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7. Genomewide association study of Parkinson's disease clinical biomarkers in 12 longitudinal patients' cohorts

Author

Iwaki, H., Blauwendraat, C., Leonard, H.L., Kim, J.J., Liu, G.Q., Maple-Grodem, J., Corvol, J.C., Pihlstrom, L., Nimwegen, M. van, Hutten, S.J., Nguyen, K.D.H., Rick, J., Eberly, S., Faghri, F., Auinger, P., Scott, K.M., Wijeyekoon, R., Deerlin, V.M. van, Hernandez, D.G., Gibbs, J.R., Chitrala, K.N., Day-Williams, A.G., Brice, A., Alves, G., Noyce, A.J., Tysnes, O.B., Evans, J.R., Breen, D.P., Estrada, K., Wegel, C.E., Danjou, F., Simon, D.K., Andreassen, O., Ravina, B., Toft, M., Heutink, P., Bloem, B.R., Weintraub, D., Barker, R.A., Williams-Gray, C.H., Warrenburg, B.P. van de, Hilten, J.J. van, Scherzer, C.R., Singleton, A.B., Nalls, M.A., and Int Parkinson's Dis Genomics Cons

Subjects
Parkinson's disease, GBA, Apolipoprotein E, genomewide association study
Published
2019

12. Prediction of cognition in Parkinson's disease with a clinical-genetic score: a longitudinal analysis of nine cohorts

Author

Liu, G, Locascio, JJ, Corvol, J-C, Boot, B, Liao, Z, Page, K, Franco, D, Burke, K, Jansen, IE, Trisini-Lipsanopoulos, A, Winder-Rhodes, S, Tanner, CM, Lang, AE, Eberly, S, Elbaz, A, Brice, A, Mangone, G, Ravina, B, Shoulson, I, Cormier-Dequaire, F, Heutink, P, Van Hilten, JJ, Barker, RA, Williams-Gray, CH, Marinus, J, Scherzer, CR, HBS, CamPaIGN, PICNICS, PROPARK, PSG, DIGPD, PDBP, Barker, Roger [0000-0001-8843-7730], Williams-Gray, Caroline [0000-0002-2648-9743], and Apollo - University of Cambridge Repository

Subjects
Aged, 80 and over, Male, DIGPD, PICNICS, CamPaIGN, Parkinson Disease, Middle Aged, Prognosis, HBS, Disease Progression, Humans, Dementia, Female, Cognitive Dysfunction, Longitudinal Studies, PDBP, PROPARK, Algorithms, PSG, Proportional Hazards Models, Aged
Abstract

Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical-genetic score to predict global cognitive impairment in patients with the disease.In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generated from the entire study population.3200 patients with Parkinson's disease who were longitudinally assessed with 27 022 study visits between 1986 and 2016 in nine cohorts from North America and Europe were assessed for eligibility. 235 patients with MMSE ≤25 at baseline and 135 whose first study visit occurred more than 12 years from disease onset were excluded. The discovery population comprised 1350 patients (after further exclusion of 334 with missing covariates) from six longitudinal cohorts with 5165 longitudinal visits over 12·8 years (median 2·8, IQR 1·6-4·6). Age at onset, baseline MMSE, years of education, motor exam score, sex, depression, and β-glucocerebrosidase (GBA) mutation status were included in the prediction model. The replication population comprised 1132 patients (further excluding 14 patients with missing covariates) from three longitudinal cohorts with 19 127 follow-up visits over 8·6 years (median 6·5, IQR 4·1-7·2). The cognitive risk score predicted cognitive impairment within 10 years of disease onset with an area under the curve (AUC) of more than 0·85 in both the discovery (95% CI 0·82-0·90) and replication (95% CI 0·78-0·91) populations. Patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile (hazard ratio 18·4 [95% CI 9·4-36·1]). Dementia or disabling cognitive impairment was predicted with an AUC of 0·88 (95% CI 0·79-0·94) and a negative predictive value of 0·92 (95% 0·88-0·95) at the predefined cutoff of 0·196. Performance was stable in 10 000 randomly resampled subsets.Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson's disease. This model could improve trials of cognitive interventions and inform on prognosis.National Institutes of Health, US Department of Defense.

Published
2017

13. Diagnosis of Parkinson's disease on the basis of clinical and genetic classification: A population-based modelling study

Author

Nalls, MA, McLean, CY, Rick, J, Eberly, S, Hutten, SJ, Gwinn, K, Sutherland, M, Martinez, M, Heutink, P, Williams, NM, Hardy, J, Gasser, T, Brice, A, Price, TR, Nicolas, A, Keller, MF, Molony, C, Gibbs, JR, Chen-Plotkin, A, Suh, E, Letson, C, Fiandaca, MS, Mapstone, M, Federoff, HJ, Noyce, AJ, Morris, H, Van Deerlin, VM, Weintraub, D, Zabetian, C, Hernandez, DG, Lesage, S, Mullins, M, Conley, ED, Northover, CAM, Frasier, M, Marek, K, Day-Williams, AG, Stone, DJ, Ioannidis, JPA, and Singleton, AB

Abstract

© 2015 Elsevier Ltd. Background: Accurate diagnosis and early detection of complex diseases, such as Parkinson's disease, has the potential to be of great benefit for researchers and clinical practice. We aimed to create a non-invasive, accurate classification model for the diagnosis of Parkinson's disease, which could serve as a basis for future disease prediction studies in longitudinal cohorts. Methods: We developed a model for disease classification using data from the Parkinson's Progression Marker Initiative (PPMI) study for 367 patients with Parkinson's disease and phenotypically typical imaging data and 165 controls without neurological disease. Olfactory function, genetic risk, family history of Parkinson's disease, age, and gender were algorithmically selected by stepwise logistic regression as significant contributors to our classifying model. We then tested the model with data from 825 patients with Parkinson's disease and 261 controls from five independent cohorts with varying recruitment strategies and designs: the Parkinson's Disease Biomarkers Program (PDBP), the Parkinson's Associated Risk Study (PARS), 23andMe, the Longitudinal and Biomarker Study in PD (LABS-PD), and the Morris K Udall Parkinson's Disease Research Center of Excellence cohort (Penn-Udall). Additionally, we used our model to investigate patients who had imaging scans without evidence of dopaminergic deficit (SWEDD). Findings: In the population from PPMI, our initial model correctly distinguished patients with Parkinson's disease from controls at an area under the curve (AUC) of 0·923 (95% CI 0·900-0·946) with high sensitivity (0·834, 95% CI 0·711-0·883) and specificity (0·903, 95% CI 0·824-0·946) at its optimum AUC threshold (0·655). All Hosmer-Lemeshow simulations suggested that when parsed into random subgroups, the subgroup data matched that of the overall cohort. External validation showed good classification of Parkinson's disease, with AUCs of 0·894 (95% CI 0·867-0·921) in the PDBP cohort, 0·998 (0·992-1·000) in PARS, 0·955 (no 95% CI available) in 23andMe, 0·929 (0·896-0·962) in LABS-PD, and 0·939 (0·891-0·986) in the Penn-Udall cohort. Four of 17 SWEDD participants who our model classified as having Parkinson's disease converted to Parkinson's disease within 1 year, whereas only one of 38 SWEDD participants who were not classified as having Parkinson's disease underwent conversion (test of proportions, p=0·003). Interpretation: Our model provides a potential new approach to distinguish participants with Parkinson's disease from controls. If the model can also identify individuals with prodromal or preclinical Parkinson's disease in prospective cohorts, it could facilitate identification of biomarkers and interventions. Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Michael J Fox Foundation.

Published
2015

14. ECMO/PPHN

Author

Montgomery V. L., Eberly S. M., Mellgren K., Skogby M., Friberg L. G., Wadenvik H., Mellgren G., Maglajlić, S., Jovanović, I., Parezanović, V., Vušurović, V., Koš, R., Laban-Nestorović, S., Mustafa, Iqbal, Sjamsubin, Embing, Martona, Marteye, Samudra, Spemato Heru, Rachmat, Yusuf, Rahayoe, Anna Ulfah, and Samsu, Zuswahyudha

Published
1996
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15. Relationship of Mediterranean diet and caloric intake to phenoconversion in Huntington disease

Author

Marder, K. Gu, Y. Eberly, S. Tanner, C.M. Scarmeas, N. Oakes, D. Shoulson, I.

Abstract

IMPORTANCE: Adherence to Mediterranean-type diet (MeDi) may delay onset of Alzheimer and Parkinson diseases. Whether adherence to MeDi affects time to phenoconversion in Huntington disease (HD), a highly penetrant, single-gene disorder, is unknown. OBJECTIVES: To determine if MeDi modifies the time to clinical onset of HD (phenoconversion) in premanifest carriers participating in Prospective Huntington at Risk Observational Study (PHAROS), and to examine the effects of body mass index and caloric intake on time to phenoconversion. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study of 41 Huntington study group sites in the United States and Canada involving 1001 participants enrolled in PHAROS between July 1999 and January 2004 who were followed up every 9 months until 2010. A total of 211 participants aged 26 to 57 years had an expanded CAG repeat length (≥37). EXPOSURE: A semiquantitative food frequency questionnaire was administered 33 months after baseline. We calculated daily gram intake for dairy, meat, fruit, vegetables, legumes, cereals, fish, monounsaturated and saturated fatty acids, and alcohol and constructed MeDi scores (0-9); higher scores indicate higher adherence. Demographics, medical history, body mass index, and Unified Huntington's Disease Rating Scale (UHDRS) score were collected. MAIN OUTCOME AND MEASURE: Cox proportional hazards regression models to determine the association of MeDi and phenoconversion. RESULTS: Age, sex, caloric intake, education status, and UHDRS motor scores did not differ among MeDi tertiles (0-3, 4-5, and 6-9). The highest body mass index was associated with the lowest adherence to MeDi. Thirty-one participants phenoconverted. In a model adjusted for age, CAG repeat length, and caloric intake, MeDi was not associated with phenoconversion (P for trend = 0.14 for tertile of MeDi, and P = .22 for continuous MeDi). When individual components of MeDi were analyzed, higher dairy consumption (hazard ratio, 2.36; 95%CI, 1.0-5.57; P = .05) and higher caloric intake (P = .04) were associated with risk of phenoconversion. CONCLUSIONS AND RELEVANCE: MeDiwas not associated with phenoconversion; however, higher consumption of dairy products had a 2-fold increased risk and may be a surrogate for lower urate levels (associated with faster progression in manifest HD). Studies of diet and energy expenditure in premanifest HDmay provide data for interventions to modify specific components of diet that may delay the onset of HD.

Published
2013

18. Children with special health care needs and managed care

Author

McBrien Dm, Van Dyke Dc, Sherbondy Al, Doolittle D, and Eberly S

Subjects
Male, Health Services Needs and Demand, Quality Assurance, Health Care, business.industry, Managed Care Programs, Children with special health care needs, Pediatrics, Disabled Children, 03 medical and health sciences, 0302 clinical medicine, Nursing, Ambulatory care, Patient Satisfaction, 030225 pediatrics, Pediatrics, Perinatology and Child Health, Health care, Self care, Medicine, Managed care, Humans, Female, business, Child, Unlicensed assistive personnel, Quality of Health Care
Published
1999

27. Life events prior to suicide in middle aged and older adults

Author

Duberstein, P., Conwell, Y., Conner, K., and Eberly, S.

Subjects
Health, Seniors
Abstract

Objective: Despite the upsurge in interest in stress and depression in late-life, there remains a paucity of controlled data on life events and suicide in middle-aged (50-64) and older (65+) adults. We hypothesized that serious illness in self would amplify suicide risk in older adults and family discord and financial trouble would confer risk in middle-aged adults. Method: We conducted a retrospective case-control study in two New York State counties (Monroe, Onondaga) and compared suicides and age-, gender and county-matched controls. Results: In 50-64 year olds, suicides were more likely to have experiences family discord, financial strain, employment change, and separation in the year prior to death/interview. Family discord and serious illness in self conferred suicide risk in individuals 65 and older. Multivariate analyses showed that illness in self amplified suicide risk even after controlling for active psychiatric disorders. Conclusions: While some events may confer suicide risk independent of age, others are more age-specific. Suicide prevention initiatives should consider the interpersonal, socioeconomic, and medical context of suicide.

Published
2002

36. Methods for estimating uncertainty in factor analytic solutions.

Author

Paatero, P., Eberly, S., G.^Brown, S., and Norris, G. A.

Subjects
*QUANTUM measurement, *HEISENBERG uncertainty principle, *DISPLACEMENT (Mechanics), *MULTIVARIATE analysis, *MATRICES (Mathematics)
Abstract

EPA PMF version 5.0 and the underlying multilinear engine executable ME-2 contain three methods for estimating uncertainty in factor analytic models: classical bootstrap (BS), displacement of factor elements (DISP), and bootstrap enhanced by displacement of factor elements (BS-DISP). The goal of these methods is to capture the uncertainty of PMF analyses due to random errors and rotational ambiguity. It is shown that the three methods complement each other: depending on characteristics of the data set, one method may provide better results than the other two. Results are presented using synthetic data sets, including interpretation of diagnostics, and recommendations are given for parameters to report when documenting uncertainty estimates from EPA PMF or ME-2 applications. [ABSTRACT FROM AUTHOR]

Published
2013
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40. Serum urate and probability of dopaminergic deficit in early "Parkinson's disease".

Author

Schwarzschild MA, Marek K, Eberly S, Oakes D, Shoulson I, Jennings D, Seibyl J, Ascherio A, Parkinson Study Group PRECEPT Investigators, Schwarzschild, Michael A, Marek, Kenneth, Eberly, Shirley, Oakes, David, Shoulson, Ira, Jennings, Danna, Seibyl, John, and Ascherio, Alberto

Abstract

The objective of this study was to investigate whether higher levels of urate, an antioxidant linked to a lower likelihood of developing Parkinson's disease, is also a predictor of having a dopamine transporter brain scan without evidence of dopaminergic deficit. In a cross-sectional study of 797 mildly affected, untreated parkinsonian subjects diagnosed with early Parkinson's disease in the Parkinson Research Examination of CEP-1347 Trial, we investigated the relationship at baseline between serum urate and striatal dopamine transporter density, determined by single-photon emission computed tomography of iodine-123-labeled 2-β-carboxymethoxy-3-β-(4-iodophenyl)tropane uptake. A scan without evidence of dopaminergic deficit was defined as lowest putamen iodine-123-labeled 2-β-carboxymethoxy-3-β-(4-iodophenyl)tropane > 80% age-expected putamen dopamine transporter density. The odds of having a scan without evidence of dopaminergic deficit rose across increasing quintiles of urate level, with an age- and sex-adjusted odds ratio of 3.2 comparing the highest to the lowest urate quintile (95% confidence interval, 1.5-7.2; P for trend = .0003), and remained significant after adjusting for potential confounding factors. The association was significant in men but not women, regardless of whether common or sex-specific quintiles of urate were used. Higher levels of urate were associated with a greater likelihood of a scan without evidence of dopaminergic deficit among subjects with early untreated parkinsonism in the Parkinson Research Examination of CEP-1347 Trial. The findings support the diagnostic utility of urate in combination with other determinants. [ABSTRACT FROM AUTHOR]

Published
2011
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42. Living alone after myocardial infarction. Impact on prognosis.

Author

Case, R B, Moss, A J, Case, N, McDermott, M, and Eberly, S

Subjects
COMPARATIVE studies, INTERPERSONAL relations, RESEARCH methodology, MEDICAL cooperation, MYOCARDIAL infarction, PROGNOSIS, RESEARCH, SINGLE people, SOCIAL isolation, DISEASE relapse, SOCIAL support, EVALUATION research, SOCIAL context, RANDOMIZED controlled trials, DISEASE incidence, PROPORTIONAL hazards models, IMPACT of Event Scale, PSYCHOLOGY
Abstract

Objective: To determine if the presence of a disrupted marriage or living alone would be an independent prognostic risk factor for a subsequent major cardiac event following an initial myocardial infarction.Design: Prospective evaluation in the placebo wing of a randomized, double-blind drug trial in patients with an enzyme-documented acute myocardial infarction who were admitted to a coronary care facility. Data for living alone and/or a marital disruption were entered into a Cox proportional hazards model constructed from important physiologic and nonphysiologic factors in the same database.Setting: Multicenter trial in a mixture of community and academic hospitals in the United States and Canada.Patients: All consenting patients who were 25 to 75 years of age and without other serious diseases were enrolled (placebo, N = 1234) within 3 to 15 days of the index infarction and followed for a period of 1 to 4 years (mean, 2.1 years). Nine hundred sixty-seven patients were followed for 1.1 years and 530 for 2.2 years.Primary Outcome Measure: Recurrent major cardiac event (either recurrent nonfatal infarction or cardiac death).Results: Living alone was an independent risk factor, with a hazard ratio of 1.54 (95% confidence interval, 1.04 to 2.29; P less than .03). Using the Kaplan-Meier statistical method for calculation, the recurrent cardiac event rate at 6 months was 15.8% in the group living alone vs 8.8% in the group not living alone. Risk remained significant throughout the follow-up period (P = .001). A disrupted marriage was not an independent risk factor.Conclusion: Living alone but not a disrupted marriage is an independent risk factor for prognosis after myocardial infarction when compared with all other known risk factors. [ABSTRACT FROM AUTHOR]

Published
1992
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43. The necessary length of hospital stay for chronic pulmonary disease.

Author

Mushlin, A I, Black, E R, Connolly, C A, Buonaccorso, K M, and Eberly, S W

Subjects
BRONCHIAL spasm, OBSTRUCTIVE lung disease treatment, CHRONIC diseases, COMPARATIVE studies, DIAGNOSIS related groups, HOSPITAL utilization, LENGTH of stay in hospitals, LONGITUDINAL method, RESEARCH methodology, MEDICAL cooperation, MEDICAL protocols, RESEARCH, RESEARCH funding, EVALUATION research, THERAPEUTICS
Abstract

Objective: --To determine the necessary length of stay for patients admitted to the hospital with an exacerbation of chronic pulmonary disease and to compare this with the length of stay assigned by the diagnosis related group system.Design: --A cohort of patients were followed up prospectively after hospital admission to determine when complications, critical incidents, and the need for monitoring occurred. The medically derived necessary lengths of stay were statistically compared with the lengths of stay assigned by the diagnosis related group. Clinical factors were used to predict long vs short necessary lengths of stay.Setting: --Two acute care hospitals: one was the principal and the other a major community teaching hospital.Patients: --A consecutive sample of 83 patients who were 45 years of age or older and who required admission for treatment of chronic pulmonary disease.Main Outcome Measures: --The occurrence and time of complications, critical interventions, and monitoring.Results: --After 6 days in the hospital, 90% of patients were free of complications or the need for monitoring. However, 16 days elapsed before 90% of patients had been discharged from the hospital. The length of stay that was considered necessary for care averaged 6.9 days; the actual mean length of stay was 8.7 days. The correlation between each patient's ideal length of stay and the length of stay assigned by the diagnosis related group was low and was not statistically significant. Three clinical variables at the time of admission (high PCO2 levels, symptoms that were present for more than 1 day, and antibiotic treatment) were associated with the need for longer hospital stays.Conclusions: --The medically required length of stay for patients with an exacerbation of chronic pulmonary disease was between 6 and 7 days, on average. This length of stay, which was based on clinical events, differs from the length of stay that was calculated as a statistical norm by the diagnosis related group system. Clinical characteristics may help to identify patients who require a longer length of stay. [ABSTRACT FROM AUTHOR]

Published
1991
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48. Bovine mitochondrial ribosomes. Elongation factor specificity.

Author

Eberly, S L, Locklear, V, and Spremulli, L L

Abstract

The activity of bovine mitochondrial ribosomes with elongation factors from a variety of sources including the mitochondria of lower eukaryotes, chloroplasts, Gram-negative bacteria, Gram-positive bacteria, and the eukaryotic cell cytoplasm has been investigated. Bovine mitochondrial ribosomes are active with homologous mitochondrial elongation factor (EF)-G but display no activity with the mitochondrial or chloroplast translocases from the lower eukaryote Euglena gracilis, with Escherichia coli or Bacillus subtilis EF-G or with cytoplasmic EF-2. In contrast to the results obtained with the translocases, E. coli EF-Tu, B. subtilis EF-Tu, and Euglena chloroplast EF-Tu all function to a significant extent on the mitochondrial ribosomes. Cytoplasmic EF-1 has barely detectable activity on the animal mitochondrial ribosomes. The polymerization of phenylalanine by these ribosomes is dependent on poly(U), displays a rather broad Mg2+ optimum around 12 mM, and proceeds most rapidly at low monovalent ion concentrations.

Published
1985
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49. Safety of rasagiline in elderly patients with Parkinson disease

Author

Goetz, C G., Schwid, S R., Eberly, S W., Oakes, D, and Shoulson, I

Abstract

The authors examined age effects on adverse events from two randomized, controlled trials of rasagiline, comparing younger (younger than70 years) and older (70 years and older) subjects. Older patients were more prone to serious adverse effects than younger patients, but there was no statistical interaction between age and rasagiline exposure. This absence of an age-rasagiline interaction suggests that rasagiline does not require special safety precautions for elderly subjects with Parkinson disease.

Published
2006
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50. Author Response

Author

Jennings, D., Siderowf, A., Stern, M., Seibyl, J., Eberly, S., Oakes, D., and Kenneth Marek

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