Advances in information technology and near ubiquity of the Internet have spawned novel modes of ... more Advances in information technology and near ubiquity of the Internet have spawned novel modes of communication and unprecedented insights into human behavior via the digital footprint. Health behavior randomized controlled trials (RCTs), especially technology-based, can leverage these advances to improve the overall clinical trials management process and benefit from improvements at every stage, from recruitment and enrollment to engagement and retention. In this paper, we report the results for recruitment and retention of participants in the SMART study and introduce a new model for clinical trials management that is a result of interdisciplinary team science. The MARKIT model brings together best practices from information technology, marketing, and clinical research into a single framework to maximize efforts for recruitment, enrollment, engagement, and retention of participants into a RCT. These practices may have contributed to the study's on-time recruitment that was with...
The effect of β-amyloid (Aβ) accumulation on regional structural brain changes in early stages of... more The effect of β-amyloid (Aβ) accumulation on regional structural brain changes in early stages of Alzheimer disease (AD) is not well understood. To test the hypothesis that the development of Aβ pathology is related to increased regional atrophy in the brains of cognitively normal (CN) persons. Longitudinal clinicobiomarker cohort study involving 47 CN control subjects and 15 patients with AD dementia. All participants underwent repeated cerebrospinal fluid Aβ42 and structural magnetic resonance imaging measurements for up to 4 years. Cognitively normal controls were classified using the longitudinal cerebrospinal fluid Aβ42 data and included 13 stable Aβ negative (normal baseline Aβ42 levels, with less than the median reduction over time), 13 declining Aβ negative (normal baseline Aβ42 levels, with greater than the median reduction over time), and 21 Aβ positive (pathologic baseline Aβ42 levels). All 15 patients with AD dementia were Aβ positive. Group effects on regional gray matt...
Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission ... more Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission tomography are biomarkers reflecting cortical amyloid load in Alzheimer's disease. However, these measurements do not always agree and may represent partly different aspects of the underlying Alzheimer's disease pathology. The goal of this study was therefore to test if cerebrospinal fluid and positron emission tomography amyloid-β biomarkers are independently related to other Alzheimer's disease markers, and to examine individuals who are discordantly classified by these two biomarker modalities. Cerebrospinal fluid and positron emission tomography amyloid-β were measured at baseline in 769 persons [161 healthy controls, 68 subjective memory complaints, 419 mild cognitive impairment and 121 Alzheimer's disease dementia, mean age 72 years (standard deviation 7 years), 47% females] and used to predict diagnosis, APOE ε4 carriage status, cerebral blood flow, cerebrospinal f...
Annals of clinical and translational neurology, 2014
Reduced cerebrospinal fluid (CSF) β-amyloid42 (Aβ42) and increased florbetapir positron emission ... more Reduced cerebrospinal fluid (CSF) β-amyloid42 (Aβ42) and increased florbetapir positron emission tomography (PET) uptake reflects brain Aβ accumulation. These biomarkers are correlated with each other and altered in Alzheimer's disease (AD), but no study has directly compared their diagnostic performance. We examined healthy controls (CN, N = 169) versus AD dementia patients (N = 118), and stable (sMCI; no dementia, followed up for at least 2 years, N = 165) versus progressive MCI (pMCI; conversion to AD dementia, N = 59). All subjects had florbetapir PET (global and regional; temporal, frontal, parietal, and cingulate) and CSF Aβ42 measurements at baseline. We compared area under the curve (AUC), sensitivity, and specificity (testing a priori and optimized cutoffs). Clinical diagnosis was the reference standard. CSF Aβ42 and (global or regional) PET florbetapir did not differ in AUC (CN vs. AD, CSF 84.4%; global PET 86.9%; difference [95% confidence interval] -6.7 to 1.5). CSF ...
Alzheimer disease has a long preclinical stage characterized by β-amyloid (Aβ) accumulation witho... more Alzheimer disease has a long preclinical stage characterized by β-amyloid (Aβ) accumulation without symptoms. Several trials focus on this stage and use biomarkers to include Aβ-positive participants, but an even earlier prevention of Aβ accumulation may be an effective treatment strategy. To determine whether people who appear to be Aβ negative but are at high risk for Aβ positivity within the near future can be identified. Longitudinal biomarker cohort study involving 35 cognitively healthy individuals who underwent cerebrospinal fluid (CSF) sampling for up to 3 years during the study (October 24, 2005, to September 1, 2014). All participants had normal CSF Aβ42 levels at baseline. Predictors of future Aβ positivity (levels of CSF Aβ42 declining below a previously validated cutoff level of 192 ng/L) tested by random forest models. Tested predictors included levels of protein in the CSF, hippocampal volume, genetics, demographics, and cognitive scores. The CSF Aβ42 levels declined ...
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 9, 2014
Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid (Aβ) associated wi... more Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid (Aβ) associated with brain atrophy and cognitive decline. The functional form to model the association between Aβ and regional brain atrophy has not been well defined. To determine the relationship between Aβ and atrophy, we compared the performance of the usual dichotomization of cerebrospinal fluid (CSF) Aβ to identify subjects as Aβ+ and Aβ- with a trilinear spline model of CSF Aβ. One hundred and eighty-three subjects with mild cognitive impairment and 108 cognitively normal controls with baseline CSF Aβ and up to 4 years of longitudinal magnetic resonance imaging data from the Alzheimer's Disease Neuroimaging Initiative were analyzed using mixed-effects regression. Piecewise-linear splines were used to evaluate the nonlinear nature of the association between CSF Aβ and regional atrophy and to identify points of acceleration of atrophy with respect to Aβ. Several parameterizations of CSF Aβ were c...
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 6, 2014
Little is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer'... more Little is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer's disease (AD). We analyzed longitudinal plasma samples from two large multicenter clinical trials: (1) donezepil and vitamin E in mild cognitive impairment (n = 405, 24 months) and (2) simvastatin in mild to moderate AD (n = 225, 18 months). Baseline plasma Aβ was not related to cognitive or clinical progression. We observed a decrease in plasma Aβ40 and 42 among apolipoprotein E epsilon 4 (APOE ε4) carriers relative to noncarriers in the mild cognitive impairment trial. Patients treated with simvastatin showed a significant increase in Aβ compared with placebo. We found significant storage time effects and considerable plate-to-plate variation. We found no support for the utility of plasma Aβ as a prognostic factor or correlate of cognitive change. Analysis of stored specimens requires careful standardization and experimental design, but plasma Aβ may prove useful in pharmacodynamic s...
In this study we aimed to explore parents&amp... more In this study we aimed to explore parents' weight perceptions of their children and of unrelated children. Parents of children < or = 18 years of age who were attending pediatric clinics throughout San Diego County, California, were surveyed concerning their children's weight status and the weight status of unrelated children in various age groups. Height and weight were measured, and weight status was determined for both the parent and child. The influence of various demographic variables on parents' weight perceptions and the relationship between parents' perceptions of weight of their children and parents' perceptions of weight of unrelated children were evaluated. Multivariate regression modeling was applied to identify predictors of parents' perceptions of weight of their own children. Of 1098 parents surveyed, 87% were women, 74% were white, and 46% reported Hispanic ethnicity. Seventy percent of the parents surveyed were overweight or obese, and 39% of their children were at risk for overweight or overweight. Sixty-one percent of parents correctly identified their children's weight status, and parents were able to correctly identify the weight status of unrelated children in 58% of reviewed photographs. Parents' weight perceptions of their children were not related to their ability to determine the weight status of unrelated children or to their ideal weight selections among unrelated children. In a multivariate logistic regression analysis, parental ability to correctly assess their child's weight status was associated with their child's age and weight status. Parents' perceptions of their own children's weight status are influenced by their children's characteristics and do not seem to correspond with their weight perceptions of unrelated children. Parental recognition of weight issues in their offspring may be impeded by their inability to apply criteria used to ascertain the weight status of unrelated children to their own children.
Advances in information technology and near ubiquity of the Internet have spawned novel modes of ... more Advances in information technology and near ubiquity of the Internet have spawned novel modes of communication and unprecedented insights into human behavior via the digital footprint. Health behavior randomized controlled trials (RCTs), especially technology-based, can leverage these advances to improve the overall clinical trials management process and benefit from improvements at every stage, from recruitment and enrollment to engagement and retention. In this paper, we report the results for recruitment and retention of participants in the SMART study and introduce a new model for clinical trials management that is a result of interdisciplinary team science. The MARKIT model brings together best practices from information technology, marketing, and clinical research into a single framework to maximize efforts for recruitment, enrollment, engagement, and retention of participants into a RCT. These practices may have contributed to the study's on-time recruitment that was with...
The effect of β-amyloid (Aβ) accumulation on regional structural brain changes in early stages of... more The effect of β-amyloid (Aβ) accumulation on regional structural brain changes in early stages of Alzheimer disease (AD) is not well understood. To test the hypothesis that the development of Aβ pathology is related to increased regional atrophy in the brains of cognitively normal (CN) persons. Longitudinal clinicobiomarker cohort study involving 47 CN control subjects and 15 patients with AD dementia. All participants underwent repeated cerebrospinal fluid Aβ42 and structural magnetic resonance imaging measurements for up to 4 years. Cognitively normal controls were classified using the longitudinal cerebrospinal fluid Aβ42 data and included 13 stable Aβ negative (normal baseline Aβ42 levels, with less than the median reduction over time), 13 declining Aβ negative (normal baseline Aβ42 levels, with greater than the median reduction over time), and 21 Aβ positive (pathologic baseline Aβ42 levels). All 15 patients with AD dementia were Aβ positive. Group effects on regional gray matt...
Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission ... more Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission tomography are biomarkers reflecting cortical amyloid load in Alzheimer's disease. However, these measurements do not always agree and may represent partly different aspects of the underlying Alzheimer's disease pathology. The goal of this study was therefore to test if cerebrospinal fluid and positron emission tomography amyloid-β biomarkers are independently related to other Alzheimer's disease markers, and to examine individuals who are discordantly classified by these two biomarker modalities. Cerebrospinal fluid and positron emission tomography amyloid-β were measured at baseline in 769 persons [161 healthy controls, 68 subjective memory complaints, 419 mild cognitive impairment and 121 Alzheimer's disease dementia, mean age 72 years (standard deviation 7 years), 47% females] and used to predict diagnosis, APOE ε4 carriage status, cerebral blood flow, cerebrospinal f...
Annals of clinical and translational neurology, 2014
Reduced cerebrospinal fluid (CSF) β-amyloid42 (Aβ42) and increased florbetapir positron emission ... more Reduced cerebrospinal fluid (CSF) β-amyloid42 (Aβ42) and increased florbetapir positron emission tomography (PET) uptake reflects brain Aβ accumulation. These biomarkers are correlated with each other and altered in Alzheimer's disease (AD), but no study has directly compared their diagnostic performance. We examined healthy controls (CN, N = 169) versus AD dementia patients (N = 118), and stable (sMCI; no dementia, followed up for at least 2 years, N = 165) versus progressive MCI (pMCI; conversion to AD dementia, N = 59). All subjects had florbetapir PET (global and regional; temporal, frontal, parietal, and cingulate) and CSF Aβ42 measurements at baseline. We compared area under the curve (AUC), sensitivity, and specificity (testing a priori and optimized cutoffs). Clinical diagnosis was the reference standard. CSF Aβ42 and (global or regional) PET florbetapir did not differ in AUC (CN vs. AD, CSF 84.4%; global PET 86.9%; difference [95% confidence interval] -6.7 to 1.5). CSF ...
Alzheimer disease has a long preclinical stage characterized by β-amyloid (Aβ) accumulation witho... more Alzheimer disease has a long preclinical stage characterized by β-amyloid (Aβ) accumulation without symptoms. Several trials focus on this stage and use biomarkers to include Aβ-positive participants, but an even earlier prevention of Aβ accumulation may be an effective treatment strategy. To determine whether people who appear to be Aβ negative but are at high risk for Aβ positivity within the near future can be identified. Longitudinal biomarker cohort study involving 35 cognitively healthy individuals who underwent cerebrospinal fluid (CSF) sampling for up to 3 years during the study (October 24, 2005, to September 1, 2014). All participants had normal CSF Aβ42 levels at baseline. Predictors of future Aβ positivity (levels of CSF Aβ42 declining below a previously validated cutoff level of 192 ng/L) tested by random forest models. Tested predictors included levels of protein in the CSF, hippocampal volume, genetics, demographics, and cognitive scores. The CSF Aβ42 levels declined ...
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 9, 2014
Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid (Aβ) associated wi... more Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid (Aβ) associated with brain atrophy and cognitive decline. The functional form to model the association between Aβ and regional brain atrophy has not been well defined. To determine the relationship between Aβ and atrophy, we compared the performance of the usual dichotomization of cerebrospinal fluid (CSF) Aβ to identify subjects as Aβ+ and Aβ- with a trilinear spline model of CSF Aβ. One hundred and eighty-three subjects with mild cognitive impairment and 108 cognitively normal controls with baseline CSF Aβ and up to 4 years of longitudinal magnetic resonance imaging data from the Alzheimer's Disease Neuroimaging Initiative were analyzed using mixed-effects regression. Piecewise-linear splines were used to evaluate the nonlinear nature of the association between CSF Aβ and regional atrophy and to identify points of acceleration of atrophy with respect to Aβ. Several parameterizations of CSF Aβ were c...
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 6, 2014
Little is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer'... more Little is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer's disease (AD). We analyzed longitudinal plasma samples from two large multicenter clinical trials: (1) donezepil and vitamin E in mild cognitive impairment (n = 405, 24 months) and (2) simvastatin in mild to moderate AD (n = 225, 18 months). Baseline plasma Aβ was not related to cognitive or clinical progression. We observed a decrease in plasma Aβ40 and 42 among apolipoprotein E epsilon 4 (APOE ε4) carriers relative to noncarriers in the mild cognitive impairment trial. Patients treated with simvastatin showed a significant increase in Aβ compared with placebo. We found significant storage time effects and considerable plate-to-plate variation. We found no support for the utility of plasma Aβ as a prognostic factor or correlate of cognitive change. Analysis of stored specimens requires careful standardization and experimental design, but plasma Aβ may prove useful in pharmacodynamic s...
In this study we aimed to explore parents&amp... more In this study we aimed to explore parents' weight perceptions of their children and of unrelated children. Parents of children < or = 18 years of age who were attending pediatric clinics throughout San Diego County, California, were surveyed concerning their children's weight status and the weight status of unrelated children in various age groups. Height and weight were measured, and weight status was determined for both the parent and child. The influence of various demographic variables on parents' weight perceptions and the relationship between parents' perceptions of weight of their children and parents' perceptions of weight of unrelated children were evaluated. Multivariate regression modeling was applied to identify predictors of parents' perceptions of weight of their own children. Of 1098 parents surveyed, 87% were women, 74% were white, and 46% reported Hispanic ethnicity. Seventy percent of the parents surveyed were overweight or obese, and 39% of their children were at risk for overweight or overweight. Sixty-one percent of parents correctly identified their children's weight status, and parents were able to correctly identify the weight status of unrelated children in 58% of reviewed photographs. Parents' weight perceptions of their children were not related to their ability to determine the weight status of unrelated children or to their ideal weight selections among unrelated children. In a multivariate logistic regression analysis, parental ability to correctly assess their child's weight status was associated with their child's age and weight status. Parents' perceptions of their own children's weight status are influenced by their children's characteristics and do not seem to correspond with their weight perceptions of unrelated children. Parental recognition of weight issues in their offspring may be impeded by their inability to apply criteria used to ascertain the weight status of unrelated children to their own children.
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Papers by Michael C Donohue