the WHO Composite International Diagnostic Interview. Work performance was assessed using the WHO Health and Work Performance Questionnaire. Significant associations of these conditions with work disability disappeared with controls for comorbid disorders, but severe or persistent migraines continued to predict work loss days even with controls. Individual-level and societal-level annual human capital values were $1165 and $9.3 billion for this subset of migraines. Roughly 20% of these associations were due to comorbidity, 60% to direct effects and 20% to indirect effects through temporally secondary comorbidities. These strong associations suggest that workplace interventions for severe or persistent migraines might have a positive return-on-investment for employers.

The prevalence and workplace costs of adult attention deficit hyperactivity disorder in a large manufacturing firm.

BACKGROUND: Little is known about the effects of adult attention deficit hyperactivity disorder (ADHD) on work performance or accidents-injuries.MethodA survey was administered in 2005 and 2006 to employees of a large manufacturing firm to assess the prevalence and correlates of adult ADHD. Respondents (4,140 in 2005, 4,423 in 2006, including 2,656 in both surveys) represented 35-38% of the workforce. ADHD was assessed with the World Health Organization (WHO) Adult ADHD Self-Report Scale (ASRS), a validated screening scale for DSM-IV adult ADHD. Sickness absence, work performance and workplace accidents-injuries were assessed with the WHO Health and Work Performance Questionnaire (HPQ). RESULTS: The estimated current prevalence (standard error) of DSM-IV ADHD was 1.9% (0.4). ADHD was associated with a 4-5% reduction in work performance (chi12=9.1, p=0.001), a 2.1 relative-odds of sickness absence (chi12=6.2, p=0.013), and a 2.0 relative-odds of workplace accidents-injuries (chi12=5.1, p=0.024). The human capital value (standard error) of the lost work performance associated with ADHD totaled USD 4,336 (676) per worker with ADHD in the year before interview. No data were available to monetize other workplace costs of accidents-injuries (e.g. destruction of equipment). Only a small minority of workers with ADHD were in treatment. CONCLUSIONS: Adult ADHD is a significantly impairing condition among workers. Given the low rate of treatment and high human capital costs, in conjunction with evidence from controlled trials that treatment can reduce ADHD-related impairments, ADHD would seem to be a good candidate for workplace trials that evaluate treatment cost-effectiveness from the employer's perspective.

Headache, cerebrovascular symptoms, and stroke: the Atherosclerosis Risk in Communities Study.

OBJECTIVE: To evaluate the occurrence of stroke/TIA symptoms and ischemic stroke events among those with a lifetime history of migraine or other headaches with some migraine features in a biracial cohort of older adults. METHODS: Participants were 12,750 African-American and white men and women from the Atherosclerosis Risk in Communities Study (1993 to 1995). The participants were queried about their lifetime headache history and characterized using modified International Headache Society diagnostic criteria. Stroke/TIA symptoms were classified using a computerized diagnostic algorithm, and ischemic stroke events were identified and validated using medical records. Multivariate logistic regression was used to assess the relationship between headache types and stroke/TIA symptoms and ischemic stroke events. RESULTS: Migraine with aura was strongly associated with stroke symptoms (odds ratio [OR] 5.46, 95% CI: 3.64 to 8.18), TIA symptoms (OR 4.28, 95% CI: 3.02 to 6.08), and verified ischemic stroke events (OR 2.81, 95% CI: 1.60 to 4.92). Similarly, other headaches with aura were significantly associated with stroke symptoms (OR 3.68, 95% CI: 2.26 to 5.99) and TIA symptoms (OR 4.53, 95% CI: 3.08 to 6.67). In contrast, the associations for migraine without aura and other headaches without aura were not as consistent or robust. CONCLUSIONS: Migraines and other headaches, particularly those accompanied by aura, were associated with an increased occurrence of stroke/TIA symptoms and ischemic stroke events.

Migraine and other headaches: associations with Rose angina and coronary heart disease.

OBJECTIVE: To examine the association between a lifetime history of migraines and other headaches with and without aura and Rose angina and coronary heart disease (CHD). METHODS: Participants were 12,409 African American and white men and women from the Atherosclerosis Risk in Communities Study, categorized by their lifetime history of headaches lasting > or =4 hours (migraine with aura, migraine without aura, other headaches with aura, other headaches without aura, no headaches). Gender-specific associations of headaches with Rose angina and CHD, adjusted for sociodemographic and cardiovascular disease risk factors, were evaluated using Poisson regression. RESULTS: Participants with a history of migraines and other headaches were more likely to have a history of Rose angina than those without headaches. The associations were stronger for migraine and other headaches with aura (prevalence ratio [PR] = 3.0, 95% CI = 2.4, 3.7 and PR = 2.0, 95% CI = 1.5, 2.7 for women; PR = 2.2, 95% CI = 1.2, 3.9 and PR = 2.4, 95% CI = 1.4, 3.9 for men) than for migraine and other headaches without aura (PR = 1.5, 95% CI = 1.2, 1.9 and PR = 1.3, 95% CI = 1.1, 1.6 for women; PR = 1.9, 95% CI = 1.2, 2.9 and OR = 1.4, 95% CI = 1.0, 1.8 for men). In contrast, migraine and other headaches were not associated with CHD, regardless of the presence of aura. CONCLUSIONS: The lack of association of migraines with coronary heart disease suggests that the association of migraine with Rose angina is not related to coronary artery disease. Future research assessing other common underlying pathologic mechanisms is warranted.

Similar effectiveness of paroxetine, fluoxetine, and sertraline in primary care: a randomized trial.

CONTEXT: Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed class of antidepressant, yet it is not known whether one SSRI is more effective than another. OBJECTIVE: To compare the effectiveness of 3 SSRIs (paroxetine, fluoxetine, and sertraline) in depressed primary care patients. DESIGN: Open-label, randomized, intention-to-treat trial, with patient enrollment occurring in April-November 1999. SETTING: Thirty-seven clinics in 2 US primary care research networks. PATIENTS: A total of 573 depressed adult patients for whom their primary care physician thought that antidepressant therapy was warranted and who completed a baseline interview. INTERVENTIONS: Patients were randomly assigned to receive paroxetine (n = 189), fluoxetine (n = 193), or sertraline (n = 191) for 9 months. Primary care physicians were allowed to switch patients to a different SSRI or non-SSRI antidepressant if they did not adequately respond to or tolerate the initial SSRI. MAIN OUTCOME MEASURES: The primary outcome measure was change in the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) Mental Component Summary score (range, 0-100), compared across treatment groups at 1, 3, 6, and 9 months. Secondary outcomes included other depression and psychological measures, multiple measures of social and work functioning, and other domains of health-related quality of life, such as physical functioning, concentration and memory, vitality, bodily pain, sleep, and sexual functioning. RESULTS: Follow-up interviews were successfully completed in 94% of patients at 1 month, 87% at 3 months, 84% at 6 months, and 79% at 9 months. Responses to the 3 SSRIs were comparable on all measures and at all time points. The mean change in the SF-36 Mental Component Summary score at 9 months was + 15.8 in the paroxetine group, + 15.1 in the fluoxetine group, and + 17.4 in the sertraline group. The drugs were also associated with similar incidences of adverse effects and discontinuation rates. CONCLUSIONS: The SSRI antidepressants paroxetine, fluoxetine, and sertraline were similar in effectiveness for depressive symptoms as well as multiple domains of health-related quality of life over the entire 9 months of this trial.

A novel, tunable manganese coordination system based on a flexible "spacer" unit: noncovalent templation effects.

The reaction of bis(hexafluoroacetylacetonato)manganese(II) trihydrate (2), an approximately 90 degrees corner unit, with flexible linking unit 4,4'-trimethylenedipyridine (1) allows for the potential formation of three different types of solid-state coordination species: infinite helical polymers, closed dimeric systems, and infinite one-dimensional polymers. While the un-templated starting material is known to give a coordination helix, the other two possible species can be realized through the selective use of a variety of simple, organic guests: toluene (3), diphenylmethane (4), cis-stilbene (5), 1,3-diphenylpropane (6), benzyl alcohol (7), nitrobenzene (8), and cyanobenzene (9). When solutions of 1 and 2 are crystallized in the presence of all of these clathrates, the dimeric macrocycles result in all cases, except for that of 6, in which a syndiotactic, wedge-shaped polymer forms. Employing a linker that is less rigid than is typically used in crystal engineering, such as 1, enables the nucleophilic donor subunit to be more than just a simple "spacer", instead making it an essential, tunable component in the overall crystal lattice. In so doing, a great deal of molecular "information" is lost, but this is compensated for by an in-depth investigation into the weaker host-guest and/or guest-guest interactions, such as nonclassical hydrogen bonding and an assortment of hydrophobic interactions, present in the various systems.

Pollen and mold exposure impairs the work performance of employees with allergic rhinitis.

BACKGROUND: Although quality of life studies suggest that allergic rhinitis has a substantial impact on work impairment, national survey estimates of the magnitude of this impairment have varied widely. Retrospective recall bias is likely to be a major cause of this variability. OBJECTIVE: This study used a nationally representative daily diary sample to obtain prospective data that improve on previous estimates of the work impairment because of allergic rhinitis. METHODS: The MacArthur Foundation National Survey of Daily Experience is a daily diary survey that included a nationally representative subsample of 739 employed people, each of whom provided daily reports on work performance for 1 randomly assigned week of the calendar year. National Allergy Bureau monitoring station data were merged with the survey data to study the association of time-space variation in pollen/mold exposure with impaired daily work quality and quantity. RESULTS: National Allergy Bureau pollen/mold counts are significantly related to work impairments only among respondents with self-reported allergic rhinitis. The average estimated monthly salary-equivalent work impairment costs associated with pollen/mold exposure for each allergy sufferer is between $109 and $156, with an annualized national projection of between $5.4 billion and $7.7 billion. CONCLUSIONS: The extent to which these costs can be recovered by increasing the proportion of allergy sufferers who are successfully treated remains unknown and can only be evaluated definitively in effectiveness trials.

Costs of care for irritable bowel syndrome patients in a health maintenance organization.

OBJECTIVES: The aims of this study were: 1) to determine the total costs of care and costs related to lower GI-related problems for patients who received a diagnosis of irritable bowel syndrome (IBS), and 2) to compare them to age- and sex-matched population controls and patients treated for inflammatory bowel disease (IBD) or gastroesophageal reflux disease (GERD). METHODS: Use and cost data were obtained through the computerized information systems of a large staff-model health maintenance organization on three groups of patients diagnosed in 1994 or 1995 with IBS, IBD, or GERD; and an age- and sex-matched control group of patients without any of these listed diagnoses. The IBS patient group was compared to the three comparison groups on components of total and IBS-related costs. RESULTS: Total costs of care for IBS patients were 49% higher than population controls during the year starting with the visit at which IBS patients were identified. In the index year, every component of total costs except inpatient care was significantly higher for IBS patients than for population controls. The costs of care for lower GI problems were significantly higher for patients with IBS than for population controls across a range of services. However, only 33% of the difference in total costs of care between IBS patients and population controls was due to lower GI-related services in the index year. In the subsequent years, lower GI-related services accounted for 18% and 20% of the total cost difference between IBS patients and population controls. The total costs of care as well as the components of costs of care were generally higher for IBD patients than for IBS patients, but were comparable for GERD and IBS patients. CONCLUSIONS: Patients with IBS show sustained increases in health care costs relative to population controls for both lower GI services and care unrelated to lower GI problems. However, the majority of the excess in health care costs resulted from medical care not directly related to lower GI problems.

Self-assembly with postmodification: kinetically stabilized metalla-supramolecular rectangles.

Interaction of a predesigned molecular "clip" (4) with rigid dipyridyl bridging ligands, in acetone/water mixtures, leads to the formation of molecular rectangles (5-8) in 92-97% isolated yields via spontaneous self-assembly. Characterization was accomplished with multinuclear NMR and UV-vis spectroscopy, FAB mass spectrometry, and X-ray crystallography. The length of these metallamacrocycles ranges from 2 to 3 nm. Postmodification via non-nucleophilic counterion exchange results in enhanced structural integrity for the assemblies.

Metal-directed formation of three-dimensional M(3)L(2) trigonal-bipyramidal cages.

[reaction: see text] The simple combination of two angular tritopic pyridine donor linkers (109 degrees bond angle) with three ditopic platinum acceptors (90 degrees bond angle) leads to essentially quantitative formation of self-assembled M(3)L(2) trigonal-bipyramidal (TBP) supramolecular species.

Estimated coronary heart disease attributable to insulin resistance in populations with and without type 2 diabetes mellitus.

OBJECTIVE: To estimate the annual number and costs of coronary heart disease (CHD) events in the United States attributable to insulin resistance among individuals with and without type 2 diabetes. RESEARCH DESIGN AND METHODS: Medline-indexed articles and government statistical reports were screened for data on the prevalence of insulin resistance, the relative risk of CHD by insulin resistance status, and number of CHD events per year among individuals with and without type 2 diabetes. These data were used to estimate the number of CHD events per year by insulin resistance and type 2 diabetes status, the proportion of CHD events attributable to insulin resistance, and the annual cost of these events. RESULTS: Of the 171,000 annual CHD events in the type 2 diabetes population, 164,000 (96%) occurred in those with insulin resistance, 80,000 of which were attributable to insulin resistance. Of the 929,000 annual CHD events in the non-type 2 diabetes population, 162,000 (17%) occurred in patients with insulin resistance, 58,000 of which were attributable to insulin resistance. Thus, insulin resistance is responsible for 46.8%, 6.2%, and 12.5% of the annual CHD events in the type 2 diabetes, non-type 2 diabetes, and total US population, respectively. The estimated annual total cost of these insulin resistance-attributable events was $12.5 billion in the United States in 1999, of which $6.6 billion were direct medical costs. CONCLUSION: Preventing or modifying insulin resistance may reduce the morbidity, mortality, and costs associated with CHD.

Workplace productivity. A review of the impact of migraine and its treatment.

Migraine is a common disorder characterised by recurrent episodes of disability. Despite the high prevalence of migraine, data have been lacking on its impact in a working population. The advent of new therapies has stimulated interest in this area, and evidence is now available that documents the substantial impact of migraine on workplace productivity and the likelihood of untreated migraine leading to unemployment or underemployment for the patient. This paper reviews current findings of both observational and interventional studies about the impact of migraine on productivity and employment. When considered in the light of migraine demographics, the high prevalence of migraine, and its low consultation and treatment rates, this evidence indicates that improved screening and treatment for this common condition could have a substantial impact on worker productivity and on patient well-being.

Palladium-catalyzed arylation of enynes and electron-deficient alkynes using diaryliodonium salts.

A new single-pot procedure for the synthesis of aryl alkynes is described. Palladium catalyzes the coupling reaction of diaryliodonium compounds with enynes and electron-deficient alkynes to give aryl alkynes in good yields.

Impact of illness and its treatment on workplace costs: regulatory and measurement issues.

In an attempt to document a broader spectrum of the benefits of their pharmaceutical products, drug companies increasingly seek to include productivity claims in their promotional campaigns. We describe the existing regulatory framework of the Food and Drug Administration (FDA) for considering productivity claims, distinguishing between the traditional "substantial evidence" standard and the "competent and reliable scientific evidence" standard. But the notion of competent and reliable scientific evidence may itself be problematic, even when it is the appropriate regulatory standard, because there exists no consistent measurement approach across diseases, workplaces, jobs, and worker capabilities that is widely accepted in this emerging area of health outcomes research. We examine the various measurement approaches that have been used to quantify the impact of illness and its treatment on workplace productivity, and we describe some of the shortcomings associated with each alternative. This discussion highlights the possible difficulties faced by the FDA in reviewing productivity-based promotional claims. Finally, we suggest possible strategies for furthering this field of investigation.