@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 {797, title = {Biomarkers of vascular calcification and mortality in patients with ESRD.}, journal = {Clin J Am Soc Nephrol}, volume = {9}, year = {2014}, month = {2014 Apr}, pages = {745-55}, abstract = {

BACKGROUND: Vascular calcification is common among patients undergoing dialysis and is associated with mortality. Factors such as osteoprotegerin (OPG), osteopontin (OPN), bone morphogenic protein-7 (BMP-7), and fetuin-A are involved in vascular calcification.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: OPG, OPN, BMP-7, and fetuin-A were measured in blood samples from 602 incident dialysis patients recruited from United States dialysis centers between 1995 and 1998 as part of the Choices for Healthy Outcomes In Caring for ESRD Study. Their association with all-cause and cardiovascular mortality were assessed using Cox proportional hazards models adjusted for demographic characteristics, comorbidity, serum phosphate, and calcium. An interaction with diabetes was tested because of its known association with vascular calcification. Predictive accuracy of selected biomarkers was explored by C-statistics in nested models with training and validation subcohorts.

RESULTS: Higher OPG and lower fetuin-A levels were associated with higher mortality over up to 13 years of follow-up (median, 3.4 years). The adjusted hazard ratios (HR) for highest versus lowest tertile were 1.49 (95\% confidence interval [95\% CI], 1.08 to 2.06) for OPG and 0.69 (95\% CI, 0.52 to 0.92) for fetuin-A. In stratified models, the highest tertile of OPG was associated with higher mortality among patients without diabetes (HR, 2.42; 95\% CI, 1.35 to 4.34), but not patients with diabetes (HR, 1.26; 95\% CI, 0.82 to 1.93; P for interaction=0.001). In terms of cardiovascular mortality, higher fetuin-A was associated with lower risk (HR, 0.85 per 0.1 g/L: 95\% CI, 0.75 to 0.96). In patients without diabetes, higher OPG was associated with greater risk (HR for highest versus lowest tertile, 2.91; 95\% CI, 1.06 to 7.99), but not in patients with diabetes or overall. OPN and BMP-7 were not independently associated with outcomes overall. The addition of OPG and fetuin-A did not significantly improve predictive accuracy of mortality.

CONCLUSIONS: OPG and fetuin-A may be risk factors for all-cause and cardiovascular mortality in patients undergoing dialysis, but do not improve risk prediction.

}, issn = {1555-905X}, doi = {10.2215/CJN.05450513}, author = {Scialla, Julia J and Kao, W H Linda and Crainiceanu, Ciprian and Sozio, Stephen M and Oberai, Pooja C and Shafi, Tariq and Coresh, Josef and Powe, Neil R and Plantinga, Laura C and Jaar, Bernard G and Parekh, Rulan S} } @article {795, title = {A comparison of supervised machine learning algorithms and feature vectors for MS lesion segmentation using multimodal structural MRI.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e95753}, abstract = {

Machine learning is a popular method for mining and analyzing large collections of medical data. We focus on a particular problem from medical research, supervised multiple sclerosis (MS) lesion segmentation in structural magnetic resonance imaging (MRI). We examine the extent to which the choice of machine learning or classification algorithm and feature extraction function impacts the performance of lesion segmentation methods. As quantitative measures derived from structural MRI are important clinical tools for research into the pathophysiology and natural history of MS, the development of automated lesion segmentation methods is an active research field. Yet, little is known about what drives performance of these methods. We evaluate the performance of automated MS lesion segmentation methods, which consist of a supervised classification algorithm composed with a feature extraction function. These feature extraction functions act on the observed T1-weighted (T1-w), T2-weighted (T2-w) and fluid-attenuated inversion recovery (FLAIR) MRI voxel intensities. Each MRI study has a manual lesion segmentation that we use to train and validate the supervised classification algorithms. Our main finding is that the differences in predictive performance are due more to differences in the feature vectors, rather than the machine learning or classification algorithms. Features that incorporate information from neighboring voxels in the brain were found to increase performance substantially. For lesion segmentation, we conclude that it is better to use simple, interpretable, and fast algorithms, such as logistic regression, linear discriminant analysis, and quadratic discriminant analysis, and to develop the features to improve performance.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0095753}, author = {Sweeney, Elizabeth M and Vogelstein, Joshua T and Cuzzocreo, Jennifer L and Calabresi, Peter A and Reich, Daniel S and Crainiceanu, Ciprian M and Shinohara, Russell T} } @article {833, title = {Cross-sectional and longitudinal association of body mass index and brain volume.}, journal = {Hum Brain Mapp}, volume = {35}, year = {2014}, month = {2014 Jan}, pages = {75-88}, abstract = {

Although a link between body mass index (BMI) and brain volume has been established in several cross-sectional studies, evidence of the association between change in BMI over time and changes in brain structure is limited. Using data from a cohort of 347 former lead workers and community controls with two magnetic resonance imaging scans over a period of ~5 years, we estimated cross-sectional and longitudinal associations of BMI and brain volume using both region of interest (ROI) and voxel-based morphometric (VBM) methods. We found that associations of BMI and brain volume were not significantly different in former lead workers when compared with community controls. In the cross-sectional analysis, higher BMIs were associated with smaller brain volumes in gray matter (GM) using both ROI and VBM approaches. No associations with white matter (WM) were observed. In the longitudinal analysis, higher baseline BMI was associated with greater decline in temporal and occipital GM ROI volumes. Change in BMI over the 5-year period was only associated with change in hippocampal volume and was not associated with change in any of the GM ROIs. Overall, higher BMI was associated with lower GM volume in several ROIs and with declines in volume in temporal and occipital GM over time. These results suggest that sustained high body mass may contribute to progressive temporal and occipital atrophy.

}, keywords = {Aged, Atrophy, Body Mass Index, Brain, Cross-Sectional Studies, Humans, Image Interpretation, Computer-Assisted, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Obesity}, issn = {1097-0193}, doi = {10.1002/hbm.22159}, author = {Bobb, Jennifer F and Schwartz, Brian S and Davatzikos, Christos and Caffo, Brian} } @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 {790, title = {Health effects of lesion localization in multiple sclerosis: spatial registration and confounding adjustment.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e107263}, abstract = {

Brain lesion localization in multiple sclerosis (MS) is thought to be associated with the type and severity of adverse health effects. However, several factors hinder statistical analyses of such associations using large MRI datasets: 1) spatial registration algorithms developed for healthy individuals may be less effective on diseased brains and lead to different spatial distributions of lesions; 2) interpretation of results requires the careful selection of confounders; and 3) most approaches have focused on voxel-wise regression approaches. In this paper, we evaluated the performance of five registration algorithms and observed that conclusions regarding lesion localization can vary substantially with the choice of registration algorithm. Methods for dealing with confounding factors due to differences in disease duration and local lesion volume are introduced. Voxel-wise regression is then extended by the introduction of a metric that measures the distance between a patient-specific lesion mask and the population prevalence map.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0107263}, author = {Eloyan, Ani and Shou, Haochang and Shinohara, Russell T and Sweeney, Elizabeth M and Nebel, Mary Beth and Cuzzocreo, Jennifer L and Calabresi, Peter A and Reich, Daniel S and Lindquist, Martin A and Crainiceanu, Ciprian M} } @article {817, title = {The neural correlates of learned motor acuity.}, journal = {J Neurophysiol}, volume = {112}, year = {2014}, month = {2014 Aug 15}, pages = {971-80}, abstract = {

We recently defined a component of motor skill learning as "motor acuity," quantified as a shift in the speed-accuracy trade-off function for a task. These shifts are primarily driven by reductions in movement variability. To determine the neural correlates of improvement in motor acuity, we devised a motor task compatible with magnetic resonance brain imaging that required subjects to make finely controlled wrist movements under visual guidance. Subjects were imaged on day 1 and day 5 while they performed this task and were trained outside the scanner on intervening days 2, 3, and 4. The potential confound of performance changes between days 1 and 5 was avoided by constraining movement time to a fixed duration. After training, subjects showed a marked increase in success rate and a reduction in trial-by-trial variability for the trained task but not for an untrained control task, without changes in mean trajectory. The decrease in variability for the trained task was associated with increased activation in contralateral primary motor and premotor cortical areas and in ipsilateral cerebellum. A global nonlocalizing multivariate analysis confirmed that learning was associated with increased overall brain activation. We suggest that motor acuity is acquired through increases in the number of neurons recruited in contralateral motor cortical areas and in ipsilateral cerebellum, which could reflect increased signal-to-noise ratio in motor output and improved state estimation for feedback corrections, respectively.

}, issn = {1522-1598}, doi = {10.1152/jn.00897.2013}, author = {Shmuelof, Lior and Yang, Juemin and Caffo, Brian and Mazzoni, Pietro and Krakauer, John W} } @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 {787, title = {Quantifying the lifetime circadian rhythm of physical activity: a covariate-dependent functional approach.}, journal = {Biostatistics}, year = {2014}, month = {2014 Oct 30}, abstract = {

Objective measurement of physical activity using wearable devices such as accelerometers may provide tantalizing new insights into the association between activity and health outcomes. Accelerometers can record quasi-continuous activity information for many days and for hundreds of individuals. For example, in the Baltimore Longitudinal Study on Aging physical activity was recorded every minute for [Formula: see text] adults for an average of [Formula: see text] days per adult. An important scientific problem is to separate and quantify the systematic and random circadian patterns of physical activity as functions of time of day, age, and gender. To capture the systematic circadian pattern, we introduce a practical bivariate smoother and two crucial innovations: (i) estimating the smoothing parameter using leave-one-subject-out cross validation to account for within-subject correlation and (ii) introducing fast computational techniques that overcome problems both with the size of the data and with the cross-validation approach to smoothing. The age-dependent random patterns are analyzed by a new functional principal component analysis that incorporates both covariate dependence and multilevel structure. For the analysis, we propose a practical and very fast trivariate spline smoother to estimate covariate-dependent covariances and their spectra. Results reveal several interesting, previously unknown, circadian patterns associated with human aging and gender.

}, issn = {1468-4357}, doi = {10.1093/biostatistics/kxu045}, author = {Xiao, Luo and Huang, Lei and Schrack, Jennifer A and Ferrucci, Luigi and Zipunnikov, Vadim and Crainiceanu, Ciprian M} } @article {792, title = {Shrinkage prediction of seed-voxel brain connectivity using resting state fMRI.}, journal = {Neuroimage}, volume = {102 Pt 2}, year = {2014}, month = {2014 Nov 15}, pages = {938-44}, abstract = {

Resting-state functional magnetic resonance imaging (rs-fMRI) is used to investigate synchronous activations in spatially distinct regions of the brain, which are thought to reflect functional systems supporting cognitive processes. Analyses are often performed using seed-based correlation analysis, allowing researchers to explore functional connectivity between data in a seed region and the rest of the brain. Using scan-rescan rs-fMRI data, we investigate how well the subject-specific seed-based correlation map from the second replication of the study can be predicted using data from the first replication. We show that one can dramatically improve prediction of subject-specific connectivity by borrowing strength from the group correlation map computed using all other subjects in the study. Even more surprisingly, we found that the group correlation map provided a better prediction of a subject{\textquoteright}s connectivity than the individual{\textquoteright}s own data. While further discussion and experimentation are required to understand how this can be used in practice, results indicate that shrinkage-based methods that borrow strength from the population mean should play a role in rs-fMRI data analysis.

}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2014.05.043}, author = {Shou, Haochang and Eloyan, Ani and Nebel, Mary Beth and Mejia, Amanda and Pekar, James J and Mostofsky, Stewart and Caffo, Brian and Lindquist, Martin A 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 {820, title = {Successful implementation of a unit-based quality nurse to reduce central line-associated bloodstream infections.}, journal = {Am J Infect Control}, volume = {42}, year = {2014}, month = {2014 Feb}, pages = {139-43}, abstract = {

BACKGROUND: Central line (CL)-associated bloodstream infections (CLABSI) are an important cause of patient morbidity and mortality. Novel strategies to prevent CLABSI are needed.

METHODS: We described a quasiexperimental study to examine the effect of the presence of a unit-based quality nurse (UQN) dedicated to perform patient safety and infection control activities with a focus on CLABSI prevention in a surgical intensive care unit (SICU).

RESULTS: From July 2008 to March 2012, there were 3,257 SICU admissions; CL utilization ratio was 0.74 (18,193 CL-days/24,576 patient-days). The UQN program began in July 2010; the nurse was present for 30\% (193/518) of the days of the intervention period of July 2010 to March 2012. The average CLABSI rate was 5.0 per 1,000 CL-days before the intervention and 1.5 after the intervention and decreased by 5.1\% (P = .005) for each additional 1\% of days of the month that the UQN was present, even after adjusting for CLABSI rates in other adult intensive care units, time, severity of illness, and Comprehensive Unit-based Safety Program participation (5.1\%, P = .004). Approximately 11.4 CLABSIs were prevented.

CONCLUSION: The presence of a UQN dedicated to perform infection control activities may be an effective strategy for CLABSI reduction.

}, keywords = {Adult, Catheter-Related Infections, Catheterization, Central Venous, Humans, Infection Control, Intensive Care Units, Nurses, Quality Control, Quality of Health Care}, issn = {1527-3296}, doi = {10.1016/j.ajic.2013.08.006}, author = {Thom, Kerri A and Li, Shanshan and Custer, Melissa and Preas, Michael Anne and Rew, Cindy D and Cafeo, Christina and Leekha, Surbhi and Caffo, Brian S and Scalea, Thomas M and Lissauer, Matthew E} } @article {788, title = {A unifying framework for marginalized random intercept models of correlated binary outcomes.}, journal = {Int Stat Rev}, volume = {82}, year = {2014}, month = {2014 Aug}, pages = {275-295}, abstract = {

We demonstrate that many current approaches for marginal modeling of correlated binary outcomes produce likelihoods that are equivalent to the copula-based models herein. These general copula models of underlying latent threshold random variables yield likelihood-based models for marginal fixed effects estimation and interpretation in the analysis of correlated binary data with exchangeable correlation structures. Moreover, we propose a nomenclature and set of model relationships that substantially elucidates the complex area of marginalized random intercept models for binary data. A diverse collection of didactic mathematical and numerical examples are given to illustrate concepts.

}, issn = {0306-7734}, doi = {10.1111/insr.12035}, author = {Swihart, Bruce J and Caffo, Brian S and Crainiceanu, Ciprian M} } @article {828, title = {Axial 3D gradient-echo imaging for improved multiple sclerosis lesion detection in the cervical spinal cord at 3T.}, journal = {Neuroradiology}, volume = {55}, year = {2013}, month = {2013 Mar}, pages = {431-9}, abstract = {

INTRODUCTION: In multiple sclerosis (MS), spinal cord imaging can help in diagnosis and follow-up evaluation. However, spinal cord magnetic resonance imaging (MRI) is technically challenging, and image quality, particularly in the axial plane, is typically poor compared to brain MRI. Because gradient-recalled echo (GRE) images might offer improved contrast resolution within the spinal cord at high magnetic field strength, both without and with a magnetization transfer prepulse, we compared them to T2-weighted fast-spin-echo (T2-FSE) images for the detection of MS lesions in the cervical cord at 3T.

METHODS: On a clinical 3T MRI scanner, we studied 62 MS cases and 19 healthy volunteers. Axial 3D GRE sequences were performed without and with off-resonance radiofrequency irradiation. To mimic clinical practice, all images were evaluated in conjunction with linked images from a sagittal short tau inversion recovery scan, which is considered the gold standard for lesion detection in MS. Two experienced observers recorded image quality, location and size of focal lesions, atrophy, swelling, and diffuse signal abnormality independently at first and then in consensus.

RESULTS: The number and volume of lesions detected with high confidence was more than three times as high on both GRE sequences compared to T2-FSE (p < 0.0001). Approximately 5 \% of GRE scans were affected by artifacts that interfered with image interpretation, not significantly different from T2W-FSE.

CONCLUSIONS: Axial 3D GRE sequences are useful for MS lesion detection when compared to 2D T2-FSE sequences in the cervical spinal cord at 3T and should be considered when examining intramedullary spinal cord lesions.

}, keywords = {Adult, Aged, Algorithms, Cervical Vertebrae, Echo-Planar Imaging, Female, Humans, Image Enhancement, Image Interpretation, Computer-Assisted, Imaging, Three-Dimensional, Male, Middle Aged, Multiple Sclerosis, Reproducibility of Results, Sensitivity and Specificity, Spinal Cord}, issn = {1432-1920}, doi = {10.1007/s00234-012-1118-5}, author = {Ozturk, Arzu and Aygun, Nafi and Smith, Seth A and Caffo, Brian and Calabresi, Peter A and Reich, Daniel S} } @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 {843, title = {Cloak and DAG: a response to the comments on our comment.}, journal = {Neuroimage}, volume = {76}, year = {2013}, month = {2013 Aug 1}, pages = {446-9}, abstract = {

Our original comment (Lindquist and Sobel, 2011) made explicit the types of assumptions neuroimaging researchers are making when directed graphical models (DGMs), which include certain types of structural equation models (SEMs), are used to estimate causal effects. When these assumptions, which many researchers are not aware of, are not met, parameters of these models should not be interpreted as effects. Thus it is imperative that neuroimaging researchers interested in issues involving causation, for example, effective connectivity, consider the plausibility of these assumptions for their particular problem before using SEMs. In cases where these additional assumptions are not met, researchers may be able to use other methods and/or design experimental studies where the use of unrealistic assumptions can be avoided. Pearl does not disagree with anything we stated. However, he takes exception to our use of potential outcomes{\textquoteright} notation, which is the standard notation used in the statistical literature on causal inference, and his comment is devoted to promoting his alternative conventions. Glymour{\textquoteright}s comment is based on three claims that he inappropriately attributes to us. Glymour is also more optimistic than us about the potential of using directed graphical models (DGMs) to discover causal relations in neuroimaging research; we briefly address this issue toward the end of our rejoinder.

}, keywords = {Artifacts, Brain, Computer Simulation, Humans, Image Interpretation, Computer-Assisted, Meta-Analysis as Topic}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2011.11.027}, author = {Lindquist, Martin A and Sobel, Michael E} } @article {810, title = {Combining hidden Markov models for comparing the dynamics of multiple sleep electroencephalograms.}, journal = {Stat Med}, volume = {32}, year = {2013}, month = {2013 Aug 30}, pages = {3342-56}, abstract = {

In this manuscript, we consider methods for the analysis of populations of electroencephalogram signals during sleep for the study of sleep disorders using hidden Markov models (HMMs). Notably, we propose an easily implemented method for simultaneously modeling multiple time series that involve large amounts of data. We apply these methods to study sleep-disordered breathing (SDB) in the Sleep Heart Health Study (SHHS), a landmark study of SDB and cardiovascular consequences. We use the entire, longitudinally collected, SHHS cohort to develop HMM population parameters, which we then apply to obtain subject-specific Markovian predictions. From these predictions, we create several indices of interest, such as transition frequencies between latent states. Our HMM analysis of electroencephalogram signals uncovers interesting findings regarding differences in brain activity during sleep between those with and without SDB. These findings include stability of the percent time spent in HMM latent states across matched diseased and non-diseased groups and differences in the rate of transitioning.

}, keywords = {Data Interpretation, Statistical, Electroencephalography, Female, Humans, Longitudinal Studies, Male, Markov Chains, Middle Aged, Models, Statistical, Sleep Apnea Syndromes}, issn = {1097-0258}, doi = {10.1002/sim.5747}, author = {Langrock, Roland and Swihart, Bruce J and Caffo, Brian S and Punjabi, Naresh M and Crainiceanu, Ciprian M} } @article {809, title = {In vivo identification of morphologic retinal abnormalities in neuromyelitis optica.}, journal = {Neurology}, volume = {80}, year = {2013}, month = {2013 Apr 9}, pages = {1406-14}, abstract = {

OBJECTIVE: To assess eyes with neuromyelitis optica (NMO) for morphologic retinal abnormalities utilizing high-definition optical coherence tomography (OCT) imaging.

METHODS: In this cross-sectional study, 39 patients with NMO spectrum disorders and 39 age- and sex-matched healthy controls underwent spectral-domain OCT and visual function testing.

RESULTS: Microcystic macular edema (MME) of the inner nuclear layer (INL) was identified in 10 of 39 patients (26\%) and was exclusively found in eyes with a history of optic neuritis (ON). MME eyes had lower high- and low-contrast letter-acuity scores (100\%: p = 0.002; 2.5\%: p = 0.002; 1.25\%: p = 0.004), lower peripapillary retinal nerve fiber layer (RNFL) thickness (p = 0.04), lower macular RNFL thickness (p = 0.004), lower ganglion cell layer + inner plexiform layer (GCIP) thickness (p = 0.007), higher INL thickness (p < 0.001), and a greater number of ON episodes (p = 0.008) relative to non-MME eyes with a history of ON. After adjusting for history of multiple ON episodes, these findings remained significant for macular-RNFL thickness (p = 0.03), INL thickness (p < 0.001), and 100\% and 2.5\% contrast letter-acuity scores (p = 0.008 and p = 0.03, respectively). NMO spectrum eyes without ON history had lower macular RNFL thickness (p = 0.003), GCIP thickness (p = 0.002), outer nuclear layer thickness (p = 0.02), and low-contrast letter-acuity scores (2.5\%: p = 0.03; 1.25\%: p = 0.002) compared to healthy controls.

CONCLUSIONS: We have identified a pattern of retinal morphologic abnormalities in NMO that is associated with severe retinal axonal and neuronal loss and corresponding visual disability. MME may contribute to poor visual outcomes following NMO-associated ON or alternatively represent a marker of ON severity. Additionally, our results support that subclinical involvement of the anterior visual pathway may occur in NMO spectrum disorders.

}, keywords = {Adolescent, Adult, Aged, Aquaporin 4, Autoantibodies, Case-Control Studies, Chi-Square Distribution, Female, Humans, Macular Edema, Male, Middle Aged, Nerve Fibers, Neuromyelitis Optica, Retina, Tomography, Optical Coherence, Vision Tests, Visual Acuity, Young Adult}, issn = {1526-632X}, doi = {10.1212/WNL.0b013e31828c2f7a}, author = {Sotirchos, Elias S and Saidha, Shiv and Byraiah, Gita and Mealy, Maureen A and Ibrahim, Mohamed A and Sepah, Yasir Jamal and Newsome, Scott D and Ratchford, John N and Frohman, Elliot M and Balcer, Laura J and Crainiceanu, Ciprian M and Nguyen, Quan Dong and Levy, Michael and Calabresi, Peter A} } @article {802, title = {OASIS is Automated Statistical Inference for Segmentation, with applications to multiple sclerosis lesion segmentation in MRI.}, journal = {Neuroimage Clin}, volume = {2}, year = {2013}, month = {2013}, pages = {402-13}, abstract = {

Magnetic resonance imaging (MRI) can be used to detect lesions in the brains of multiple sclerosis (MS) patients and is essential for diagnosing the disease and monitoring its progression. In practice, lesion load is often quantified by either manual or semi-automated segmentation of MRI, which is time-consuming, costly, and associated with large inter- and intra-observer variability. We propose OASIS is Automated Statistical Inference for Segmentation (OASIS), an automated statistical method for segmenting MS lesions in MRI studies. We use logistic regression models incorporating multiple MRI modalities to estimate voxel-level probabilities of lesion presence. Intensity-normalized T1-weighted, T2-weighted, fluid-attenuated inversion recovery and proton density volumes from 131 MRI studies (98 MS subjects, 33 healthy subjects) with manual lesion segmentations were used to train and validate our model. Within this set, OASIS detected lesions with a partial area under the receiver operating characteristic curve for clinically relevant false positive rates of 1\% and below of 0.59\% (95\% CI; [0.50\%, 0.67\%]) at the voxel level. An experienced MS neuroradiologist compared these segmentations to those produced by LesionTOADS, an image segmentation software that provides segmentation of both lesions and normal brain structures. For lesions, OASIS out-performed LesionTOADS in 74\% (95\% CI: [65\%, 82\%]) of cases for the 98 MS subjects. To further validate the method, we applied OASIS to 169 MRI studies acquired at a separate center. The neuroradiologist again compared the OASIS segmentations to those from LesionTOADS. For lesions, OASIS ranked higher than LesionTOADS in 77\% (95\% CI: [71\%, 83\%]) of cases. For a randomly selected subset of 50 of these studies, one additional radiologist and one neurologist also scored the images. Within this set, the neuroradiologist ranked OASIS higher than LesionTOADS in 76\% (95\% CI: [64\%, 88\%]) of cases, the neurologist 66\% (95\% CI: [52\%, 78\%]) and the radiologist 52\% (95\% CI: [38\%, 66\%]). OASIS obtains the estimated probability for each voxel to be part of a lesion by weighting each imaging modality with coefficient weights. These coefficients are explicit, obtained using standard model fitting techniques, and can be reused in other imaging studies. This fully automated method allows sensitive and specific detection of lesion presence and may be rapidly applied to large collections of images.

}, issn = {2213-1582}, doi = {10.1016/j.nicl.2013.03.002}, author = {Sweeney, Elizabeth M and Shinohara, Russell T and Shiee, Navid and Mateen, Farrah J and Chudgar, Avni A and Cuzzocreo, Jennifer L and Calabresi, Peter A and Pham, Dzung L and Reich, Daniel S and Crainiceanu, Ciprian M} } @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 {801, title = {Quantification of multiple-sclerosis-related brain atrophy in two heterogeneous MRI datasets using mixed-effects modeling.}, journal = {Neuroimage Clin}, volume = {3}, year = {2013}, month = {2013}, pages = {171-9}, abstract = {

Brain atrophy, measured by MRI, has been proposed as a useful surrogate marker for disease progression in multiple sclerosis (MS). However, it is conventionally assumed that the accurate quantification of brain atrophy is made difficult, if not impossible, by changes in the parameters of the MRI acquisition, which are almost inevitable over the course of a longitudinal study since MRI technology changes rapidly. This state of affairs can negatively affect clinical trial design and limit the use of historical data. Here, we investigate whether we can coherently estimate brain atrophy rates in a heterogeneous MS sample via linear mixed-effects multivariable regression, incorporating three critical assumptions: (1) using age at time of scanning, rather than time since baseline, as the regressor of interest; (2) scanning individuals with a variety of techniques; and (3) introducing a simple additive correction for major differences in MRI protocol. We fit the model to several measures of brain volume as the outcome in two MS populations: 1123 scans from 195 cases acquired for over approximately 7~years in two natural history protocols (Cohort 1), and 1331 scans from 69 cases seen for over 11~years who were primarily treated with two specific MS disease-modifying therapies (Cohort 2). We compared the mixed-effects model with additive correction for MRI acquisition parameters to a model fit without this correction and performed sample-size calculations to provide an estimate of the number of participants in an MS clinical trial that might be required to see a therapeutic effect of treatment using the approach described here. The results show that without the additive correction for T1-weighted protocol parameters, atrophy was underestimated and subject-specific estimates were more narrowly distributed about the population mean. Ventricular CSF is the most consistently estimated brain volume, with a mean of 2.8\%/year increase in Cohort 1 and 4.4\%/year increase in Cohort 2. An interesting observation was that gray matter volume decreased and white matter volume remained essentially unchanged in both cohorts, suggesting that changes in ventricular CSF volume are a surrogate for changes in gray matter volume. In conclusion, the mixed-effects modeling framework presented here allows effective use of heterogeneously acquired and historical data in the study of brain atrophy in MS, potentially simplifying the design of future single- and multi-site clinical trials and natural history studies.

}, issn = {2213-1582}, doi = {10.1016/j.nicl.2013.08.001}, author = {Jones, Blake C and Nair, Govind and Shea, Colin D and Crainiceanu, Ciprian M and Cortese, Irene C M and Reich, Daniel S} } @article {803, title = {Quantifying the reliability of image replication studies: the image intraclass correlation coefficient (I2C2).}, journal = {Cogn Affect Behav Neurosci}, volume = {13}, year = {2013}, month = {2013 Dec}, pages = {714-24}, abstract = {

This article proposes the image intraclass correlation (I2C2) coefficient as a global measure of reliability for imaging studies. The I2C2 generalizes the classic intraclass correlation (ICC) coefficient to the case when the data of interest are images, thereby providing a measure that is both intuitive and convenient. Drawing a connection with classical measurement error models for replication experiments, the I2C2 can be computed quickly, even in high-dimensional imaging studies. A nonparametric bootstrap procedure is introduced to quantify the variability of the I2C2 estimator. Furthermore, a Monte Carlo permutation is utilized to test reproducibility versus a zero I2C2, representing complete lack of reproducibility. Methodologies are applied to three replication studies arising from different brain imaging modalities and settings: regional analysis of volumes in normalized space imaging for characterizing brain morphology, seed-voxel brain activation maps based on resting-state functional magnetic resonance imaging (fMRI), and fractional anisotropy in an area surrounding the corpus callosum via diffusion tensor imaging. Notably, resting-state fMRI brain activation maps are found to have low reliability, ranging from .2 to .4. Software and data are available to provide easy access to the proposed methods.

}, keywords = {Adult, Brain, brain mapping, Computer Simulation, Female, Humans, Male, Models, Biological, Neuroimaging, Reproducibility of Results, Statistics as Topic}, issn = {1531-135X}, doi = {10.3758/s13415-013-0196-0}, author = {Shou, H and Eloyan, A and Lee, S and Zipunnikov, V and Crainiceanu, A N and Nebel, N B and Caffo, B and Lindquist, M A and Crainiceanu, C M} } @article {811, title = {Relationships between retinal axonal and neuronal measures and global central nervous system pathology in multiple sclerosis.}, journal = {JAMA Neurol}, volume = {70}, year = {2013}, month = {2013 Jan}, pages = {34-43}, abstract = {

OBJECTIVE: To determine the relationships between conventional and segmentation-derived optical coherence tomography (OCT) retinal layer thickness measures with intracranial volume (a surrogate of head size) and brain substructure volumes in multiple sclerosis (MS).

DESIGN: Cross-sectional study.

SETTING: Johns Hopkins University, Baltimore, Maryland.

PARTICIPANTS: A total of 84 patients with MS and 24 healthy control subjects.

MAIN OUTCOME MEASURES: High-definition spectral-domain OCT conventional and automated segmentation-derived discrete retinal layer thicknesses and 3-T magnetic resonance imaging brain substructure volumes.

RESULTS: Peripapillary retinal nerve fiber layer as well as composite ganglion cell layer+inner plexiform layer thicknesses in the eyes of patients with MS without a history of optic neuritis were associated with cortical gray matter (P=.01 and P=.04, respectively) and caudate (P=.04 and P=.03, respectively) volumes. Inner nuclear layer thickness, also in eyes without a history of optic neuritis, was associated with fluid-attenuated inversion recovery lesion volume (P=.007) and inversely associated with normal-appearing white matter volume (P=.005) in relapsing-remitting MS. As intracranial volume was found to be related with several of the OCT measures in patients with MS and healthy control subjects and is already known to be associated with brain substructure volumes, all OCT-brain substructure relationships were adjusted for intracranial volume. CONCLUSIONS Retinal measures reflect global central nervous system pathology in multiple sclerosis, with thicknesses of discrete retinal layers each appearing to be associated with distinct central nervous system processes. Moreover, OCT measures appear to correlate with intracranial volume in patients with MS and healthy control subjects, an important unexpected factor unaccounted for in prior studies examining the relationships between peripapillary retinal nerve fiber layer thickness and brain substructure volumes.

}, keywords = {Adult, Axons, Caudate Nucleus, Central Nervous System, Cerebral Cortex, Cross-Sectional Studies, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, Retina, Retinal Neurons, Tomography, Optical Coherence}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2013.573}, author = {Saidha, Shiv and Sotirchos, Elias S and Oh, Jiwon and Syc, Stephanie B and Seigo, Michaela A and Shiee, Navid and Eckstein, Chistopher and Durbin, Mary K and Oakley, Jonathan D and Meyer, Scott A and Frohman, Teresa C and Newsome, Scott and Ratchford, John N and Balcer, Laura J and Pham, Dzung L and Crainiceanu, Ciprian M and Frohman, Elliot M and Reich, Daniel S and Calabresi, Peter A} } @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 {621, title = {Automatic Lesion Incidence Estimation and Detection in Multiple Sclerosis Using Multisequence Longitudinal MRI.}, journal = {AJNR Am J Neuroradiol}, year = {2012}, month = {2012 Jul 5}, abstract = {

BACKGROUND AND PURPOSE:Detecting incidence and enlargement of lesions is essential in monitoring the progression of MS. In clinical trials, lesion load is observed by manually segmenting and comparing serial MR images, which is time consuming, costly, and prone to inter- and intraobserver variability. Subtracting images from consecutive time points nulls stable lesions, leaving only new lesion activity. We propose SuBLIME, an automated method for segmenting incident lesion voxels.MATERIALS AND METHODS:We used logistic regression models incorporating multiple MR imaging sequences and subtraction images from consecutive longitudinal studies to estimate voxel-level probabilities of lesion incidence. We used T1-weighted, T2-weighted, FLAIR, and PD volumes from a total of 110 MR imaging studies from 10 subjects.RESULTS:To assess the performance of the model, we assigned 5 subjects to a training set and the remaining 5 to a validation set. With SuBLIME, lesion incidence is detected and delineated in the validation set with an AUC of 99\% (95\% CI [97\%, 100\%]) at the voxel level.CONCLUSIONS:This fully automated and computationally fast method allows sensitive and specific detection of lesion incidence that can be applied to large collections of images. Using the explicit form of the statistical model, SuBLIME can easily be adapted to cases when more or fewer imaging sequences are available.

}, issn = {1936-959X}, doi = {10.3174/ajnr.A3172}, author = {Sweeney, E M and Shinohara, R and Shea, C D and Reich, D S and Crainiceanu, C} } @article {679, title = {Bootstrap-based inference on the difference in the means of two correlated functional processes.}, journal = {Stat Med}, year = {2012}, month = {2012 Aug 1}, abstract = {

We propose nonparametric inference methods on the mean difference between two correlated functional processes. We compare methods that (1) incorporate different levels of smoothing of the mean and covariance; (2) preserve the sampling design; and (3) use parametric and nonparametric estimation of the mean functions. We apply our method to estimating the mean difference between average normalized δ power of sleep electroencephalograms for 51 subjects with severe sleep apnea and 51 matched controls in the first 4\ ;h after sleep onset. We obtain data from the Sleep Heart Health Study, the largest community cohort study of sleep. Although methods are applied to a single case study, they can be applied to a large number of studies that have correlated functional data. Copyright {\textcopyright} 2012 John Wiley \& Sons, Ltd.

}, issn = {1097-0258}, doi = {10.1002/sim.5439}, author = {Crainiceanu, C and Staicu, A. M. and Ray, Shubankar and Punjabi, Naresh} } @article {LS11b, title = {Cloak and DAG: A response to the comments on our comment}, journal = {NeuroImage, to appear}, year = {2012}, issn = {1053-8119}, doi = {10.1016/j.neuroimage.2011.11.027}, url = {http://www.sciencedirect.com/science/article/pii/S1053811911013085}, author = {Lindquist, Martin A and Sobel, M.E.} } @article {thom, title = {Comparison of swab versus sponge methodology for the identification of acinetobacter baumannii from the hospital environment}, journal = {Accepted in the Journal of Clinical Microbiology}, year = {2012}, author = {Thom, K and Howard, T and Sembajwe, S and Harris, A and Strassle, P and Caffo, B and Caroll, K and Johnson, J} } @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 {cstechn2012, title = {Discussion of {\textquoteleft}Clustering random curves under spatial interdependence with application to service accessibility{\textquoteright}}, journal = {Technometrics}, year = {2012}, pages = {to appear}, author = {Crainiceanu, C and Staicu, A. M.} } @article {841, title = {Dissociable influences of opiates and expectations on pain.}, journal = {J Neurosci}, volume = {32}, year = {2012}, month = {2012 Jun 6}, pages = {8053-64}, abstract = {

Placebo treatments and opiate drugs are thought to have common effects on the opioid system and pain-related brain processes. This has created excitement about the potential for expectations to modulate drug effects themselves. If drug effects differ as a function of belief, this would challenge the assumptions underlying the standard clinical trial. We conducted two studies to directly examine the relationship between expectations and opioid analgesia. We administered the opioid agonist remifentanil to human subjects during experimental thermal pain and manipulated participants{\textquoteright} knowledge of drug delivery using an open-hidden design. This allowed us to test drug effects, expectancy (knowledge) effects, and their interactions on pain reports and pain-related responses in the brain. Remifentanil and expectancy both reduced pain, but drug effects on pain reports and fMRI activity did not interact with expectancy. Regions associated with pain processing showed drug-induced modulation during both Open and Hidden conditions, with no differences in drug effects as a function of expectation. Instead, expectancy modulated activity in frontal cortex, with a separable time course from drug effects. These findings reveal that opiates and placebo treatments both influence clinically relevant outcomes and operate without mutual interference.

}, keywords = {Analgesics, Opioid, Anticipation, Psychological, Behavior, brain mapping, Dose-Response Relationship, Drug, Female, Hemodynamics, Hot Temperature, Humans, Image Processing, Computer-Assisted, Injections, Intravenous, Linear Models, Magnetic Resonance Imaging, Male, Pain, Pain Measurement, Piperidines, Young Adult}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.0383-12.2012}, author = {Atlas, Lauren Y and Whittington, Robert A and Lindquist, Martin A and Wielgosz, Joe and Sonty, Nomita and Wager, Tor D} } @article {pmid22221585, title = {Effect of correcting for long-term variation in major coronary heart disease risk factors: relative hazard estimation and risk prediction in the Atherosclerosis Risk in Communities Study}, journal = {Ann Epidemiol}, volume = {22}, number = {3}, year = {2012}, month = {Mar}, pages = {191{\textendash}197}, author = {Paynter, N. P. and Crainiceanu, C and Sharrett, A. R. and Chambless, L. E. and Coresh, J.} } @article {lindquist2012estimating, title = {Estimating and testing variance components in a multi-level GLM}, journal = {Neuroimage}, volume = {59}, number = {1}, year = {2012}, pages = {490{\textendash}501}, publisher = {Elsevier}, author = {Lindquist, Martin A and Spicer, Julie and Asllani, Iris and Wager, Tor D} } @article {844, title = {Estimating and testing variance components in a multi-level GLM.}, journal = {Neuroimage}, volume = {59}, year = {2012}, month = {2012 Jan 2}, pages = {490-501}, abstract = {

Most analysis of multi-subject fMRI data is concerned with determining whether there exists a significant population-wide {\textquoteright}activation{\textquoteright} in a comparison between two or more conditions. This is typically assessed by testing the average value of a contrast of parameter estimates (COPE) against zero in a general linear model (GLM) analysis. However, important information can also be obtained by testing whether there exist significant individual differences in effect magnitude between subjects, i.e. whether the variance of a COPE is significantly different from zero. Intuitively, such a test amounts to testing whether inter-individual differences are larger than would be expected given the within-subject error variance. We compare several methods for estimating variance components, including a) a na{\"\i}ve estimate using ordinary least squares (OLS); b) linear mixed effects in R (LMER); c) a novel Matlab implementation of iterative generalized least squares (IGLS) and its restricted maximum likelihood variant (RIGLS). All methods produced reasonable estimates of within- and between-subject variance components, with IGLS providing an attractive balance between sensitivity and appropriate control of false positives. Finally, we use the IGLS method to estimate inter-subject variance in a perfusion fMRI study (N=18) of social evaluative threat, and show evidence for significant inter-individual differences in ventromedial prefrontal cortex (VMPFC), amygdala, hippocampus and medial temporal lobes, insula, and brainstem, with predicted inverse coupling between VMPFC and the midbrain periaqueductal gray only when high inter-individual variance was used to define the seed for functional connectivity analyses. In sum, tests of variance provides a way of selecting regions that show significant inter-individual variability for subsequent analyses that attempt to explain those individual differences.

}, keywords = {Brain, brain mapping, Humans, Image Interpretation, Computer-Assisted, Linear Models, Magnetic Resonance Imaging, Models, Neurological, Sensitivity and Specificity}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2011.07.077}, author = {Lindquist, Martin A and Spicer, Julie and Asllani, Iris and Wager, Tor D} } @article {mhssr2012, title = {Functional Generalized Additive Models}, journal = {J. of Computational and Graphical Statistics}, year = {2012}, pages = {to appear}, author = {McLean, M. and Hooker, G. and Staicu, A. M. and Scheipl, F. and Ruppert, D.} } @article {james, title = {Genetic risk factors for longitudinal changes in structural MRI in former organolead workers}, journal = {Accepted in the Journal of Aging Research}, year = {2012}, author = {James, B and Caffo, B and Stewart, W and Yousem, D and Davatzikos, C. and Schwartz, B} } @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 {pmid22241689, title = {Mixed effect Poisson log-linear models for clinical and epidemiological sleep hypnogram data}, journal = {Stat Med}, volume = {31}, number = {9}, year = {2012}, month = {Apr}, pages = {855{\textendash}870}, author = {Swihart, B and Caffo, B and Crainiceanu, C and Punjabi, N.M.} } @article {swihartTransition, title = {Models of sleep hypnograms scalable to epidemiological studies}, journal = {Tentatively accepted in Statistics in Medicine}, year = {2012}, author = {Swihart, B and Caffo, B and Crainiceanu, C and Punjabi, N} } @article {barber, title = {Motor "dexterity"?: evidence that left hemisphere lateralization of motor circuit connectivity is associated with better motor performance in children}, journal = {Cerebral Cortex}, year = {2012}, author = {Barber, A and Srinivasan, P and Joel, S. and Caffo, B and Pekar, J and Mostofsky, S} } @article {pmid22006982, title = {Optical coherence tomography segmentation reveals ganglion cell layer pathology after optic neuritis}, journal = {Brain}, volume = {135}, number = {Pt 2}, year = {2012}, month = {Feb}, pages = {521{\textendash}533}, author = {Syc, S. B. and Saidha, S. and Newsome, S and Ratchford, J and Levy, M. and Ford, E. and Crainiceanu, C and Durbin, M. K. and Oakley, J. D. and Meyer, S. A. and Frohman, E. M. and Calabresi, P} } @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 {710, title = {Relationships Between Retinal Axonal and Neuronal Measures and Global Central Nervous System Pathology in Multiple Sclerosis.}, journal = {Arch Neurol}, year = {2012}, month = {2012 Oct 1}, pages = {1-10}, abstract = {

OBJECTIVE To determine the relationships between conventional and segmentation-derived optical coherence tomography (OCT) retinal layer thickness measures with intracranial volume (a surrogate of head size) and brain substructure volumes in multiple sclerosis (MS). DESIGN Cross-sectional study. SETTING Johns Hopkins University, Baltimore, Maryland. PARTICIPANTS A total of 84 patients with MS and 24 healthy control subjects. MAIN OUTCOME MEASURES High-definition spectral-domain OCT conventional and automated segmentation-derived discrete retinal layer thicknesses and 3-T magnetic resonance imaging brain substructure volumes. RESULTS Peripapillary retinal nerve fiber layer as well as composite ganglion cell layer\ +\ inner plexiform layer thicknesses in the eyes of patients with MS without a history of optic neuritis were associated with cortical gray matter (P\ =\ .01 and P\ =\ .04, respectively) and caudate (P\ =\ .04 and P\ =\ .03, respectively) volumes. Inner nuclear layer thickness, also in eyes without a history of optic neuritis, was associated with fluid-attenuated inversion recovery lesion volume (P\ =\ .007) and inversely associated with normal-appearing white matter volume (P\ =\ .005) in relapsing-remitting MS. As intracranial volume was found to be related with several of the OCT measures in patients with MS and healthy control subjects and is already known to be associated with brain substructure volumes, all OCT-brain substructure relationships were adjusted for intracranial volume. CONCLUSIONS Retinal measures reflect global central nervous system pathology in multiple sclerosis, with thicknesses of discrete retinal layers each appearing to be associated with distinct central nervous system processes. Moreover, OCT measures appear to correlate with intracranial volume in patients with MS and healthy control subjects, an important unexpected factor unaccounted for in prior studies examining the relationships between peripapillary retinal nerve fiber layer thickness and brain substructure volumes.

}, issn = {1538-3687}, doi = {10.1001/archneurol.2013.573}, author = {Saidha, Shiv and Sotirchos, Elias S and Oh, Jiwon and Syc, Stephanie B and Seigo, Michaela A and Shiee, Navid and Eckstein, Chistopher and Durbin, Mary K and Oakley, Jonathan D and Meyer, Scott A and Frohman, Teresa C and Newsome, Scott and Ratchford, John N and Balcer, Laura J and Pham, Dzung L and Crainiceanu, Ciprian M and Frohman, Elliot M and Reich, Daniel S and Calabresi, Peter A} } @article {shee, title = {Revisiting Brain Atrophy and Its Relationship to Disability in Multiple Sclerosis}, journal = {PLoS ONE}, volume = {7}, number = {5}, year = {2012}, month = {05}, pages = {e37049}, publisher = {Public Library of Science}, doi = {10.1371/journal.pone.0037049}, url = {http://dx.doi.org/10.1371\%2Fjournal.pone.0037049}, author = {Shiee, N and Bazin, P and Zackowski, K and Farrell, S and Harrison, D and Newsome, S and Ratchford, J and Caffo, B and Calabresi, P and Pham, D and Reich, D.} } @article {830, title = {Total white matter hyperintensity volume in bipolar disorder patients and their healthy relatives.}, journal = {Bipolar Disord}, volume = {14}, year = {2012}, month = {2012 Dec}, pages = {888-93}, abstract = {

OBJECTIVES: White matter hyperintensities (WMH) are more common in subjects with bipolar disorder (BP) than in healthy subjects (HS). Few studies have examined the effect of the diagnostic type of bipolar illness on WMH burden, and none have approached this question through a direct measurement of the volume of affected white matter in relationship to familiality. In this pilot study, we utilized a volumetric measurement of WMH to investigate the relationship between the total volume of WMH and the familiality and type of BP.

METHODS: Forty-five individuals with bipolar I disorder (BP-I) with psychotic features, BP-I without psychotic features, or bipolar II disorder (BP-II), seven of their unaffected relatives, and 32 HS were recruited for participation. T-2 weighted magnetic resonance imaging scans were obtained on all subjects, and the total volume of all WMH for each subject was measured in cubic centimeters. The significance of difference between groups was tested using ANOVA with post-hoc adjustment for multiple comparisons. Further, we used logistic regression to test for trends between symptom load and total WMH volume.

RESULTS: The mean total volume of WMH in BP-I patients with psychotic features was significantly higher (p < 0.05) than that of HS. Further, we observed a positive linear trend by familiality and type of affectedness when comparing mean total WMH volume of HS, unaffected family members, subjects with BP-II, and BP-I with and without a history of psychosis (p < 0.05).

CONCLUSIONS: Based on a quantitative technique, WMH burden appears to be associated with familiality and type of BP. The significance of these findings remains to be fully elucidated.

}, keywords = {Adult, Analysis of Variance, Bipolar Disorder, Brain, Female, Humans, Image Processing, Computer-Assisted, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Nerve Fibers, Myelinated}, issn = {1399-5618}, doi = {10.1111/bdi.12019}, author = {Tighe, Sarah K and Reading, Sarah A and Rivkin, Paul and Caffo, Brian and Schweizer, Barbara and Pearlson, Godfrey and Potash, James B and Depaulo, J Raymond and Bassett, Susan S} } @article {springerlink:10.1007/s10928-011-9211-7, title = {A Bayesian hierarchical nonlinear mixture model in the presence of artifactual outliers in a population pharmacokinetic study}, journal = {Journal of Pharmacokinetics and Pharmacodynamics}, volume = {38}, year = {2011}, note = {10.1007/s10928-011-9211-7}, pages = {613-636}, publisher = {Springer Netherlands}, issn = {1567-567X}, url = {http://dx.doi.org/10.1007/s10928-011-9211-7}, author = {Choi, L and Caffo, B and Kohli, U and Pandharipande, P and Kurnik, D and Ely, E and Stein, C} } @article {lewis2011differential, title = {Differential involvement of striato-and cerebello-thalamo-cortical pathways in tremor-and akinetic/rigid-predominant Parkinson{\textquoteright}s disease}, journal = {Neuroscience}, year = {2011}, publisher = {Elsevier}, author = {Lewis, M.M. and Du, G. and Sen, S. and Kawaguchi, A. and Truong, Y. and Lee, S. and Mailman, R.B. and Huang, X.} } @article {vadimNI, title = {Functional principal components model for high-dimensional brain imaging}, journal = {Neuroimage, NIHSMID: 316403}, volume = {58}, number = {3}, year = {2011}, pages = {772 {\textendash} 784}, author = {Zipunnikov, V. and Caffo, B and Yousem, D and Davatziko, C and Schwartz, B and Crainiceanu, C} } @article {LS11a, title = {Graphical models, potential outcomes and causal inference: Comment on Ramsey, Spirtes and Glymour}, journal = {NeuroImage}, volume = {57}, year = {2011}, pages = {334-336}, issn = {1053-8119}, doi = {10.1016/j.neuroimage.2010.10.020}, url = {http://www.sciencedirect.com/science/article/pii/S1053811910013121}, author = {Lindquist, Martin A and Sobel, M.E.} } @article {845, title = {Graphical models, potential outcomes and causal inference: comment on Ramsey, Spirtes and Glymour.}, journal = {Neuroimage}, volume = {57}, year = {2011}, month = {2011 Jul 15}, pages = {334-6}, abstract = {

Ramsey, Spirtes and Glymour (RSG) critique a method proposed by Neumann et al. (2010) for the discovery of functional networks from fMRI meta-analysis data. We concur with this critique, but are unconvinced that directed graphical models (DGMs) are generally useful for estimating causal effects. We express our reservations using the "potential outcomes" framework for causal inference widely used in statistics.

}, keywords = {Artifacts, Brain, Computer Simulation, Humans, Image Interpretation, Computer-Assisted, Meta-Analysis as Topic}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2010.10.020}, author = {Lindquist, Martin A and Sobel, Michael E} } @article {pmid21853058, title = {The impact of utilizing different optical coherence tomography devices for clinical purposes and in multiple sclerosis trials}, journal = {PLoS ONE}, volume = {6}, number = {8}, year = {2011}, pages = {e22947}, author = {Warner, C. V. and Syc, S. B. and Stankiewicz, A. M. and Hiremath, G. and Farrell, S and Crainiceanu, C and Conger, A. and Frohman, T. C. and Bisker, E. R. and Balcer, L and Frohman, E. M. and Calabresi, P and Saidha, S.} } @article {lee2011independent, title = {Independent Component Analysis Involving Autocorrelated Sources With an Application to Functional Magnetic Resonance Imaging}, journal = {Journal of the American Statistical Association}, volume = {106}, number = {495}, year = {2011}, pages = {1009{\textendash}1024}, publisher = {ASA}, author = {Lee, S. and Shen, H. and Truong, Y. and Lewis, M. and Huang, X.} } @article {shinohara2011longitudinal, title = {Longitudinal Analysis of Spatiotemporal Processes: A Case Study of Dynamic Contrast-Enhanced Magnetic Resonance in Multiple Sclerosis}, journal = {Johns Hopkins University, Dept. of Biostatistics Working Papers}, year = {2011}, pages = {231}, publisher = {bepress}, author = {Shinohara, R and Crainiceanu, C and Caffo, B and Reich, D S} } @article {harrison, title = {Longitudinal changes in diffusion-tensor-based quantitative MRI in multiple sclerosis}, journal = {Neurology, PMCID: PMC3030233}, volume = {76}, year = {2011}, pages = {179{\textendash}186}, author = {Harrison, D and Caffo, B and Shiee, N and Farrell, J Bazin, P and Farrell, S and Ratchford, J and Calabresi, P and Reich, D.} } @article {AJT:AJT3735, title = {MELD Exceptions and Rates of Waiting List Outcomes}, journal = {American Journal of Transplantation}, volume = {11}, number = {11}, year = {2011}, pages = {2362{\textendash}2371}, publisher = {Blackwell Publishing Inc}, keywords = {Liver transplantation, MELD score, organ allocation}, issn = {1600-6143}, doi = {10.1111/j.1600-6143.2011.03735.x}, url = {http://dx.doi.org/10.1111/j.1600-6143.2011.03735.x}, author = {Massie, A and Caffo, B and Gentry, S and Hall, E and Axelrod, D and Lentine, K and Schnitzler, M and Gheorghian, A and Salvalaggio, P and Segev, D} } @article {pmid22050118, title = {Modeling Functional Data with Spatially Heterogeneous Shape Characteristics}, journal = {Biometrics}, year = {2011}, month = {Nov}, author = {Staicu, A. M. and Crainiceanu, C and Reich, D S and Ruppert, D.} } @article {vadimHDMFPCA, title = {Multilevel functional principal component analysis for high-dimensional data}, journal = {Journal of Computational and Graphical Statistics, NIMHID: 306063}, volume = {20}, number = {4}, year = {2011}, pages = {852{\textendash}873}, author = {Zipunnikov, V. and Caffo, B and Crainiceanu, C and Yousem, D and Davatzikos, C. and Schwartz, B} } @article {caffoSleep, title = {A novel approach to prediction of mild sleep disorders in a population-based sample: the Sleep Heart Health Study}, journal = {Sleep, PMCID: PMC2982734}, volume = {33}, number = {12}, year = {2011}, pages = {1641{\textendash}1648}, author = {Caffo, B and Diener-West, M and Punjabi, N and Samet, J} } @article {takiPCA, title = {Population-wide principal component-based quantification of blood-brain-barrier dynamics in multiple sclerosis}, journal = {Neuroimage, PMCID: PMC3138825}, volume = {57}, number = {4}, year = {2011}, pages = {1430 {\textendash} 1446}, author = {Shinohara, R and Crainiceanu, C and Caffo, B and Gaitan, M and Reich, D.} } @article {pmid20693268, title = {Cadmium and peripheral arterial disease: gender differences in the 1999-2004 US National Health and Nutrition Examination Survey}, journal = {Am. J. Epidemiol.}, volume = {172}, number = {6}, year = {2010}, month = {Sep}, pages = {671{\textendash}681}, author = {Tellez-Plaza, M. and Navas-Acien, A. and Crainiceanu, C and Sharrett, A. R. and Guallar, E.} } @article {staicu2010, title = {On the equivalence of the prospective and retrospective likelihood methods in casecontrol studies}, journal = {Biometrika}, volume = {97}, year = {2010}, pages = {990{\textendash}996}, author = {Staicu, A. M.} } @article {schwartz2010evaluation, title = {Evaluation of Cumulative Lead Dose and Longitudinal Changes in Structural Magnetic Resonance Imaging in Former Organolead Workers}, journal = {Journal of Occupational and Environmental Medicine, PMCID: PMC2869464}, volume = {52}, number = {4}, year = {2010}, pages = {407{\textendash}414}, author = {Schwartz, B and Caffo, B and Stewart, W and Hedlin, H and James, B and Yousem, D and Davatzikos, C.} } @article {pmid20089508, title = {Fast methods for spatially correlated multilevel functional data}, journal = {Biostatistics}, volume = {11}, number = {2}, year = {2010}, month = {Apr}, pages = {177{\textendash}194}, author = {Staicu, A. M. and Crainiceanu, C and Carroll, R. J.} } @article {swihart2009lasagna, title = {Lasagna plots: A Saucy alternative to spaghetti plots}, journal = {Epidemiology}, volume = {21}, number = {5}, year = {2010}, pages = {621{\textendash}625}, author = {Swihart, B and Caffo, B and James, B and Strand, M. and Schwartz, B and Punjabi, N} } @article {reich2, title = {MRI of the Corpus Callosum in Multiple Sclerosis: Association with Disability}, journal = {Multiple Sclerosis, PMCID: PMC2820126}, volume = {16}, number = {2}, year = {2010}, pages = {166{\textendash}177}, author = {Ozturk, A and Smith, S and Gordon-Lipkin, E and Harrison, D and Shiee, N and Pham, D and Caffo, B and Calabresi, P and Reich, D.} } @article {Paninski2010, title = {A new look at state-space models for neural data.}, journal = {Journal of computational neuroscience}, volume = {29}, number = {1-2}, year = {2010}, pages = {107{\textendash}26}, abstract = {

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 {segev2010perioperative, title = {Perioperative Mortality and Long-term Survival Following Live Kidney Donation}, journal = {Journal of the American Medical Association, NIHMSID: 316358}, volume = {303}, number = {10}, year = {2010}, pages = {959{\textendash}966}, publisher = {Am Med Assoc}, author = {Segev, D and Muzaale, A and Caffo, B and Mehta, S and Singer, A and Taranto, S and McBride, M and Montgomery, R} } @article {nazarian:qrs, title = {QRS Prolongation in Myotonic Muscular Dystrophy and Diffuse Fibrosis on Cardiac Magnetic Resonance}, journal = {Magnetic Resonance in Medicine, PMCID: PMC3034129}, volume = {64}, number = {1}, year = {2010}, pages = {107{\textendash}114}, author = {Nazarian, S and Bluemke, D and Wagner, K and Zviman, M and Turkbey, E and Caffo, B and Shehata, M and Edwards,D and Butcher, B and Calkins, H and Berger, R and Halperin, H and Tomaselli, G} } @article {vidwan2010relation, title = {Relation of platelet count to bleeding and vascular complications in patients undergoing coronary angiography}, journal = {The American journal of cardiology}, volume = {105}, number = {9}, year = {2010}, pages = {1219{\textendash}1222}, publisher = {Elsevier}, author = {Vidwan, P. and Lee, S. and Rossi, J.S. and Stouffer, G.A.} } @article {frfrst2010, title = {The second order ancillary}, journal = {Bernoulli}, volume = {16}, year = {2010}, pages = {1208{\textendash}1223}, author = {Fraser, A.M. and Fraser, D.A.S. and Staicu, A. M.} } @article {laffan2010utility, title = {Utility of sleep stage transitions in assessing sleep continuity}, journal = {Sleep, PMCID: PMC2982738}, volume = {33}, number = {12}, year = {2010}, pages = {1681}, issn = {0161-8105}, author = {Laffan, A and Caffo, B and Swihart, B and Punjabi, N} } @article {chen2009adaptive, title = {Adaptive control of the false discovery rate in voxel-based morphometry}, journal = {Human Brain Mapping, NIHMSID: 316414}, volume = {30}, number = {7}, year = {2009}, pages = {2304{\textendash}2311}, publisher = {Wiley Subscription Services, Inc., A Wiley Company Hoboken}, author = {Chen, S and Wang, C. and Eberly, L and Caffo, B and Schwartz, B} } @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 {pmid20625442, title = {Generalized Multilevel Functional Regression}, journal = {J Am Stat Assoc}, volume = {104}, number = {488}, year = {2009}, month = {Dec}, pages = {1550{\textendash}1561}, author = {Crainiceanu, C and Staicu, A. M. and Di, C.Z.} } @article {staicu2009, title = {Higher order approximations for interval estimation in binomial settings}, journal = {J. of Statistical Planning and Inference}, volume = {139}, year = {2009}, pages = {3393{\textendash}3404}, author = {Staicu, A. M.} } @article {pmid20049214, title = {Mercury induces an unopposed inflammatory response in human peripheral blood mononuclear cells in vitro}, journal = {Environ. Health Perspect.}, volume = {117}, number = {12}, year = {2009}, month = {Dec}, pages = {1932{\textendash}1938}, author = {Gardner, R. M. and Nyland, J. F. and Evans, S. L. and Wang, S. B. and Doyle, K. M. and Crainiceanu, C and Silbergeld, E. K.} } @article {su2009modified, title = {Modified test statistics by inter-voxel variance shrinkage with an application to fMRI}, journal = {Biostatistics, NIHMSID: 316409}, volume = {10}, number = {2}, year = {2009}, pages = {219-227}, author = {Su, S and Caffo, B and Garrett-Mayer, E and Bassett, S} } @article {caffo2009overview, title = {An overview of observational sleep research with application to sleep stage transitioning}, journal = {Chance, PMCID: PMC2800358}, volume = {22}, number = {1}, year = {2009}, pages = {10{\textendash}15}, publisher = {Springer}, author = {Caffo, B and Swihart, B and Crainiceanu, C and Laffan, A and Punjabi, N} } @article {Caff:Swih:Crai:Laff:Punj:an:2009, title = {An Overview of Observational Sleep Research with Application to Sleep State Transitioning}, journal = {Chance}, volume = {22}, number = {1}, year = {2009}, pages = {10{\textendash}15}, author = {Caffo, B and Swihart, B and Crainiceanu, C and Laffan, A and Punjabi, Naresh} } @article {o2009prospective, title = {Prospective Study of Sleep-disordered Breathing and Hypertension: The Sleep Heart Health Study}, journal = {American Journal of Respiratory and Critical Care Medicine, PMCID: PMC2695498}, volume = {179}, number = {12}, year = {2009}, pages = {1159{\textendash}1164}, publisher = {Am Thoracic Soc}, author = {O{\textquoteright}Connor, G and Caffo, B and Newman, A and Quan, S and Rapoport, D and Redline, S and Resnick, H and Samet, J and Shahar, E} } @article {punjabi, title = {Sleep-disordered Breathing and Mortality: a Prospective Cohort Study}, journal = {PLOS Medicine, PMCID: PMC2722083}, volume = {6}, year = {2009}, author = {Punjabi, N and Caffo, B and Goodwin, J and Gottlieb, D and Newman, A and O{\textquoteright}Connor, G and Rapoport, D and Redline, S and Resnick, H and Robbins, J and Samet, J and Shahar, E and Unruh, M} } @article {pmid19750109, title = {Urine arsenic concentrations and species excretion patterns in American Indian communities over a 10-year period: the Strong Heart Study}, journal = {Environ. Health Perspect.}, volume = {117}, number = {9}, year = {2009}, month = {Sep}, pages = {1428{\textendash}1433}, author = {Navas-Acien, A. and Umans, J. G. and Howard, B. V. and Goessler, W. and Francesconi, K. A. and Crainiceanu, C and Silbergeld, E. K. and Guallar, E.} } @article {scharfstein2008accounting, title = {Accounting for within-patient correlation in assessing relative sensitivity of an adjunctive diagnostic test: Application to lung cancer}, journal = {Statistics in Medicine}, volume = {27}, number = {12}, year = {2008}, pages = {2110{\textendash}2126}, publisher = {John Wiley \& Sons, Ltd Chichester, UK}, author = {Scharfstein, D and Ryea, J and Caffo, B} } @article {swihart2008quantitative, title = {Characterizing Sleep Structure Using the Hypnogram}, journal = {Journal of Clinical Sleep Medicine, PMCID: PMC2542492}, volume = {4}, number = {4}, year = {2008}, pages = {349{\textendash}355}, author = {Swihart, B and Caffo, B and Bandeen-Roche, K and Punjabi, N} } @article {stamatakis2008fasting, title = {Fasting Glycemia in Sleep Disordered Breathing: Lowering the Threshold on Oxyhemoglobin Desaturation}, journal = {Sleep, PMCID: PMC2491502}, volume = {31}, number = {7}, year = {2008}, pages = {1018{\textendash}1024}, publisher = {American Academy of Sleep Medicine}, author = {Stamatakis, K and Sanders, M and Caffo, B and Resnick, H and Gottlieb, D and Mehra, R and Punjabi, N} } @article {suskauer2008fmri, title = {fMRI of Intrasubject Variability in ADHD: Anomalous Premotor Activity With Prefrontal Compensation}, journal = {Journal of American Academy of Child \& Adolescent Psychiatry, NIHMSID: 71813}, volume = {47}, number = {10}, year = {2008}, pages = {1141{\textendash}1150}, author = {Suskauer, S and Simmonds, D and Caffo, B and Denckla, M and Pekar, J and Mostofsky, S} } @article {caffo2008likelihood, title = {Likelihood Estimation of Conjugacy Relationships in Linear Models with Applications to High-Throughput Genomics}, journal = {International Journal of Biostatistics, PMCID: PMC2827886}, volume = {5}, year = {2008}, note = {Issue 18}, publisher = {bepress}, author = {Caffo, B and Dongmei, L and Scharpf, R and Parmigiani, G.} } @article {zhang2008power, title = {Power Spectral Analysis of EEG Activity During Sleep in Cigarette Smokers}, journal = {Chest}, volume = {133}, number = {2}, year = {2008}, pages = {427{\textendash}432}, publisher = {Am Coll Chest Phys}, author = {Zhang, L and Samet, J and Caffo, B and Bankman, I and Punjabi, N} } @article {streid2008, title = {On probability matching priors}, journal = {The Canadian J. of Statistics}, volume = {36}, year = {2008}, pages = {613{\textendash}622}, author = {Staicu, A. M. and Reid, N} } @article {lindquist2008rapid, title = {Rapid three-dimensional functional magnetic resonance imaging}, year = {2008}, author = {Lindquist, Martin A and Zhang, Cun-Hui and Glover, Gary and Shepp, Lawrence} } @article {caffo2007brain, title = {Are Brain Volumes based on Magnetic Resonance Imaging Mediators of the Associations of Cumulative Lead Dose with Cognitive Function?}, journal = {American Journal of Epidemiology}, volume = {167}, number = {4}, year = {2007}, pages = {429{\textendash}437}, publisher = {Oxford Univ Press}, author = {Caffo, B and Chen, S and Stewart, W and Bolla, K and Yousem, D and Davatzikos, C. and Schwartz, B} } @article {li2007potential, title = {On the potential for ill logic with logically defined outcomes}, journal = {Biostatistics}, volume = {8}, number = {4}, year = {2007}, pages = {800}, author = {Li, X and Caffo, B and Scharfstein, D} } @article {schwartz2007relations, title = {Relations of brain volumes with cognitive function in males 45 years and older with past lead exposure}, journal = {Neuroimage, PMCID: PMC2038986}, volume = {37}, number = {2}, year = {2007}, pages = {633{\textendash}641}, publisher = {Elsevier}, author = {Schwartz, B and Chen, S and Caffo, B and Stewart, W and Bolla, K and Yousem, D and Davatzikos, C.} } @article {pmid17646610, title = {Short-term variability in measures of glycemia and implications for the classification of diabetes}, journal = {Arch. Intern. Med.}, volume = {167}, number = {14}, year = {2007}, month = {Jul}, pages = {1545{\textendash}1551}, author = {Selvin, E. and Crainiceanu, C and Brancati, F. L. and Coresh, J.} } @article {zhang2006cigarette, title = {Cigarette smoking and nocturnal sleep architecture}, journal = {American Journal of Epidemiology}, volume = {164}, number = {6}, year = {2006}, pages = {529}, publisher = {Oxford Univ Press}, author = {Zhang, L and Samet, J and Caffo, B and Punjabi, N} } @article {pmid15817517, title = {Electrocorticographic high gamma activity versus electrical cortical stimulation mapping of naming}, journal = {Brain}, volume = {128}, number = {Pt 7}, year = {2005}, month = {Jul}, pages = {1556{\textendash}1570}, author = {Sinai, A. and Bowers, C. W. and Crainiceanu, C and Boatman, D. and Gordon, B. and Lesser, R. P. and Lenz, F. A. and Crone, N.E.} } @article {pmid12941553, title = {Prevalence estimates for paratuberculosis adjusted for test variability using Bayesian analysis}, journal = {Prev. Vet. Med.}, volume = {60}, number = {4}, year = {2003}, month = {Sep}, pages = {281{\textendash}295}, author = {van Schaik, G. and Schukken, Y. H. and Crainiceanu, C and Muskens, J. and VanLeeuwen, J. A.} } @conference {Crai:Rupp:Sted:Behr:impr:2002, title = {Improving MCMC Mixing for a GLMM Describing Pathogen Concentrations in Water Supplies}, booktitle = {Case Studies in Bayesian Statistics, Volume V (Lecture Notes in Statistics Vol. 162)}, year = {2002}, pages = {207{\textendash}221}, publisher = {Springer-Verlag Inc}, organization = {Springer-Verlag Inc}, keywords = {Ecology}, author = {Crainiceanu, C and Ruppert, D. and Stedinger, Jery R. and Behr, Christopher T.} } @article {Greenspan1997, title = {Loss of FHIT expression in cervical carcinoma cell lines and primary tumors.}, journal = {Cancer Research}, volume = {57}, number = {21}, year = {1997}, pages = {4692{\textendash}4698}, publisher = {Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.}, abstract = {

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} }