@article {798, title = {Assessing the "physical cliff": detailed quantification of age-related differences in daily patterns of physical activity.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {69}, year = {2014}, month = {2014 Aug}, pages = {973-9}, abstract = {

BACKGROUND: In spite of evidence that physical activity has beneficial effects on health and age-related functional decline, there is a scarcity of detailed and accurate information on objectively measured daily activity and patterns of such activity in older adults.

METHODS: Participants in the Baltimore Longitudinal Study of Aging (n = 611, 50\% male, mean age 67, range 32-93) wore the Actiheart portable activity monitor for 7 days in the free-living environment. The association between activity and age was modeled using a continuous log-linear regression of activity counts on age with sex, body mass index, employment status, functional performance, and comorbid conditions as covariates.

RESULTS: In the fully adjusted model, continuous analyses demonstrated that overall physical activity counts were 1.3\% lower for each year increase in age. Although there were no differences among morning levels of activity, there was significantly lower afternoon and evening activity in older individuals (p < .01). After adjusting for age, poor functional performance, nonworking status, and higher body mass index were independently associated with less physical activity (p < .001).

CONCLUSIONS: The use of accelerometers to characterize minute-by-minute intensity, cumulative physical activity counts, and daily activity patterns provides detailed data not gathered by traditional subjective methods, particularly at low levels of activity. The findings of a 1.3\% decrease per year in activity from mid-to-late life, and the corresponding drop in afternoon and evening activity, provide new information that may be useful when targeting future interventions. Further, this methodology addresses essential gaps in understanding activity patterns and trends in more sedentary sectors of the population.

}, keywords = {Accelerometry, Adult, Age Factors, Aged, Aged, 80 and over, Employment, Female, Health Behavior, Humans, Linear Models, Longitudinal Studies, Male, Middle Aged, Motor Activity, Physical Fitness, Sedentary Lifestyle}, issn = {1758-535X}, doi = {10.1093/gerona/glt199}, author = {Schrack, Jennifer A and Zipunnikov, Vadim and Goldsmith, Jeff and Bai, Jiawei and Simonsick, Eleanor M and Crainiceanu, Ciprian and Ferrucci, Luigi} } @article {794, title = {Estimating energy expenditure from heart rate in older adults: a case for calibration.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e93520}, abstract = {

BACKGROUND: Accurate measurement of free-living energy expenditure is vital to understanding changes in energy metabolism with aging. The efficacy of heart rate as a surrogate for energy expenditure is rooted in the assumption of a linear function between heart rate and energy expenditure, but its validity and reliability in older adults remains unclear.

OBJECTIVE: To assess the validity and reliability of the linear function between heart rate and energy expenditure in older adults using different levels of calibration.

DESIGN: Heart rate and energy expenditure were assessed across five levels of exertion in 290 adults participating in the Baltimore Longitudinal Study of Aging. Correlation and random effects regression analyses assessed the linearity of the relationship between heart rate and energy expenditure and cross-validation models assessed predictive performance.

RESULTS: Heart rate and energy expenditure were highly correlated (r=0.98) and linear regardless of age or sex. Intra-person variability was low but inter-person variability was high, with substantial heterogeneity of the random intercept (s.d. =0.372) despite similar slopes. Cross-validation models indicated individual calibration data substantially improves accuracy predictions of energy expenditure from heart rate, reducing the potential for considerable measurement bias. Although using five calibration measures provided the greatest reduction in the standard deviation of prediction errors (1.08 kcals/min), substantial improvement was also noted with two (0.75 kcals/min).

CONCLUSION: These findings indicate standard regression equations may be used to make population-level inferences when estimating energy expenditure from heart rate in older adults but caution should be exercised when making inferences at the individual level without proper calibration.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0093520}, author = {Schrack, Jennifer A and Zipunnikov, Vadim and Goldsmith, Jeff and Bandeen-Roche, Karen and Crainiceanu, Ciprian M and Ferrucci, Luigi} } @article {815, title = {Neuroinflammation and brain atrophy in former NFL players: An in vivo multimodal imaging pilot study.}, journal = {Neurobiol Dis}, volume = {74C}, year = {2014}, month = {2014 Nov 7}, pages = {58-65}, abstract = {

There are growing concerns about potential delayed, neuropsychiatric consequences (e.g, cognitive decline, mood or anxiety disorders) of sports-related traumatic brain injury (TBI). Autopsy studies of brains from a limited number of former athletes have described characteristic, pathologic changes of chronic traumatic encephalopathy (CTE) leading to questions about the relationship between these pathologic and the neuropsychiatric disturbances seen in former athletes. Research in this area will depend on in vivo methods that characterize molecular changes in the brain, linking CTE and other sports-related pathologies with delayed emergence of neuropsychiatric symptoms. In this pilot project we studied former National Football League (NFL) players using new neuroimaging techniques and clinical measures of cognitive functioning. We hypothesized that former NFL players would show molecular and structural changes in medial temporal and parietal lobe structures as well as specific cognitive deficits, namely those of verbal learning and memory. We observed a significant increase in binding of [(11)C]DPA-713 to the translocator protein (TSPO), a marker of brain injury and repair, in several brain regions, such as the supramarginal gyrus and right amygdala, in 9 former NFL players compared to 9 age-matched, healthy controls. We also observed significant atrophy of the right hippocampus. Finally, we report that these same former players had varied performance on a test of verbal learning and memory, suggesting that these molecular and pathologic changes may play a role in cognitive decline. These results suggest that localized brain injury and repair, indicated by increased [(11)C]DPA-713 binding to TSPO, may be linked to history of NFL play. [(11)C]DPA-713 PET is a promising new tool that can be used in future study design to examine further the relationship between TSPO expression in brain injury and repair, selective regional brain atrophy, and the potential link to deficits in verbal learning and memory after NFL play.

}, issn = {1095-953X}, doi = {10.1016/j.nbd.2014.10.019}, author = {Coughlin, Jennifer M and Wang, Yuchuan and Munro, Cynthia A and Ma, Shuangchao and Yue, Chen and Chen, Shaojie and Airan, Raag and Kim, Pearl K and Adams, Ashley V and Garcia, Cinthya and Higgs, Cecilia and Sair, Haris I and Sawa, Akira and Smith, Gwenn and Lyketsos, Constantine G and Caffo, Brian and Kassiou, Michael and Guilarte, Tomas R and Pomper, Martin G} } @article {804, title = {Normalization and extraction of interpretable metrics from raw accelerometry data.}, journal = {Biostatistics}, volume = {15}, year = {2014}, month = {2014 Jan}, pages = {102-16}, abstract = {

We introduce an explicit set of metrics for human activity based on high-density acceleration recordings from a hip-worn tri-axial accelerometer. These metrics are based on two concepts: (i) Time Active, a measure of the length of time when activity is distinguishable from rest and (ii) AI, a measure of the relative amplitude of activity relative to rest. All measurements are normalized (have the same interpretation across subjects and days), easy to explain and implement, and reproducible across platforms and software implementations. Metrics were validated by visual inspection of results and quantitative in-lab replication studies, and by an association study with health outcomes.

}, keywords = {Acceleration, Aged, Baltimore, Cohort Studies, Data Interpretation, Statistical, Female, Humans, Male, Motor Activity}, issn = {1468-4357}, doi = {10.1093/biostatistics/kxt029}, author = {Bai, Jiawei and He, Bing and Shou, Haochang and Zipunnikov, Vadim and Glass, Thomas A and Crainiceanu, Ciprian M} } @article {Bai2014Metrics, title = {Normalization and extraction of interpretable metrics from raw accelerometry data}, journal = {Biostatistics}, volume = {15}, number = {1}, year = {2014}, pages = {102{\textendash}116}, abstract = {

We introduce an explicit set of metrics for human activity based on high-density acceleration recordings from a hip-worn tri-axial accelerometer. These metrics are based on two concepts: (i) Time Active, a measure of the length of time when activity is distinguishable from rest and (ii) AI, a measure of the relative amplitude of activity relative to rest. All measurements are normalized (have the same interpretation across subjects and days), easy to explain and implement, and reproducible across platforms and software implementations. Metrics were validated by visual inspection of results and quantitative in-lab replication studies, and by an association study with health outcomes.

}, keywords = {Activity intensity, Movelets, Movement, Signal processing, Time active, Tri-axial accelerometer}, issn = {14654644}, author = {Bai, Jiawei and He, Bing and Shou, Haochang and Zipunnikov, Vadim and Glass, Thomas A. and Crainiceanu, Ciprian M.} } @article {791, title = {Predicting human movement with multiple accelerometers using movelets.}, journal = {Med Sci Sports Exerc}, volume = {46}, year = {2014}, month = {2014 Sep}, pages = {1859-66}, abstract = {

PURPOSE: The study aims were 1) to develop transparent algorithms that use short segments of training data for predicting activity types and 2) to compare the prediction performance of the proposed algorithms using single accelerometers and multiple accelerometers.

METHODS: Sixteen participants (age, 80.6 yr (4.8 yr); body mass index, 26.1 kg{\textperiodcentered}m (2.5 kg{\textperiodcentered}m)) performed 15 lifestyle activities in the laboratory, each wearing three accelerometers at the right hip and left and right wrists. Triaxial accelerometry data were collected at 80 Hz using ActiGraph GT3X+. Prediction algorithms were developed, which, instead of extracting features, build activity-specific dictionaries composed of short signal segments called movelets. Three alternative approaches were proposed to integrate the information from the multiple accelerometers.

RESULTS: With at most several seconds of training data per activity, the prediction accuracy at the second-level temporal resolution was very high for lying, standing, normal/fast walking, and standing up from a chair (the median prediction accuracy ranged from 88.2\% to 99.9\% on the basis of the single-accelerometer movelet approach). For these activities, wrist-worn accelerometers performed almost as well as hip-worn accelerometers (the median difference in accuracy between wrist and hip ranged from -2.7\% to 5.8\%). Modest improvements in prediction accuracy were achieved by integrating information from multiple accelerometers.

DISCUSSION AND CONCLUSIONS: It is possible to achieve high prediction accuracy at the second-level temporal resolution with very limited training data. To increase prediction accuracy from the simultaneous use of multiple accelerometers, a careful selection of integrative approaches is required.

}, issn = {1530-0315}, doi = {10.1249/MSS.0000000000000285}, author = {He, Bing and Bai, Jiawei and Zipunnikov, Vadim V and Koster, Annemarie and Caserotti, Paolo and Lange-Maia, Brittney and Glynn, Nancy W and Harris, Tamara B and Crainiceanu, Ciprian M} } @article {796, title = {Smooth Scalar-on-Image Regression via Spatial Bayesian Variable Selection.}, journal = {J Comput Graph Stat}, volume = {23}, year = {2014}, month = {2014 Jan 1}, pages = {46-64}, abstract = {

We develop scalar-on-image regression models when images are registered multidimensional manifolds. We propose a fast and scalable Bayes inferential procedure to estimate the image coefficient. The central idea is the combination of an Ising prior distribution, which controls a latent binary indicator map, and an intrinsic Gaussian Markov random field, which controls the smoothness of the nonzero coefficients. The model is fit using a single-site Gibbs sampler, which allows fitting within minutes for hundreds of subjects with predictor images containing thousands of locations. The code is simple and is provided in less than one page in the Appendix. We apply this method to a neuroimaging study where cognitive outcomes are regressed on measures of white matter microstructure at every voxel of the corpus callosum for hundreds of subjects.

}, issn = {1061-8600}, doi = {10.1080/10618600.2012.743437}, author = {Goldsmith, Jeff and Huang, Lei and Crainiceanu, Ciprian M} } @article {786, title = {Statistical normalization techniques for magnetic resonance imaging.}, journal = {Neuroimage Clin}, volume = {6}, year = {2014}, month = {2014}, pages = {9-19}, abstract = {

While computed tomography and other imaging techniques are measured in absolute units with physical meaning, magnetic resonance images are expressed in arbitrary units that are difficult to interpret and differ between study visits and subjects. Much work in the image processing literature on intensity normalization has focused on histogram matching and other histogram mapping techniques, with little emphasis on normalizing images to have biologically interpretable units. Furthermore, there are no formalized principles or goals for the crucial comparability of image intensities within and across subjects. To address this, we propose a set of criteria necessary for the normalization of images. We further propose simple and robust biologically motivated normalization techniques for multisequence brain imaging that have the same interpretation across acquisitions and satisfy the proposed criteria. We compare the performance of different normalization methods in thousands of images of patients with Alzheimer{\textquoteright}s disease, hundreds of patients with multiple sclerosis, and hundreds of healthy subjects obtained in several different studies at dozens of imaging centers.

}, issn = {2213-1582}, doi = {10.1016/j.nicl.2014.08.008}, author = {Shinohara, Russell T and Sweeney, Elizabeth M and Goldsmith, Jeff and Shiee, Navid and Mateen, Farrah J and Calabresi, Peter A and Jarso, Samson and Pham, Dzung L and Reich, Daniel S and Crainiceanu, Ciprian M} } @article {789, title = {Structured functional principal component analysis.}, journal = {Biometrics}, year = {2014}, month = {2014 Oct 18}, abstract = {

Motivated by modern observational studies, we introduce a class of functional models that expand nested and crossed designs. These models account for the natural inheritance of the correlation structures from sampling designs in studies where the fundamental unit is a function or image. Inference is based on functional quadratics and their relationship with the underlying covariance structure of the latent processes. A computationally fast and scalable estimation procedure is developed for high-dimensional data. Methods are used in applications including high-frequency accelerometer data for daily activity, pitch linguistic data for phonetic analysis, and EEG data for studying electrical brain activity during sleep.

}, issn = {1541-0420}, doi = {10.1111/biom.12236}, author = {Shou, Haochang and Zipunnikov, Vadim and Crainiceanu, Ciprian M and Greven, Sonja} } @article {806, title = {Acute lesions that impair affective empathy.}, journal = {Brain}, volume = {136}, year = {2013}, month = {2013 Aug}, pages = {2539-49}, abstract = {

Functional imaging studies of healthy participants and previous lesion studies have provided evidence that empathy involves dissociable cognitive functions that rely on at least partially distinct neural networks that can be individually impaired by brain damage. These studies converge in support of the proposal that affective empathy--making inferences about how another person feels--engages at least the following areas: prefrontal cortex, orbitofrontal gyrus, anterior insula, anterior cingulate cortex, temporal pole, amygdala and temporoparietal junction. We hypothesized that right-sided lesions to any one of these structures, except temporoparietal junction, would cause impaired affective empathy (whereas bilateral damage to temporoparietal junction would be required to disrupt empathy). We studied 27 patients with acute right hemisphere ischaemic stroke and 24 neurologically intact inpatients on a test of affective empathy. Acute impairment of affective empathy was associated with infarcts in the hypothesized network, particularly temporal pole and anterior insula. All patients with impaired affective empathy were also impaired in comprehension of affective prosody, but many patients with impairments in prosodic comprehension had spared affective empathy. Patients with impaired affective empathy were older, but showed no difference in performance on tests of hemispatial neglect, volume of infarct or sex distribution compared with patients with intact affective empathy.

}, keywords = {Adult, Aged, Brain, Brain Ischemia, brain mapping, Cognition, Emotions, Empathy, Female, Functional Laterality, Humans, Male, Middle Aged, Nerve Net, Social Perception, Stroke}, issn = {1460-2156}, doi = {10.1093/brain/awt177}, author = {Leigh, Richard and Oishi, Kenichi and Hsu, John and Lindquist, Martin and Gottesman, Rebecca F and Jarso, Samson and Crainiceanu, Ciprian and Mori, Susumu and Hillis, Argye E} } @article {807, title = {Bayesian scalar-on-image regression with application to association between intracranial DTI and cognitive outcomes.}, journal = {Neuroimage}, volume = {83}, year = {2013}, month = {2013 Dec}, pages = {210-23}, abstract = {

Diffusion tensor imaging (DTI) measures water diffusion within white matter, allowing for in vivo quantification of brain pathways. These pathways often subserve specific functions, and impairment of those functions is often associated with imaging abnormalities. As a method for predicting clinical disability from DTI images, we propose a hierarchical Bayesian "scalar-on-image" regression procedure. Our procedure introduces a latent binary map that estimates the locations of predictive voxels and penalizes the magnitude of effect sizes in these voxels, thereby resolving the ill-posed nature of the problem. By inducing a spatial prior structure, the procedure yields a sparse association map that also maintains spatial continuity of predictive regions. The method is demonstrated on a simulation study and on a study of association between fractional anisotropy and cognitive disability in a cross-sectional sample of 135 multiple sclerosis patients.

}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2013.06.020}, author = {Huang, Lei and Goldsmith, Jeff and Reiss, Philip T and Reich, Daniel S and Crainiceanu, Ciprian M} } @article {799, title = {Body composition and arsenic metabolism: a cross-sectional analysis in the Strong Heart Study.}, journal = {Environ Health}, volume = {12}, year = {2013}, month = {2013}, pages = {107}, abstract = {

OBJECTIVE: The objective of this study was to evaluate the association between measures of body composition and patterns of urine arsenic metabolites in the 1989-1991 baseline visit of the Strong Heart Study, a cardiovascular disease cohort of adults recruited from rural communities in Arizona, Oklahoma, North Dakota and South Dakota.

METHODS: We evaluated 3,663 Strong Heart Study participants with urine arsenic species above the limit of detection and no missing data on body mass index, \% body fat and fat free mass measured by bioelectrical impedance, waist circumference and other variables. We summarized urine arsenic species patterns as the relative contribution of inorganic (iAs), methylarsonate (MMA) and dimethylarsinate (DMA) species to their sum. We modeled the associations of \% arsenic species biomarkers with body mass index, \% body fat, fat free mass, and waist circumference categories in unadjusted regression models and in models including all measures of body composition. We also considered adjustment for arsenic exposure and demographics.

RESULTS: Increasing body mass index was associated with higher mean \% DMA and lower mean \% MMA before and after adjustment for sociodemographic variables, arsenic exposure, and for other measures of body composition. In unadjusted linear regression models, \% DMA was 2.4 (2.1, 2.6) \% higher per increase in body mass index category (< 25, >=25 \& <30, >=30 \& <35, >=35 kg/m2), and \% MMA was 1.6 (1.4, 1.7) \% lower. Similar patterns were observed for \% body fat, fat free mass, and waist circumference measures in unadjusted models and in models adjusted for potential confounders, but the associations were largely attenuated or disappeared when adjusted for body mass index.

CONCLUSION: Measures of body size, especially body mass index, are associated with arsenic metabolism biomarkers. The association may be related to adiposity, fat free mass or body size. Future epidemiologic studies of arsenic should consider body mass index as a potential modifier for arsenic-related health effects.

}, issn = {1476-069X}, doi = {10.1186/1476-069X-12-107}, author = {Gribble, Matthew O and Crainiceanu, Ciprian M and Howard, Barbara V and Umans, Jason G and Francesconi, Kevin A and Goessler, Walter and Zhang, Ying and Silbergeld, Ellen K and Guallar, Eliseo and Navas-Acien, Ana} } @article {684, title = {Corrected confidence bands for functional data using principal components.}, journal = {Biometrics}, volume = {69}, year = {2013}, month = {2013 Mar}, pages = {41-51}, abstract = {

Functional principal components (FPC) analysis is widely used to decompose and express functional observations. Curve estimates implicitly condition on basis functions and other quantities derived from FPC decompositions; however these objects are unknown in practice. In this article, we propose a method for obtaining correct curve estimates by accounting for uncertainty in FPC decompositions. Additionally, pointwise and simultaneous confidence intervals that account for both model- and decomposition-based variability are constructed. Standard mixed model representations of functional expansions are used to construct curve estimates and variances conditional on a specific decomposition. Iterated expectation and variance formulas combine model-based conditional estimates across the distribution of decompositions. A bootstrap procedure is implemented to understand the uncertainty in principal component decomposition quantities. Our method compares favorably to competing approaches in simulation studies that include both densely and sparsely observed functions. We apply our method to sparse observations of CD4 cell counts and to dense white-matter tract profiles. Code for the analyses and simulations is publicly available, and our method is implemented in the R package refund on CRAN.

}, keywords = {Brain, CD4 Lymphocyte Count, Computer Simulation, Confidence Intervals, HIV, HIV Infections, Humans, Magnetic Resonance Imaging, Models, Statistical, Multiple Sclerosis, Principal Component Analysis}, issn = {1541-0420}, doi = {10.1111/j.1541-0420.2012.01808.x}, author = {Goldsmith, J and Greven, S and Crainiceanu, C} } @article {825, title = {Isoosmolar enemas demonstrate preferential gastrointestinal distribution, safety, and acceptability compared with hyperosmolar and hypoosmolar enemas as a potential delivery vehicle for rectal microbicides.}, journal = {AIDS Res Hum Retroviruses}, volume = {29}, year = {2013}, month = {2013 Nov}, pages = {1487-95}, abstract = {

Rectally applied antiretroviral microbicides for preexposure prophylaxis (PrEP) of HIV infection are currently in development. Since enemas (rectal douches) are commonly used by men who have sex with men prior to receptive anal intercourse, a microbicide enema could enhance PrEP adherence by fitting seamlessly within the usual sexual practices. We assessed the distribution, safety, and acceptability of three enema types-hyperosmolar (Fleet), hypoosmolar (distilled water), and isoosmolar (Normosol-R)-in a crossover design. Nine men received each enema type in random order. Enemas were radiolabeled [(99m)Tc-diethylene triamine pentaacetic acid (DTPA)] to assess enema distribution in the colon using single photon emission computed tomography/computed tomography (SPECT/CT) imaging. Plasma (99m)Tc-DTPA indicated mucosal permeability. Sigmoidoscopic colon tissue biopsies were taken to assess injury as well as tissue penetration of the (99m)Tc-DTPA. Acceptability was assessed after each product use and at the end of the study. SPECT/CT imaging showed that the isoosmolar enema had greater proximal colonic distribution (up to the splenic flexure) and greater luminal and colon tissue concentrations of (99m)Tc-DTPA when compared to the other enemas (p<0.01). Colon biopsies also showed that only the hyperosmolar enema caused sloughing of the colonic epithelium (p<0.05). In permeability testing, the hypoosmolar enema had higher plasma (99m)Tc-DTPA 24-h area under the concentration-time curve and peak concentration compared to the hyperosmolar and isoosmolar enemas, respectively. Acceptability was generally good with no clear preferences among the three enema types. The isoosmolar enema was superior or similar to the other enemas in all categories and is a good candidate for further development as a rectal microbicide vehicle.

}, keywords = {Anti-Infective Agents, Biopsy, Colon, Sigmoid, Enema, HIV Infections, Humans, Intestinal Mucosa, Male, Patient Acceptance of Health Care, Solutions, Tomography, Emission-Computed, Single-Photon}, issn = {1931-8405}, doi = {10.1089/AID.2013.0189}, author = {Leyva, Francisco J and Bakshi, Rahul P and Fuchs, Edward J and Li, Liye and Caffo, Brian S and Goldsmith, Arthur J and Ventuneac, Ana and Carballo-Di{\'e}guez, Alex and Du, Yong and Leal, Jeffrey P and Lee, Linda A and Torbenson, Michael S and Hendrix, Craig W} } @article {814, title = {Longitudinal scalar-on-functions regression with application to tractography data.}, journal = {Biostatistics}, volume = {14}, year = {2013}, month = {2013 Jul}, pages = {447-61}, abstract = {

We propose a class of estimation techniques for scalar-on-function regression where both outcomes and functional predictors may be observed at multiple visits. Our methods are motivated by a longitudinal brain diffusion tensor imaging tractography study. One of the study{\textquoteright}s primary goals is to evaluate the contemporaneous association between human function and brain imaging over time. The complexity of the study requires the development of methods that can simultaneously incorporate: (1) multiple functional (and scalar) regressors; (2) longitudinal outcome and predictor measurements per patient; (3) Gaussian or non-Gaussian outcomes; and (4) missing values within functional predictors. We propose two versions of a new method, longitudinal functional principal components regression (PCR). These methods extend the well-known functional PCR and allow for different effects of subject-specific trends in curves and of visit-specific deviations from that trend. The new methods are compared with existing approaches, and the most promising techniques are used for analyzing the tractography data.

}, keywords = {Anisotropy, Biostatistics, Brain, Diffusion Tensor Imaging, Humans, Linear Models, Models, Statistical, Multiple Sclerosis, Principal Component Analysis, Regression Analysis}, issn = {1468-4357}, doi = {10.1093/biostatistics/kxs051}, author = {Gertheiss, Jan and Goldsmith, Jeff and Crainiceanu, Ciprian and Greven, Sonja} } @article {821, title = {Practical Marginalized Multilevel Models.}, journal = {Stat}, volume = {2}, year = {2013}, month = {2013}, abstract = {

Clustered data analysis is characterized by the need to describe both systematic variation in a mean model and cluster-dependent random variation in an association model. Marginalized multilevel models embrace the robustness and interpretations of a marginal mean model, while retaining the likelihood inference capabilities and flexible dependence structures of a conditional association model. Although there has been increasing recognition of the attractiveness of marginalized multilevel models, there has been a gap in their practical application arising from a lack of readily available estimation procedures. We extend the marginalized multilevel model to allow for nonlinear functions in both the mean and association aspects. We then formulate marginal models through conditional specifications to facilitate estimation with mixed model computational solutions already in place. We illustrate the MMM and approximate MMM approaches on a cerebrovascular deficiency crossover trial using SAS and an epidemiological study on race and visual impairment using R. Datasets, SAS and R code are included as supplemental materials.

}, issn = {0038-9986}, doi = {10.1002/sta4.22}, author = {Griswold, Michael E and Swihart, Bruce J and Caffo, Brian S and Zeger, Scott L} } @article {708, title = {Arsenic exposure, diabetes prevalence, and diabetes control in the Strong Heart Study.}, journal = {Am J Epidemiol}, volume = {176}, year = {2012}, month = {2012 Nov 15}, pages = {865-74}, abstract = {

This study evaluated the association of arsenic exposure, as measured in urine, with diabetes prevalence, glycated hemoglobin, and insulin resistance in American Indian adults from Arizona, Oklahoma, and North and South Dakota (1989-1991). We studied 3,925 men and women 45-74 years of age with available urine arsenic measures. Diabetes was defined as a fasting glucose level of 126 mg/dL or higher, a 2-hour glucose level of 200 mg/dL or higher, a hemoglobin A1c (HbA1c) of 6.5\% or higher, or diabetes treatment. Median urine arsenic concentration was 14.1 {\textmu}g/L (interquartile range, 7.9-24.2). Diabetes prevalence was 49.4\%. After adjustment for sociodemographic factors, diabetes risk factors, and urine creatinine, the prevalence ratio of diabetes comparing the 75th versus 25th percentiles of total arsenic concentrations was 1.14 (95\% confidence interval: 1.08, 1.21). The association between arsenic and diabetes was restricted to participants with poor diabetes control (HbA1c >=8\%). Arsenic was positively associated with HbA1c levels in participants with diabetes. Arsenic was not associated with HbA1c or with insulin resistance (assessed by homeostatic model assessment to quantify insulin resistance) in participants without diabetes. Urine arsenic was associated with diabetes control in a population from rural communities in the United States with a high burden of diabetes. Prospective studies that evaluate the direction of the relation between poor diabetes control and arsenic exposure are needed.

}, keywords = {Aged, Arizona, Arsenicals, Blood Glucose, Creatinine, Diabetes Mellitus, Environmental Exposure, Female, Hemoglobin A, Glycosylated, Humans, Indians, North American, Male, Middle Aged, North Dakota, Oklahoma, Poisson Distribution, Prevalence, Regression Analysis, Risk Factors, South Dakota}, issn = {1476-6256}, doi = {10.1093/aje/kws153}, author = {Gribble, Matthew O and Howard, Barbara V and Umans, Jason G and Shara, Nawar M and Francesconi, Kevin A and Goessler, Walter and Crainiceanu, Ciprian M and Silbergeld, Ellen K and Guallar, Eliseo and Navas-Acien, Ana} } @article {pmid22472185, title = {Cadmium Exposure and All Cause and Cardiovascular Mortality in the US General Population}, journal = {Environ Health Perspect}, year = {2012}, month = {Apr}, author = {Tellez-Plaza, M. and Navas-Acien, A. and Menke, A. and Crainiceanu, C and Pastor-Barriuso, R. and Guallar, E.} } @article {ellignton, title = {Computerized lung sound analysis to improve the specificity of pediatric pneumonia in resource-poor settings}, journal = {Accepted in the British Medical Journal Open}, year = {2012}, author = {Ellington, L and Gilman, R and Tielsch, J and Steinhoff, M and Figueroa, D and Rodriguez, S and Caffo, B and Tracey, B and West, J and Checkley, W} } @article {nicole, title = {Distribution of cell-free and cell-associated HIV surrogates in the female genital tract following simulated vaginal intercourse}, journal = {Appeared online in the Journal of Infectious Diseases}, year = {2012}, author = {Louissaint, N and Nimmagadda, S and Bakshi, R and Du, Y and Macura, K and King, K and Wahl, R and Goldsmith, J and Caffo, B and Cao, Y and Anderson, J and Fuchs, E and Hendrix, C} } @article {goldsmith, title = {Longitudinal penalized functional regression for cognitive outcomes on neuronal tract measurements}, journal = {Journal of the Royal Statistical Society Series C}, number = {61}, year = {2012}, pages = {453{\textendash}469}, author = {Goldsmith, J and Crainiceanu, C and Caffo, B and Reich, D.} } @article {709, title = {Microcystic macular oedema, thickness of the inner nuclear layer of the retina, and disease characteristics in multiple sclerosis: a retrospective study.}, journal = {Lancet Neurol}, volume = {11}, year = {2012}, month = {2012 Nov}, pages = {963-72}, abstract = {

BACKGROUND: Microcystic macular oedema (MMO) of the retinal inner nuclear layer (INL) has been identified in patients with multiple sclerosis (MS) by use of optical coherence tomography (OCT). We aimed to determine whether MMO of the INL, and increased thickness of the INL are associated with disease activity or disability progression.

METHODS: This retrospective study was done at the Johns Hopkins Hospital (Baltimore, MD, USA), between September, 2008, and March, 2012. Patients with MS and healthy controls underwent serial OCT scans and clinical assessments including visual function. OCT scanning, including automated intraretinal layer segmentation, yielded thicknesses of the retinal nerve fibre layer, the ganglion cell layer plus inner plexiform layer, the INL plus outer plexiform layer (the combined thickness of these layers was used as a surrogate measure of INL thickness), and the outer nuclear layer. Patients with MS also underwent annual brain MRI scans. Disability scores were compared with the Wilcoxon rank-sum test. Mixed-effects linear regression was used to compare OCT measures and letter-acuity scores. Logistic regression was used to examine the relations of baseline OCT thicknesses with clinical and radiological parameters.

FINDINGS: 164 patients with MS and 60 healthy controls were assessed. Mean follow-up was 25{\textperiodcentered}8 months (SD 9{\textperiodcentered}1) for patients with MS and 22{\textperiodcentered}4 months (11{\textperiodcentered}4) for healthy controls. Ten (6\%) patients with MS had MMO during at least one study visit; MMO was visible at baseline in four of these patients. Healthy controls did not have MMO. Patients with MS and MMO had higher baseline MS severity scores (median 5{\textperiodcentered}93 [range 2{\textperiodcentered}44-8{\textperiodcentered}91]) than those who did not have MMO at any time during the study (151 patients; 3{\textperiodcentered}81 [0{\textperiodcentered}13-9{\textperiodcentered}47]; p=0{\textperiodcentered}032), although expanded disability status scale (EDSS) scores were not significantly different (5{\textperiodcentered}2 [1{\textperiodcentered}0-6{\textperiodcentered}5] for patients with MS and MMO vs 2{\textperiodcentered}5 [0{\textperiodcentered}0-8{\textperiodcentered}0] for those without MMO; p=0{\textperiodcentered}097). The eyes of patients with MS and MMO (12 eyes) versus those without MMO (302 eyes) had lower letter-acuity scores (100\% contrast, p=0{\textperiodcentered}017; 2{\textperiodcentered}5\% contrast, p=0{\textperiodcentered}031; 1{\textperiodcentered}25\% contrast, p=0{\textperiodcentered}014), and increased INL thicknesses (p=0{\textperiodcentered}003) at baseline. Increased baseline INL thickness in patients with MS was associated with the development of contrast-enhancing lesions (p=0{\textperiodcentered}007), new T2 lesions (p=0{\textperiodcentered}015), EDSS progression (p=0{\textperiodcentered}034), and relapses in patients with relapsing-remitting MS (p=0{\textperiodcentered}008) during the study. MMO was not associated with disease activity during follow-up.

INTERPRETATION: Increased INL thickness on OCT is associated with disease activity in MS. If this finding is confirmed, INL thickness could be a useful predictor of disease progression in patients with MS.

FUNDING: National Multiple Sclerosis Society, National Eye Institute, Braxton Debbie Angela Dillon and Skip Donor Advisor Fund.

}, keywords = {Adult, Cohort Studies, Female, Follow-Up Studies, Humans, Macular Edema, Male, Middle Aged, Multiple Sclerosis, Retina, Retinal Ganglion Cells, Retrospective Studies, Tomography, Optical Coherence}, issn = {1474-4465}, doi = {10.1016/S1474-4422(12)70213-2}, author = {Saidha, Shiv and Sotirchos, Elias S and Ibrahim, Mohamed A and Crainiceanu, Ciprian M and Gelfand, Jeffrey M and Sepah, Yasir J and Ratchford, John N and Oh, Jiwon and Seigo, Michaela A and Newsome, Scott D and Balcer, Laura J and Frohman, Elliot M and Green, Ari J and Nguyen, Quan D and Calabresi, Peter A} } @article {BaGoCaGlCr2012, title = {Movelets: A dictionary of movement}, journal = {Electronic Journal of Statistics}, volume = {6}, year = {2012}, pages = {559-578}, issn = {1935-7524}, doi = {10.1214/12-EJS684}, author = {Bai, J and Goldsmith, J and Caffo, B and Glass, T and Crainiceanu, C} } @article {813, title = {Movelets: A dictionary of movement.}, journal = {Electron J Stat}, volume = {6}, year = {2012}, month = {2012}, pages = {559-578}, abstract = {

Recent technological advances provide researchers with a way of gathering real-time information on an individual{\textquoteright}s movement through the use of wearable devices that record acceleration. In this paper, we propose a method for identifying activity types, like walking, standing, and resting, from acceleration data. Our approach decomposes movements into short components called "movelets", and builds a reference for each activity type. Unknown activities are predicted by matching new movelets to the reference. We apply our method to data collected from a single, three-axis accelerometer and focus on activities of interest in studying physical function in elderly populations. An important technical advantage of our methods is that they allow identification of short activities, such as taking two or three steps and then stopping, as well as low frequency rare(compared with the whole time series) activities, such as sitting on a chair. Based on our results we provide simple and actionable recommendations for the design and implementation of large epidemiological studies that could collect accelerometry data for the purpose of predicting the time series of activities and connecting it to health outcomes.

}, issn = {1935-7524}, doi = {10.1214/12-EJS684}, author = {Bai, Jiawei and Goldsmith, Jeff and Caffo, Brian and Glass, Thomas A and Crainiceanu, Ciprian M} } @article {goldsmithNI, title = {Penalized functional regression analysis of white-matter tract profiles in multiple sclerosis}, journal = {Accepted in Neuroimage, PMCID: PMC3114268}, year = {2012}, author = {Goldsmith, J and Crainiceanu, C and Caffo, B and Reich, D.} } @article {pmid22442041, title = {Predicting Breakdown of the Blood-Brain Barrier in Multiple Sclerosis without Contrast Agents}, journal = {AJNR Am J Neuroradiol}, year = {2012}, month = {Mar}, author = {Shinohara, R and Goldsmith, J and Mateen, F J and Crainiceanu, C and Reich, D S} } @article {rectalab, title = {Quantification of the spatial distribution of rectally-applied surrogates for microbicide and semen in colon with SPECT imaging}, journal = {Accepted in the British Journal of Clinical Pharmacology}, year = {2012}, author = {Cao, Y and Caffo, B and Fuchs, 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State space methods have proven indispensable in neural data analysis. However, common methods for performing inference in state-space models with non-Gaussian observations rely on certain approximations which are not always accurate. Here we review direct optimization methods that avoid these approximations, but that nonetheless retain the computational efficiency of the approximate methods. We discuss a variety of examples, applying these direct optimization techniques to problems in spike train smoothing, stimulus decoding, parameter estimation, and inference of synaptic properties. Along the way, we point out connections to some related standard statistical methods, including spline smoothing and isotonic regression. Finally, we note that the computational methods reviewed here do not in fact depend on the state-space setting at all; instead, the key property we are exploiting involves the bandedness of certain matrices. We close by discussing some applications of this more general point of view, including Markov chain Monte Carlo methods for neural decoding and efficient estimation of spatially-varying firing rates.

}, keywords = {1 introduction, Action Potentials, Action Potentials: physiology, Animals, Computer Simulation, for inference in state-space, forward-backward methods, hidden markov model, models, neural coding, Neurological, Neurons, Neurons: physiology, Retinal Ganglion Cells, Retinal Ganglion Cells: physiology, state-space models, Statistical, Synapses, Synapses: physiology, tridiagonal matrix}, issn = {1573-6873}, doi = {10.1007/s10827-009-0179-x}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19649698}, author = {Paninski, Liam and Ahmadian, Yashar and Gil, Daniel and Shinsuke, Ferreira and Rahnama, Kamiar and Michael, Rad and Vogelstein, Joshua T and Wu, Wei and Ferreira, Daniel Gil and Koyama, Shinsuke and {Rahnama Rad}, Kamiar and Vidne, Michael} } @article {lindquist2009correlations, title = {Correlations and multiple comparisons in functional imaging: a statistical perspective (Commentary on Vul et al., 2009)}, journal = {Perspectives on Psychological Science}, volume = {4}, number = {3}, year = {2009}, pages = {310{\textendash}313}, publisher = {SAGE Publications}, author = {Lindquist, Martin A and Gelman, Andrew} } @article {reich2009damage, title = {Damage to the Optic Radiation in Multiple Sclerosis Is Associated With Retinal Injury and Visual Disability}, journal = {Archives of Neurology, PMCID: PMC2784485}, volume = {66}, number = {8}, year = {2009}, pages = {998{\textendash}1006}, publisher = {Am Med Assoc}, author = {Reich, D. and Smith, S and Gordon-Lipkin, E and Ozturk, A and Caffo, B and Balcer, L and Calabresi, P} } @article {mostofsky2009decreased, title = {Decreased connectivity and cerebellar activity in autism during motor task performance}, journal = {Brain, PMCID: PMC2732264}, volume = {132}, number = {9}, year = {2009}, pages = {2413{\textendash}2425}, publisher = {Oxford Univ Press}, author = {Mostofsky, S and Powell, S and Simmonds, D and Goldberg, M and Caffo, B and Pekar, J} } @article {pmid20049214, title = {Mercury induces an unopposed inflammatory response in human peripheral blood mononuclear cells in vitro}, journal = {Environ. 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Allelic deletions involving the short arm of chromosome 3 (3p13-21.1) have been observed frequently in cervical carcinomas. Recently, a candidate tumor suppressor gene, FHIT (Fragile Histidine Triad), was cloned and mapped to this chromosomal region (3p14.2). Abnormal FHIT transcripts have been identified previously in a variety of tumor cell lines and primary carcinomas, although their significance and the molecular mechanisms underlying their origin remain incompletely defined. In addition, integration of human papillomavirus DNA has been identified at a fragile site (FRA3B) within the FHIT locus in cervical cancer. These observations motivated us to evaluate FHIT mRNA and protein expression in cervical cancer cell lines, primary cervical carcinomas, and normal tissues. Transcripts of the expected size and sequence were the predominant species identified by reverse transcription (RT)-PCR in cultured keratinocytes and all normal tissues evaluated. In contrast, aberrant FHIT transcripts were readily demonstrated in 6 of 7 cervical carcinoma cell lines and 17 of 25 (68\%) primary cervical carcinomas. Northern blot analyses demonstrated reduced or absent FHIT expression in the cervical carcinoma cell lines, particularly those with aberrant RT-PCR products. Immunohistochemical analysis of Fhit expression in cervical tissues revealed strong immunoreactivity in nonneoplastic squamous and glandular cervical epithelium and marked reduction or loss of Fhit protein in 25 of 33 (76\%) primary cervical carcinomas. In those cervical cancer cell lines and primary tumors with exclusively aberrant or absent FHIT transcripts by RT-PCR, Fhit protein expression was always markedly reduced or absent. The frequent alterations in FHIT expression in many cervical carcinomas, but not in normal tissues, suggest that FHIT gene alterations may play an important role in cervical tumorigenesis.

}, url = {http://www.ncbi.nlm.nih.gov/pubmed/9354423}, author = {Greenspan, D L and Connolly, D C and Wu, R and Lei, R Y and Vogelstein, Joshua T and Kim, Y T and Mok, J E and Mu{\~n}oz, N and Bosch, F X and Shah, K and Cho, K R} }