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Lydia Coulter Kwee,
Yutao Liu,
Carol Haynes,
Jason R Gibson,
Annjanette Stone,
Steven A Schichman,
Freya Kamel, Lorene M Nelson,
Barbara Topol,
Stephen K Van den Eeden,
Caroline M Tanner,
Merit E Cudkowicz,
Daniela L Grasso,
Robert Lawson,
Sumitra Muralidhar,
Eugene Z Oddone,
Silke Schmidt,
Michael A Hauser
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ABSTRACT: Following reports of an increased incidence of amyotrophic lateral sclerosis (ALS) in U.S. veterans, we have conducted a high-density genome-wide association study (GWAS) of ALS outcome and survival time in a sample of U.S. veterans. We tested ∼1.3 million single nucleotide polymorphisms (SNPs) for association with ALS outcome in 442 incident Caucasian veteran cases diagnosed with definite or probable ALS and 348 Caucasian veteran controls. To increase power, we also included genotypes from 5909 publicly-available non-veteran controls in the analysis. In the survival analysis, we tested for association between SNPs and post-diagnosis survival time in 639 Caucasian veteran cases with definite or probable ALS. After this discovery phase, we performed follow-up genotyping of 299 SNPs in an independent replication sample of Caucasian veterans and non-veterans (ALS outcome: 183 cases and 961 controls; survival: 118 cases). Although no SNPs reached genome-wide significance in the discovery phase for either phenotype, three SNPs were statistically significant in the replication analysis of ALS outcome: rs6080539 (177 kb from PCSK2), rs7000234 (4 kb from ZNF704), and rs3113494 (13 kb from LOC100506746). Two SNPs located in genes that were implicated by previous GWA studies of ALS were marginally significant in the pooled analysis of discovery and replication samples: rs17174381 in DPP6 (p = 4.4×10(-4)) and rs6985069 near ELP3 (p = 4.8×10(-4)). Our results underscore the difficulty of identifying and convincingly replicating genetic associations with a rare and genetically heterogeneous disorder such as ALS, and suggest that common SNPs are unlikely to account for a substantial proportion of patients affected by this devastating disorder.
PLoS ONE 01/2012; 7(3):e32768. · 4.09 Impact Factor
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ABSTRACT: Radiotherapy may improve the outcome of patients with pancreatic cancer but at an increased cost. In this study, the authors evaluated the cost-effectiveness of modern radiotherapy techniques in the treatment of locally advanced pancreatic cancer.
A Markov decision-analytic model was constructed to compare the cost-effectiveness of 4 treatment regimens: gemcitabine alone, gemcitabine plus conventional radiotherapy, gemcitabine plus intensity-modulated radiotherapy (IMRT); and gemcitabine with stereotactic body radiotherapy (SBRT). Patients transitioned between the following 5 health states: stable disease, local progression, distant failure, local and distant failure, and death. Health utility tolls were assessed for radiotherapy and chemotherapy treatments and for radiation toxicity.
SBRT increased life expectancy by 0.20 quality-adjusted life years (QALY) at an increased cost of $13,700 compared with gemcitabine alone (incremental cost-effectiveness ratio [ICER] = $69,500 per QALY). SBRT was more effective and less costly than conventional radiotherapy and IMRT. An analysis that excluded SBRT demonstrated that conventional radiotherapy had an ICER of $126,800 per QALY compared with gemcitabine alone, and IMRT had an ICER of $1,584,100 per QALY compared with conventional radiotherapy. A probabilistic sensitivity analysis demonstrated that the probability of cost-effectiveness at a willingness to pay of $50,000 per QALY was 78% for gemcitabine alone, 21% for SBRT, 1.4% for conventional radiotherapy, and 0.01% for IMRT. At a willingness to pay of $200,000 per QALY, the probability of cost-effectiveness was 73% for SBRT, 20% for conventional radiotherapy, 7% for gemcitabine alone, and 0.7% for IMRT.
The current results indicated that IMRT in locally advanced pancreatic cancer exceeds what society considers cost-effective. In contrast, combining gemcitabine with SBRT increased clinical effectiveness beyond that of gemcitabine alone at a cost potentially acceptable by today's standards.
Cancer 07/2011; 118(4):1119-29. · 4.77 Impact Factor
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ABSTRACT: To assess the familial aggregation of Parkinson's disease (PD), we compared the cumulative incidence of PD among first-degree relatives of PD cases and controls. We identified newly diagnosed patients with PD (n = 573) during 1994 to 1995 within Kaiser Permanente Medical Care Program of Northern California and recruited 496 cases (87%) for the case-control study. Of 720 eligible controls matched by birth year and sex to cases, 541 (75%) agreed to participate. Information on family history of PD and other neurodegenerative diseases was obtained by in-person structured interview. We used the reconstructed cohort approach that provides a better estimate of the risk. The cumulative incidence of PD was significantly higher among relatives of PD patients compared with relatives of controls (2.0 vs. 0.7%; relative risk (RR) = 3.4, 95% confidence interval (CI) 1.9-5.9; P = 0.0001). The degree of familial aggregation was higher among first-degree relatives of Hispanic PD cases compared with Hispanic controls (3.7% vs. 0.4%; RR = 8.5, 95% CI 1.0-68.9) than it was among non-Hispanic Caucasian cases and controls (2.0% vs. 0.8%; RR = 2.7, 95% CI 1.5-5.1; P = 0.02). The familial aggregation of PD was stronger among the siblings of PD cases (RR = 5.4, 95% CI 1.8-16.0) than among parents (RR = 2.7, 95% CI 1.3-5.2). The incidence and familial aggregation of PD is highest among Hispanics, warranting further studies of genetic and environmental risk factors in the Hispanic population.
Movement Disorders 11/2010; 25(15):2587-94. · 4.51 Impact Factor
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ABSTRACT: To determine whether low levels of 25-hydroxyvitamin D (25[OH]D) contribute to the increased risk of postpartum multiple sclerosis (MS) relapses.
Prospective cohort study.
Outpatients identified through membership records of Kaiser Permanente Northern California or Stanford University outpatient neurology clinics.
Twenty-eight pregnant women with MS.
We prospectively followed up patients through the postpartum year and assessed exposures and symptoms through structured interviews. Total serum 25(OH)D levels were measured using the DiaSorin Liaison Assay during the third trimester and 2, 4, and 6 months after giving birth. The data were analyzed using longitudinal multivariable methods.
Levels of 25(OH)D and relapse rate.
Fourteen (50%) women breastfed exclusively, and 12 women (43%) relapsed within 6 months after giving birth. During pregnancy, the average 25(OH)D levels were 25.4 ng/mL (range, 13.7-42.6) and were affected only by season (P=.009). In contrast, in the postpartum period, 25(OH)D levels were significantly affected by breastfeeding and relapse status. Levels of 25(OH)D remained low in the exclusive breastfeeding group, yet rose significantly in the nonexclusive breastfeeding group regardless of season (P=.007, unadjusted; P=.02, adjusted for season). By 4 and 6 months after childbirth, 25(OH)D levels were, on average, 5 ng/mL lower in the women who breastfed exclusively compared with the nonbreastfeeding group (P=.001).
Pregnancy and exclusive breastfeeding are strongly associated with low 25(OH)D levels in women with MS. However, these lower vitamin D levels were not associated with an increased risk of postpartum MS relapses. These data suggest that low vitamin D in isolation is not an important risk factor for postpartum MS relapses.
Archives of neurology 11/2010; 68(3):310-3. · 6.31 Impact Factor
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ABSTRACT: The aim of this article was to evaluate cancer occurrence before and after diagnosis of Parkinson's disease (PD). We investigated 692 patients newly diagnosed with PD and 761 age- and sex-matched control subjects identified during two periods (1994-1995 and 2000-2003) within Kaiser Permanente Medical Care Program of Northern California. Primary cancers were searched and dated, and all participants were followed up until the end of membership, death, or December 31, 2008. We used unconditional logistic regression to evaluate the PD-cancer association before the date of PD diagnosis or the index date and Cox proportional hazards regression to evaluate the PD-cancer association after the index date. Nearly 20% (140 of 692) of the PD patients and 25% (188 of 761) of the non-PD controls had ever had a cancer diagnosis. Before the index date, the prevalence of cancer was not significantly lower in patients with PD (8.1% PD vs. 9.2% controls; OR = 0.83; 95% CI 0.54-1.3). After the index date, the risk of developing a cancer did not differ between PD cases and controls (relative risk [RR] = 0.94; 95% CI 0.70-1.3). Among specific cancers, melanoma was more common among PD cases (before PD, OR = 1.5; 95% CI 0.40-5.2; after PD, RR = 1.6; 95% CI 0.71-3.6), but independent of dopaminergic therapy. Cancer occurrence is not significantly lower among patients with PD. The positive association between PD and subsequent melanoma merits further investigation, as it does not seem to be attributable to dopaminergic therapy, pigmentation, or confounding by smoking.
Movement Disorders 09/2010; 25(12):1809-17. · 4.51 Impact Factor
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ABSTRACT: Osteoporosis and fragility fractures are associated with significant morbidity for patients with systemic lupus erythematosus (SLE). New quality indicators (QIs) for SLE advise bone mineral density testing, calcium and vitamin D use, and antiresorptive or anabolic treatment for specific subgroups of patients receiving high-dose steroids.
Subjects were participants in the University of California, San Francisco Lupus Outcomes Study, an ongoing longitudinal study of patients with physician-confirmed SLE, in 2007-2008. Patients responded to an annual telephone survey and were queried regarding demographic, clinical, and other health care-related variables. Multiple logistic regression was used to predict receipt of care per the QIs described above.
One hundred twenty-seven patients met the criteria for the formal definitions of the denominators for QI I (screening) and QI II (calcium and vitamin D); 91 met the formal criteria for QI III (treatment). The proportions of patients receiving care consistent with the QIs were 74%, 58%, and 56% for QIs I, II, and III, respectively. In a sensitivity analysis of all steroid users (n = 427 for QI I and II and n = 224 for QI III), rates were slightly lower. Predictors of receiving care varied by QI and by denominator; however, female sex, older age, white race, and longer disease duration were associated with higher-quality care.
Bone health-related care in this community-based cohort of SLE patients is suboptimal. Quality improvement efforts should address osteoporosis prevention and care among all SLE patients, especially those receiving high-dose, prolonged steroids.
Arthritis care & research. 07/2010; 62(7):993-1001.
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Rita A Popat,
Stephen K Van Den Eeden,
Caroline M Tanner,
Clete A Kushida,
Anil N Rama,
Jed E Black,
Allan Bernstein,
Meike Kasten,
Anabel Chade,
Amethyst Leimpeter,
John Cassidy,
Valerie McGuire, Lorene M Nelson
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ABSTRACT: A reliable and valid questionnaire for screening restless legs syndrome (RLS) is essential for determining accurate estimates of disease frequency. In a 2002 NIH-sponsored workshop, experts suggested three mandatory questions for identifying RLS in epidemiologic studies. We evaluated the reliability and validity of this RLS-NIH questionnaire in a community-based sample and concurrently developed and evaluated the utility of an expanded screening questionnaire, the RLS-EXP.
The study was conducted at Kaiser Permanente of Northern California and the Stanford University Sleep Clinic. We evaluated test-retest reliability in a random sample of subjects with prior physician-assigned RLS (n=87), subjects with conditions frequently misclassified as RLS (n=31), and healthy subjects (n=9). Validity of both instruments was evaluated in a random sample of 32 subjects, and in-person examination by two RLS specialists was used as the gold standard.
For the first three RLS-NIH questions, the kappa statistic for test-retest reliability ranged from 0.5 to 1.0, and sensitivity and specificity was 86% and 45%, respectively. For the subset of five questions on RLS-EXP that encompassed cardinal features for diagnosing RLS, kappas were 0.4-0.8, and sensitivity and specificity were 81% and 73%, respectively.
Sensitivity of RLS-NIH is good; however, the specificity of the instrument is poor when examined in a sample that over-represents subjects with conditions that are commonly misclassified as RLS. Specificity can be improved by including separate questions on cardinal features, as used in the RLS-EXP, and by including a few questions that identify RLS mimics, thereby reducing false positives.
Sleep Medicine 02/2010; 11(2):154-60. · 3.40 Impact Factor
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Annette Langer-Gould,
Rohit Gupta,
Stella Huang,
Adam Hagan,
Kondala Atkuri,
Amethyst D Leimpeter,
Kathleen B Albers,
Eleni Greenwood,
Stephen K Van Den Eeden,
Lawrence Steinman, Lorene M Nelson
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ABSTRACT: To determine whether fluctuations in functional T-cell subsets can explain why multiple sclerosis (MS) relapses decline during pregnancy and increase in the postpartum period.
Case-control study.
Kaiser Permanente Northern California and Stanford University.
Twenty-six pregnant women with MS and 24 age-matched, pregnant controls. Intervention We prospectively followed up the pregnant women with MS and the age-matched, pregnant controls; conducted structured interviews; and collected peripheral blood mononuclear cells during each trimester and 2, 4, 6, 9, and 12 months post partum.
Sixteen functional cell types, including interferon-gamma (IFN-gamma)- and tumor necrosis factor-producing T-cell subsets, were measured using multicolor flow cytometry. Since these cell types may also fluctuate with pregnancy, lactational amenorrhea, or MS treatment, the data were analyzed taking into account these factors.
Fifteen women with MS (58%) had relapses during the postpartum year. CD4(+)IFN-gamma-producing cells fluctuated with MS relapses, declining during pregnancy in women with MS (P < .001) and continuing to decline after parturition in women with relapses (P = .001), yet rising or remaining stable in women with nonrelapsing MS or healthy pregnant women. Lactational amenorrhea was associated with a rise in CD4(+)IFN-gamma-producing cells in women with MS (P = .009). In contrast, CD4(+) tumor necrosis factor-producing cells decreased during lactational amenorrhea in all groups of women and, once this was taken into account, obscured any relationship to MS relapses. CD8(+)IFN-gamma-producing cells were elevated in women with MS throughout the study (P < .001) but did not fluctuate with relapses.
Our findings suggest that a decline in circulating CD4(+)IFN-gamma-producing cells leads to postpartum MS relapses. Our findings also suggest that the decline in these cells may begin during late pregnancy and that lactational amenorrhea induced by exclusive breastfeeding may be able to interrupt this process.
Archives of neurology 01/2010; 67(1):51-7. · 6.31 Impact Factor
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ABSTRACT: To examine the association between demographic and clinical features in early Parkinson disease (PD) and length of survival in a multiethnic population.
Clinical features within 2 years of diagnosis were determined for an inception cohort established during 1994-1995. Vital status was determined through December 31, 2005. Predictor variables included age at diagnosis, sex, race/ethnicity, as well as clinical subtype (modified tremor dominant, postural instability gait difficulty), symmetry, cognitive impairment, depression, dysphagia, and hallucinations. Cox proportional hazards regression analysis was used to identify factors associated with shorter survival.
Kaiser Permanente Medical Care Program, northern California.
Five hundred seventy-three men and women with newly diagnosed PD.
Three hundred fifty-two participants in the PD cohort (61.4%) had died in the follow-up period. Older age at diagnosis (hazard ratio [HR], 1.1; 95% confidence interval [CI], 1.09-1.12), modified postural instability gait difficulty subtype (HR, 1.8; 95% CI, 1.3-2.7), symmetry of motor signs (HR, 2.0; 95% CI, 1.1-3.7), mild (HR, 1.7; 95% CI, 1.3-2.2) and severe (HR, 2.7; 95% CI, 1.9-3.9) cognitive impairment, dysphagia (HR, 1.4; 95% CI, 1.1-1.9), and hallucinations (HR, 2.1; 95% CI, 1.3-3.2) were associated with increased all-cause mortality, after adjusting for age, sex, and race/ethnicity. None of the other factors altered mortality risk. In an empirical predictive analysis, most previous significant predictors remained associated with shorter survival.
Both motor and nonmotor features in early PD predict increased mortality risk, particularly postural instability gait difficulty, cognitive impairment, and hallucinations. These predictors may be useful in clinical practice and when designing clinical trials.
Archives of neurology 11/2009; 66(11):1353-8. · 6.31 Impact Factor
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ABSTRACT: To estimate the national occurrence of pregnancies in women with multiple sclerosis (MS) and epilepsy and to compare these pregnancy outcomes cross-sectionally with those in women with pregestational diabetes mellitus (DM) and the general obstetric population.
We studied the 2003-2006 Nationwide Inpatient Sample, of the Healthcare Cost and Utilization Project, to estimate the number of deliveries in women with MS, epilepsy, DM, and the general obstetric population. Pregnancy outcomes included length of hospital stay, hypertensive disorders including preeclampsia (HTN), premature rupture of membranes (PROM), intrauterine growth restriction (IUGR), and cesarean delivery. Multivariable regression analyses used maternal age and race/ethnicity as covariates.
Of an estimated 18.8 million deliveries, 10,055 occurred in women with MS, 4,730 with epilepsy, and 187,239 with DM. MS was associated with mildly increased odds of antenatal hospitalization (odds ratio [OR] 1.3, 95% confidence interval [CI] 1.2-1.5), IUGR (OR 1.7, 95% CI 1.2-2.4), and cesarean delivery (OR 1.3, 95% CI 1.1-1.4). Similarly, epilepsy was associated with increased rates of antenatal hospitalization (OR 3.0, 95% CI 2.6-3.5), IUGR (OR 1.9, 95% CI 1.2-3.3), and cesarean delivery (OR 1.5, 95% CI 1.3-1.9). HTN and PROM were not increased in either group. DM was associated with an increased risk of all adverse outcomes. Length of stay was modestly increased in all groups compared with controls.
In this large national database study of pregnancy outcomes in women with multiple sclerosis and epilepsy, rates of intrauterine growth restriction and cesarean delivery were only marginally higher than the general obstetric population without increases in other adverse outcomes.
Neurology 11/2009; 73(22):1831-6. · 8.31 Impact Factor
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ABSTRACT: To determine if exclusive breastfeeding protects against postpartum relapses of multiple sclerosis (MS) and, if so, whether this protection is related to prolonged lactational amenorrhea.
We conducted structured interviews to assess clinical, menstrual, and breastfeeding history during each trimester and 2, 4, 6, 9, and 12 months postpartum and collected neurological examination findings from the treating physicians of women with MS. Hazards ratios (HRs) were adjusted for measures of disease severity and age.
Kaiser Permanente Northern California and Stanford University.
We prospectively enrolled 32 pregnant women with MS and 29 age-matched, pregnant controls. Main Outcome Measure Postpartum relapse.
Of the 52% of women with MS who did not breastfeed or began regular supplemental feedings within 2 months postpartum, 87% had a postpartum relapse, compared with 36% of the women with MS who breastfed exclusively for at least 2 months postpartum (unadjusted HR, 5.0; 95% confidence interval, 1.7-14.2; P = .003; adjusted HR, 7.1; 95% confidence interval, 2.1-24.3; P = .002). Sixty percent reported that the primary reason for foregoing exclusive breastfeeding was to resume MS therapies. Women who breastfed exclusively had a later return of menses (P = .001) than women who did not, and lactational amenorrhea was associated with a reduced risk of postpartum relapses (P = .01).
Our findings suggest that exclusive breastfeeding and concomitant suppression of menses significantly reduce the risk of postpartum relapses in MS. Our findings call into question the benefit of foregoing breastfeeding to start MS therapies and should be confirmed in a larger study.
Archives of neurology 07/2009; 66(8):958-63. · 6.31 Impact Factor
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ABSTRACT: To use unweighted counts of dependencies in activities of daily living (ADLs) to assess the impact of functional impairment requires an assumption of equal preferences for each ADL dependency. To test this assumption, we analyzed standard gamble (SG) utilities of single and combination ADL dependencies among older adults.
Four hundred older adults used multimedia software (FLAIR1) to report SG utilities for their current health and hypothetical health states of dependency in each of 7 ADLs and 8 of 30 combinations of ADL dependencies.
Utilities for health states of multiple ADL dependencies were often greater than for states of single ADL dependencies. Dependence in eating, which is the ADL dependency with the lowest utility rating of the single ADL dependencies, ranked lower than 7 combination states. Similarly, some combination states with fewer ADL dependencies had lower utilities than those with more ADL dependencies. These findings were consistent across groups by gender, age, and education.
Our results suggest that the count of ADL dependencies does not adequately represent the utility for a health state. Cost-effectiveness analyses and other evaluations of programs that prevent or treat functional dependency should apply utility weights rather than relying on simple ADL counts.
Journal of clinical epidemiology 09/2008; 61(12):1261-70. · 2.96 Impact Factor
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Silke Schmidt,
Kelli D Allen,
Valerie T Loiacono,
Barbara Norman,
Catherine L Stanwyck,
Kristina M Nord,
Christina D Williams,
Edward J Kasarskis,
Freya Kamel,
Valerie McGuire, Lorene M Nelson,
Eugene Z Oddone
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ABSTRACT: Recent reports of a potentially increased risk of amyotrophic lateral sclerosis (ALS) for veterans deployed to the 1990-1991 Persian Gulf War prompted the Department of Veterans Affairs to establish a National Registry of Veterans with ALS, charged with the goal of enrolling all US veterans with a neurologist-confirmed diagnosis of ALS. The Genes and Environmental Exposures in Veterans with ALS study (GENEVA) is a case-control study presently enrolling cases from the Department of Veterans Affairs registry and a representative sample of veteran controls to evaluate the joint contributions of genetic susceptibility and environmental exposures to the risk of sporadic ALS. The GENEVA study design, recruitment strategies, methods of collecting DNA samples and environmental risk factor information are described here, along with a summary of demographic characteristics of the participants (537 cases, 292 controls) enrolled to date.
Neuroepidemiology 02/2008; 30(3):191-204. · 2.31 Impact Factor
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ABSTRACT: Epidemiologic studies have reported that cigarette smoking is inversely associated with Parkinson disease (PD). However, questions remain regarding the effect of age at smoking onset, time since quitting, and race/ethnicity that have not been addressed due to sample size constraints. This comprehensive assessment of the apparent reduced risk of PD associated with smoking may provide important leads for treatment and prevention.
To determine whether race/ethnicity, sex, education, age at diagnosis, and type of tobacco modify the observed effects of smoking on PD.
We conducted the first ever pooled analysis of PD combining individual-level data from 8 US case-control and 3 cohort studies (Nurses' Health Study, Health Professionals Follow-Up Study, and Honolulu-Asia Aging Study) conducted between 1960 and 2004. Case-control studies provided data for 2328 PD cases and 4113 controls matched by age, sex, and ethnicity; cohort studies contributed 488 cases and 4880 controls selected from age- and sex-matched risk sets.
Incident PD.
We confirmed inverse associations between PD and smoking and found these to be generally stronger in current compared with former smokers; the associations were stronger in cohort than in case-control studies. We observed inverse trends with pack-years smoked at every age at onset except the very elderly (>75 years of age), and the reduction of risk lessened with years since quitting smoking. The risk reductions we observed for white and Asian patients were not seen in Hispanic and African American patients. We also found an inverse association both for smoking cigars and/or pipes and for chewing tobacco in male subjects.
Our data support a dose-dependent reduction of PD risk associated with cigarette smoking and potentially with other types of tobacco use. Importantly, effects seemed not to be influenced by sex or education. Differences observed by race and age at diagnosis warrant further study.
Archives of Neurology 08/2007; 64(7):990-7. · 7.58 Impact Factor
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ABSTRACT: Inflammatory processes may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). We examined the association of non-steroidal anti-inflammatory drugs (NSAIDs) with the risk of ALS in case-control study of incident cases (n = 111) conducted within the Kaiser Permanente Medical Care Program of Northern California during the years 1996-2000. Controls (n = 258) randomly selected from the same population were frequency matched by age and gender to the ALS cases. Information regarding use of NSAIDs (non-aspirin and aspirin) and three classes of 'control' medications was collected by in-person structured interview. Subjects who used medication at least twice a week for at least a month were classified as 'ever users'. Multivariable logistic regression models were adjusted for age, gender, history of osteoarthritis/rheumatoid arthritis and pain, and other medication use. Overall, there was no association between NSAID use and ALS; however, some sex differences were noted for non-aspirin NSAID use. Among men, non-aspirin NSAID use was associated with a two-fold increased risk of ALS (adjusted odds ratio (OR) 2.0, 95% confidence interval (CI) 1.0-3.9), whereas among women, non-aspirin NSAID use was not associated with increased ALS risk (adjusted OR 0.5, 95% CI 0.2-1.2). ALS risk was not associated with aspirin use or with 'control' medications. This study did not find any evidence to suggest that NSAID use reduces the risk of ALS. The observed sex differences with non-aspirin NSAID use could be due to chance or an unmeasured confounder.
Amyotrophic lateral sclerosis: official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases 07/2007; 8(3):157-63. · 3.09 Impact Factor
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ABSTRACT: To identify clinical and demographic factors associated with long-term disability in patients with relapsing-remitting multiple sclerosis.
We searched the MEDLINE (1966-May 2005), EMBASE, CINAHL, Cochrane, and PsycINFO computerized databases, and reviewed reference lists of retrieved articles.
We included studies that examined predictors of long-term disability in patients with relapsing-remitting multiple sclerosis. We excluded studies that did not distinguish relapsing-remitting multiple sclerosis from primary progressive multiple sclerosis, enrolled fewer than 40 subjects, observed subjects for less than 5 years, or collected follow-up information in less than 80% of the inception cohort.
Two reviewers assessed study quality in 4 domains: cohort assembly, definitions and assessments of prognostic factors and outcomes, and statistical methods. One reviewer extracted data on the direction, magnitude, precision, and statistical significance of the effect of each predictor on prognosis.
Heterogeneity of study designs precluded us from pooling the results of 27 eligible studies. Study quality was limited by cross-sectional design, enrollment of prevalent cases from referral centers, and lack of multivariate adjustment. Sphincter symptoms at onset (hazard ratio, 1.1-3.1), incomplete recovery from the first attack (hazard ratio, 1.3-3.3), and a short interval between the first and second attack (hazard ratio, 1.6-1.9) were most strongly and consistently associated with poor prognosis. Other factors widely believed to be of prognostic importance, including sex and age at onset, demonstrated inconsistent or weak effects on prognosis.
The most robust predictors of long-term physical disability in relapsing-remitting multiple sclerosis are sphincter symptoms at onset and early disease course outcomes. These factors can be used to guide treatment decisions for drugs with significant toxicities.
Archives of Neurology 01/2007; 63(12):1686-91. · 7.58 Impact Factor
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Alexis Elbaz, Lorene M Nelson,
Haydeh Payami,
John P A Ioannidis,
Brian K Fiske,
Grazia Annesi,
Andrea Carmine Belin,
Stewart A Factor,
Carlo Ferrarese,
Georgios M Hadjigeorgiou, [......],
Caroline M Tanner,
Christine Van Broeckhoven,
Stephen K Van Den Eeden,
Karin Wirdefeldt,
Cyrus P Zabetian,
Marie Dehem,
Jennifer S Montimurro,
Audrey Southwick,
Richard M Myers,
Thomas A Trikalinos
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ABSTRACT: A genome-wide association study identified 13 single-nucleotide polymorphisms (SNPs) significantly associated with Parkinson's disease. Small-scale replication studies were largely non-confirmatory, but a meta-analysis that included data from the original study could not exclude all SNP associations, leaving relevance of several markers uncertain.
Investigators from three Michael J Fox Foundation for Parkinson's Research-funded genetics consortia-comprising 14 teams-contributed DNA samples from 5526 patients with Parkinson's disease and 6682 controls, which were genotyped for the 13 SNPs. Most (88%) participants were of white, non-Hispanic descent. We assessed log-additive genetic effects using fixed and random effects models stratified by team and ethnic origin, and tested for heterogeneity across strata. A meta-analysis was undertaken that incorporated data from the original genome-wide study as well as subsequent replication studies.
In fixed and random-effects models no associations with any of the 13 SNPs were identified (odds ratios 0.89 to 1.09). Heterogeneity between studies and between ethnic groups was low for all SNPs. Subgroup analyses by age at study entry, ethnic origin, sex, and family history did not show any consistent associations. In our meta-analysis, no SNP showed significant association (summary odds ratios 0.95 to 1.08); there was little heterogeneity except for SNP rs7520966.
Our results do not lend support to the finding that the 13 SNPs reported in the original genome-wide association study are genetic susceptibility factors for Parkinson's disease.
The Lancet Neurology 12/2006; 5(11):917-23. · 23.46 Impact Factor
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ABSTRACT: To examine the associations of reproductive factors and postmenopausal hormone use with the risk of amyotrophic lateral sclerosis (ALS) among women.
This case-control study was conducted within the Kaiser Permanente Medical Care Program (KPMCP) of Northern California during the years 1996-2000. Among the 193 postmenopausal women, 62 were incident ALS cases and 131 were controls randomly selected from KPMCP members and frequency matched by age and respondent type (self versus proxy) to the cases. Statistical analyses were carried out using logistic regression.
Reproductive factors such as age at menarche, age at final menstrual period, parity, oral contraceptive use, and type of menopause (natural vs. hysterectomy with or without oophorectomy) were not associated with risk of ALS. Postmenopausal hormone use was positively, but not significantly, associated with the risk of ALS (adjusted OR 1.9, 95% CI 0.9-3.8).
Reproductive factors were not associated with ALS risk. There is no evidence that suggests a protective effect of postmenopausal hormone use against the development of ALS. However, due to insufficient power, we cannot rule out a possible increase in ALS risk associated with postmenopausal hormone use.
Neuroepidemiology 02/2006; 27(3):117-21. · 2.31 Impact Factor
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ABSTRACT: To determine the risk for malignant primary adult-onset glioma (MPAG) associated with cigarette smoking and other lifestyle behaviors in a large, multiethnic, managed-care cohort.
The study population included a cohort of 133,811 subscribers to the Kaiser Permanente Medical Care Program of Northern California who had received a multiphasic health checkup and questionnaire between 1977 and 1985, were at least 25 years old at their start of follow-up, and had no prior history of benign or malignant brain tumors. In this cohort, patients were followed for up to 21 years for the development of MPAG.
Risk for MPAG among women increased with increasing packs of cigarettes smoked per day (p-for-trend = 0.04), adjusting for cigar and pipe smoking, patient age, sex, race, education, alcohol use and coffee consumption. A similar pattern was not observed for men. Individuals who smoked marijuana at least once a month, adjusting for cigarette smoking (packs smoked per day) and for the factors noted above, had a 2.8-fold (CI = 1.3-6.2) increased risk for MPAG. Relative risk for MPAG increased with increasing consumption of coffee (p-for-trend = 0.05).
Cigarette smoking was associated with an increased risk for MPAG among women but not among men. Individuals who smoked marijuana at least once a month had an increased risk for MPAG, although no dose-response relation was observed. Drinkers of >7 cups of coffee per day had a 70% increased risk for MPAG and smaller risk elevation for lower consumption. Alcohol usage was not associated with an increased risk for MPAG.
Journal of Neuro-Oncology 05/2004; 68(1):57-69. · 3.21 Impact Factor
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ABSTRACT: The goal of this study was to estimate the incidence of Parkinson's disease by age, gender, and ethnicity. Newly diagnosed Parkinson's disease cases in 1994-1995 were identified among members of the Kaiser Permanente Medical Care Program of Northern California, a large health maintenance organization. Each case met modified standardized criteria/Hughes diagnostic criteria as applied by a movement disorder specialist. Incidence rates per 100,000 person-years were calculated using the Kaiser Permanente membership information as the denominator and adjusted for age and/or gender using the direct method of standardization. A total of 588 newly diagnosed (incident) cases of Parkinson's disease were identified, which gave an overall annualized age- and gender-adjusted incidence rate of 13.4 per 100,000 (95% confidence interval (CI): 11.4, 15.5). The incidence rapidly increased over the age of 60 years, with only 4% of the cases being under the age of 50 years. The rate for men (19.0 per 100,000, 95% CI: 16.1, 21.8) was 91% higher than that for women (9.9 per 100,000, 95% CI: 7.6, 12.2). The age- and gender-adjusted rate per 100,000 was highest among Hispanics (16.6, 95% CI: 12.0, 21.3), followed by non-Hispanic Whites (13.6, 95% CI: 11.5, 15.7), Asians (11.3, 95% CI: 7.2, 15.3), and Blacks (10.2, 95% CI: 6.4, 14.0). These data suggest that the incidence of Parkinson's disease varies by race/ethnicity.
American Journal of Epidemiology 07/2003; 157(11):1015-22. · 5.22 Impact Factor
