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1.  Pharmacologic treatment of anxiety disorders in Parkinson's disease 
Neither best practices nor an evidence-base for the pharmacologic treatment of anxiety in Parkinson's disease has been established. This study investigated pharmacologic treatment of anxiety disorders in idiopathic Parkinson's disease and the associated clinical features.
Three community-based movement disorder neurology practices
250 subjects with Parkinson's disease.
Anxiety disorder diagnoses were established by consensus using a panel of six psychiatrists with expertise in geriatric psychiatry and movement disorders. Current medications were provided by the treating neurologists at the time of interview.
Amongst subjects with anxiety disorders only, 53% were untreated with medications. However, when anxious subjects with comorbid depressive disorders were included, 70.8% were on medications effective for treatment of anxiety. Subjects with anxiety and comorbid depressive disorders were more likely to be treated for their psychiatric disturbances than subjects with anxiety disorders alone (Odds Ratio 8.33) as were subjects with comorbid motor fluctuations (Odds Ratio, 3.65). There were no differences in the types of anti-anxiety medications used in regard to the presence of depression or motor fluctuations.
These findings suggest that over half of non-depressed Parkinson's disease patients with clinically significant anxiety are untreated with medication. A better understanding of the role of clinical features associated with anxiety in PD, such as depression and motor fluctuations, may improve the recognition and treatment of anxiety disorders in this population.
PMCID: PMC3655116  PMID: 23567419
Parkinson’s disease; Non-motor symptoms; Anxiety; Anxiety disorders; Psychiatric disorders; Treatment
2.  Anxiety and self-perceived health status in Parkinson's disease 
Parkinsonism & related disorders  2011;17(4):249-254.
Both anxiety and depression are associated with lower self-perceived health status (HS) in persons with Parkinson's disease (PD). Given the high co-morbidity with depression and other non-motor symptoms, it is unclear whether anxiety disorders, in general, versus specific anxiety subtypes have an independent effect on HS in PD. To examine this question, comprehensive assessments of motor and non-motor symptoms from 249 subjects with idiopathic PD followed in three community-based movement disorders neurology practices were analyzed. HS was measured using the 8-item PD Questionnaire (PDQ-8). Psychiatric diagnoses were established by consensus using a panel of six psychiatrists with expertise in geriatric psychiatry and movement disorders. Stepwise multiple regression analyses were used, with the PDQ-8 score as the dependent variable, to identify independent predictors of HS among motor, psychiatric, and other non-motor variables. Among the anxiety disorders, only anxiety associated with motor fluctuations was an independent predictor of HS after accounting for co-morbid depression and other clinical features. In addition, depressive disorders were also an independent predictor of lower HS. Prevention or treatment of state-dependent anxiety may improve HS in persons with PD.
PMCID: PMC3081400  PMID: 21292531
Parkinson's disease; Non-motor symptoms; Anxiety; Psychiatric disorders; Quality of Life; Fluctuations
3.  Prevalence of Anxiety Disorders and Anxiety Subtypes in Patients With Parkinson's Disease 
Anxiety disorders are common in Parkinson's Disease (PD), but are not well-characterized. This study determined the prevalence and clinical correlates of all DSM-IV-TR anxiety disorder diagnoses in a sample of 127 subjects with idiopathic PD who underwent comprehensive assessments administered by a psychiatrist and neurologist. A panel of six psychiatrists with expertise in geriatric psychiatry and/or movement disorders established by consensus all psychiatric diagnoses. Current and lifetime prevalence of at least one anxiety disorder diagnosis was 43% (n=55) and 49% (n=63), respectively. Anxiety Disorder Not Otherwise Specified, a DSM diagnosis used for anxiety disturbances not meeting criteria for defined subtypes, was the most common diagnosis (30% lifetime prevalence, n=38). Compared to non-anxious subjects, panic disorder (n=13) was associated with earlier age of PD onset [50.3(12.2) vs. 61.0(13.7) years, p<.01], higher rates of motor fluctuations [77% (10/13) vs. 39% (25/64), p=.01] and morning dystonia [38% (5/13) vs. 13% (8/62), p<.03]. This high prevalence of anxiety disorders, including disturbances often not meeting conventional diagnostic criteria, suggests that anxiety in PD is likely under-diagnosed and under-treated and refined characterization of anxiety disorders in PD is needed. In addition, certain anxiety subtypes may be clinically useful markers associated with disease impact in PD.
PMCID: PMC2830642  PMID: 19425086
Parkinson's disease; Non-motor symptoms; Anxiety; Psychiatric disorders
4.  Women's Preconceptional Health and Use of Health Services: Implications for Preconception Care 
Health Services Research  2008;43(1 Pt 1):54-75.
To improve understanding of women's use of health care before pregnancy, by analyzing how the health status and health risks of pre- and interconceptional women are associated with health services use.
Data Source
Data are from a cross-sectional random-digit dial telephone survey of a representative sample of 2002 women ages 18–45 years from the Central Pennsylvania Women's Health Study (CePAWHS). A subsample of 1,325 respondents with current reproductive capacity, classified by reproductive life stage (preconceptional or interconceptional), was analyzed.
Study Design
Bivariate and multiple logistic regression analyses were conducted to determine how health needs (including indices of health status and health risks related to adverse pregnancy outcomes) are associated with five indicators of health services use (receipt of a regular physical exam, obstetrician–gynecologist [ob/gyn] visit, receipt of a set of recommended screening services, receipt of health counseling services on general health topics, and receipt of pregnancy-related counseling), controlling for predisposing and enabling variables.
Principal Findings
Only half of women at risk of pregnancy report receiving counseling about pregnancy planning in the past year. One-third of women surveyed did not receive routine physical examinations and screening services, and over half received little or no health counseling. Multivariate analyses showed that all the measures of health needs except for negative health behavior were related to some type of health services use. Psychosocial stress was associated with having a recent ob/gyn visit, with receiving general health counseling, and with receiving pregnancy planning counseling. Cardiovascular risk was positively associated with receiving general health counseling and a regular physical exam, but negatively associated with seeing an ob/gyn. Positive health behaviors were associated with receiving screening services and with receiving general health counseling. Preconceptional reproductive life stage was positively associated with receiving a regular physical exam and negatively associated with having an ob/gyn visit.
Pre- and interconceptional women with specific health care needs may not receive appropriate health care before pregnancy. Improving pregnancy experiences and outcomes requires more comprehensive preconception health care and more preventive care before the first pregnancy.
PMCID: PMC2323151  PMID: 18211518
Women's health; pregnancy; preconception health; health care utilization; surveys
This study examines nonpregnant women's beliefs about whether or not they can influence their future birth outcomes with respect to the baby's health and factors associated with internal locus of control for birth outcomes. Perceived internal control of birth outcomes could be a predisposing factor for use of preconception care, which is recommended for all women of childbearing age by the Centers for Disease Control and Prevention. The overall hypothesis is that internal control of birth outcomes is a function of prior pregnancy experiences, current health status and stress levels, access to health care, and sociodemographics.
Data are from the Central Pennsylvania Women's Health Study random digit dial telephone survey of 2,002 women ages 18−45; the analytic sample is 614 nonpregnant women with current reproductive capacity who reported that they are considering a future pregnancy. Internal control of birth outcomes is measured using 1) a 4-item Internal Control of Birth Outcomes Scale, 2) a single-item measure of Preconceptional Control, and 3) a score reflecting high internal control on both of these measures.
In multiple logistic regression analyses, internal control of birth outcomes is positively associated with older age (35−45 vs. 18−34 years), higher education (some college or more), marital status (currently married or living with a partner), and higher self-rated physical health status on the SF-12v2 (but not mental health status or psychosocial stress). Previous adverse pregnancy outcomes and current access to health care have no association with internal control for birth outcomes.
Variables associated with internal control of birth outcomes among women contemplating a future pregnancy are primarily sociodemographic and physical health related. Educational and social marketing efforts to increase women's use of preconception care may be particularly important for women who are likely to have lower internal control, including younger, less educated, unmarried, and less healthy women.
PMCID: PMC2696461  PMID: 17951072
6.  Design of the Central Pennsylvania Women's Health Study (CePAWHS) Strong Healthy Women Intervention: Improving Preconceptional Health 
Considerable evidence suggests that modifiable risk factors for adverse pregnancy outcomes such as preterm birth and low birthweight include obesity, sedentary behavior, and infections. There is a growing consensus that the preconceptional and interconceptional periods may be an ideal time for preventive intervention targeting these risk factors; enhancing health before pregnancy would subsequently reduce the risk for poor pregnancy outcomes. This paper provides an overview of the development of a health behavior intervention, Strong Healthy Women, that aims to improve women's preconceptional and interconceptional health. We describe the rationale, delivery, and targeted outcomes of the program, as well as the design of an ongoing trial currently testing program efficacy. The content areas are also discussed and include pregnancy-conception, stress, physical activity, nutrition, infection, sources of smoke in the home, and substance use. This intervention protocol may offer researchers and healthcare professionals a framework for designing other programs aiming to improve women's preconceptional health.
PMCID: PMC2696480  PMID: 18270808
Interconception; Physical activity; Nutrition; Stress; Infection; Alcohol; Sources of smoke in home
7.  Perceived risk of preterm and low-birthweight birth in the Central Pennsylvania Women's Health Study 
Engaging women in preconception prevention may be challenging if at-risk women do not perceive increased risk. This study examined predictors of perceiving increased risk for preterm/low birth-weight birth.
Using the Central Pennsylvania Women's Health Study, a population-based sample of reproductive-age women, we analyzed whether sociodemographics, health and pregnancy history, health behaviors, attitudes, or health care utilization predicted risk perception of preterm/low-birthweight birth.
Of the 645 women analyzed, 157 (24%) estimated their risk of preterm/low-birthweight birth to be very or somewhat likely. Higher perceived risk was associated with being underweight, previous preterm/low-birthweight birth, having a mother with previous preterm/low-birthweight birth, lower perceived severity of preterm/low birth-weight, and smoking.
Several factors known to predict preterm/low birth-weight did influence risk perception in this study, whereas others did not. Further research on how these factors have an impact on participation in preconception care programs is warranted.
PMCID: PMC2696487  PMID: 18455138
adverse pregnancy outcome; low birthweight; preterm birth; risk perception
8.  Novel Genes Identified in a High Density Genome Wide Association Study for Nicotine Dependence 
Human molecular genetics  2006;16(1):24-35.
Tobacco use is a leading contributor to disability and death worldwide, and genetic factors contribute in part to the development of nicotine dependence. To identify novel genes for which natural variation contributes to the development of nicotine dependence, we performed a comprehensive genome wide association study using nicotine dependent smokers as cases and non-dependent smokers as controls. To allow the efficient, rapid, and cost effective screen of the genome, the study was carried out using a two-stage design. In the first stage, genotyping of over 2.4 million SNPs was completed in case and control pools. In the second stage, we selected SNPs for individual genotyping based on the most significant allele frequency differences between cases and controls from the pooled results. Individual genotyping was performed in 1050 cases and 879 controls using 31,960 selected SNPs. The primary analysis, a logistic regression model with covariates of age, gender, genotype and gender by genotype interaction, identified 35 SNPs with p-values less than 10-4 (minimum p-value 1.53 × 10-6). Although none of the individual findings is statistically significant after correcting for multiple tests, additional statistical analyses support the existence of true findings in this group. Our study nominates several novel genes, such as Neurexin 1 (NRXN1), in the development of nicotine dependence while also identifying a known candidate gene, the β3 nicotinic cholinergic receptor. This work anticipates the future directions of large-scale genome wide association studies with state-of-the-art methodological approaches and sharing of data with the scientific community.
PMCID: PMC2278047  PMID: 17158188
9.  Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs 
Human molecular genetics  2006;16(1):36-49.
Nicotine dependence is one of the world’s leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the β3 nicotinic receptor subunit gene (P = 9.4 × 10−5). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the α5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 × 10−4). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies.
PMCID: PMC2270437  PMID: 17135278
10.  Comparison of type I error for multiple test corrections in large single-nucleotide polymorphism studies using principal components versus haplotype blocking algorithms 
BMC Genetics  2005;6(Suppl 1):S78.
Although permutation testing has been the gold standard for assessing significance levels in studies using multiple markers, it is time-consuming. A Bonferroni correction to the nominal p-value that uses the underlying pair-wise linkage disequilibrium (LD) structure among the markers to determine the number of effectively independent tests has recently been proposed. We propose using the number of independent LD blocks plus the number of independent single-nucleotide polymorphisms for correction. Using the Collaborative Study on the Genetics of Alcoholism LD data for chromosome 21, we simulated 1,000 replicates of parent-child trio data under the null hypothesis with two levels of LD: moderate and high. Assuming haplotype blocks were independent, we calculated the number of independent statistical tests using 3 haplotype blocking algorithms. We then compared the type I error rates using a principal components-based method, the three blocking methods, a traditional Bonferroni correction, and the unadjusted p-values obtained from FBAT. Under high LD conditions, the PC method and one of the blocking methods were slightly conservative, whereas the 2 other blocking methods exceeded the target type I error rate. Under conditions of moderate LD, we show that the blocking algorithm corrections are closest to the desired type I error, although still slightly conservative, with the principal components-based method being almost as conservative as the traditional Bonferroni correction.
PMCID: PMC1866703  PMID: 16451692
11.  Using mixture models to characterize disease-related traits 
BMC Genetics  2005;6(Suppl 1):S99.
We consider 12 event-related potentials and one electroencephalogram measure as disease-related traits to compare alcohol-dependent individuals (cases) to unaffected individuals (controls). We use two approaches: 1) two-way analysis of variance (with sex and alcohol dependency as the factors), and 2) likelihood ratio tests comparing sex adjusted values of cases to controls assuming that within each group the trait has a 2 (or 3) component normal mixture distribution. In the second approach, we test the null hypothesis that the parameters of the mixtures are equal for the cases and controls. Based on the two-way analysis of variance, we find 1) males have significantly (p < 0.05) lower mean response values than females for 7 of these traits. 2) Alcohol-dependent cases have significantly lower mean response than controls for 3 traits. The mixture analysis of sex-adjusted values of 1 of these traits, the event-related potential obtained at the parietal midline channel (ttth4), found the appearance of a 3-component normal mixture in cases and controls. The mixtures differed in that the cases had significantly lower mean values than controls and significantly different mixing proportions in 2 of the 3 components. Implications of this study are: 1) Sex needs to be taken into account when studying risk factors for alcohol dependency to prevent finding a spurious association between alcohol dependency and the risk factor. 2) Mixture analysis indicates that for the event-related potential "ttth4", the difference observed reflects strong evidence of heterogeneity of response in both the cases and controls.
PMCID: PMC1866680  PMID: 16451715
12.  Use of susceptibility scoring in conjunction with the genotypic transmission disequilibrium test 
BMC Genetics  2005;6(Suppl 1):S137.
We explored the utility of selecting a genetically predisposed subgroup to increase the finding of a genetic signal in the Genetic Analysis Workshop 14 Collaborative Study on the Genetics of Alcoholism dataset. A subgroup of affected probands with low environmental risk exposures was defined using a susceptibility score calculated from an environmental risk model. Thirty-nine probands with highly positive scores were selected, along with their parents, for use in a genotypic transmission disequilibrium test (TDT) test. We compared the results of the genotypic TDT in this subgroup to the TDT results using all probands and their parents. For some markers, the susceptibility scoring approach resulted in smaller p-values, while for other markers, evidence for a genetic signal weakened. Further explorations into genetic and environmental population characteristics that benefit from this approach are warranted.
PMCID: PMC1866799  PMID: 16451596
13.  The impact of population heterogeneity on risk estimation in genetic counseling 
BMC Medical Genetics  2004;5:18.
Genetic counseling has been an important tool for evaluating and communicating disease susceptibility for decades, and it has been applied to predict risks for a wide class of hereditary disorders. Most diseases are complex in nature and are affected by multiple genes and environmental conditions; it is highly likely that DNA tests alone do not define all the genetic factors responsible for a disease, so that persons classified into the same risk group by DNA testing actually could have different disease susceptibilities. Ignorance of population heterogeneity may lead to biased risk estimates, whereas additional information on population heterogeneity may improve the precision of such estimates.
Although DNA tests are widely used, few studies have investigated the accuracy of the predicted risks. We examined the impact of population heterogeneity on predicted disease risks by simulation of three different heterogeneity scenarios and studied the precision and accuracy of the risks estimated from a logistic regression model that ignored population heterogeneity. Moreover, we also incorporated information about population heterogeneity into our original model and investigated the resulting improvement in the accuracy of risk estimation.
We found that heterogeneity in one or more categories could lead to biased estimates not only in the "contaminated" categories but also in other homogeneous categories. Incorporating information about population heterogeneity into the original model greatly improved the accuracy of risk estimation.
Our findings imply that without thorough knowledge about genetic basis of the disease, risks estimated from DNA tests may be misleading. Caution should be taken when evaluating the predicted risks obtained from genetic counseling. On the other hand, the improved accuracy of risk estimates after incorporating population heterogeneity information into the model did point out a promising direction for genetic counseling, since more and more new techniques are being invented and disease etiology is being better understood.
PMCID: PMC449710  PMID: 15228628
14.  Susceptibility scoring in family-based association testing 
BMC Genetics  2003;4(Suppl 1):S49.
Family-based association testing is an important part of genetic epidemiology. Tests are available to include multiple siblings, unaffected offspring, and to adjust for environmental covariates. We explore a susceptibility residual method of adjustment for covariates.
Through simulation, we show that environmental adjustments that down-weight persons who are "destined" to be affected decrease the power to detect genetic association. We used the residual adjusted method on the Framingham Heart Study offspring data, provided for Genetic Analysis Workshop 13, and got mixed results.
When the genetic effect and environmental effects are independent, a susceptibility residual method of adjustment for environmental covariates reduces the power of the association test. Further study is necessary to determine if residual adjustment is appropriate in more complex disease models.
PMCID: PMC1866485  PMID: 14975117
15.  Analysis of gene × environment interactions in sibships using mixed models 
BMC Genetics  2003;4(Suppl 1):S18.
Gene × environment models are widely used to assess genetic and environmental risks and their association with a phenotype of interest for many complex diseases. Mixed generalized linear models were used to assess gene × environment interactions with respect to systolic blood pressure on sibships adjusting for repeated measures and hierarchical nesting structures. A data set containing 410 sibships from the Framingham Heart Study offspring cohort (part of the Genetic Analysis Workshop 13 data) was used for all analyses. Three mixed gene × environment models, all adjusting for repeated measurement and varying levels of nesting, were compared for precision of estimates: 1) all sibships with adjustment for two levels of nesting (sibs within sibships and sibs within pedigrees), 2) all sibships with adjustment for one level of nesting (sibs within sibships), and 3) 100 data sets containing random draws of one sibship per extended pedigree adjusting for one level of nesting.
The main effects were: gender, baseline age, body mass index (BMI), hypertensive treatment, cigarettes per day, grams of alcohol per day, and marker GATA48G07A. The interaction fixed effects were: baseline age by gender, baseline age by cigarettes per day, baseline age by hypertensive treatment, baseline age by BMI, hypertensive treatment by BMI, and baseline age by marker GATA48G07A. The estimates for all three nesting techniques were not widely discrepant, but precision of estimates and determination of significant effects did change with the change in adjustment for nesting.
Our results show the importance of the adjustment for all levels of hierarchical nesting of sibs in the presence of repeated measures.
PMCID: PMC1866452  PMID: 14975086
16.  Impact of Medicare payment policy on home health resources utilization 
Health Care Financing Review  1991;13(2):13-18.
In this study, the association between Medicare regulations and the provision of public home health care is examined. Medicare clients were compared with non-Medicare groups of those 65 years of age or over and those under 65. Results suggested that both age- and payer-related factors contribute to utilization of services. Older patients showed greater need for chronic illness care relative to younger patients; however, Medicare patients used fewer resources and had poorer outcomes relative to older non-Medicare patients.
PMCID: PMC4193216  PMID: 10122359
17.  Comparison of Two Intravenous Sedation Techniques for Percutaneous Radiofrequency Trigeminal Rhizotomy 
Anesthesia Progress  1987;34(6):207-210.
Conscious sedation, as used in dentistry and oral surgery, has been used satisfactorily to manage patients undergoing the intense pain encountered in radio frequency trigeminal rhizotomy for tic douloureux. The pain produced by this procedure cannot be blocked by local anesthesia. General anesthesia cannot be used because of the need for sensory testing in an awake, cooperative patient. Conscious sedation using alphaprodine, hydroxyzine, methohexital, and intensive behavioral modification was compared with a neuroleptic intravenous sedation technique using droperidol, fentanyl, and thiopental. Patients managed with conscious sedation were found to be more amnestic for the pain of surgery, a difference that persisted six months later.
PMCID: PMC2190044  PMID: 3481517

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