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With the rapid development in design and synthesis, carbon nanotubes (CNTs) are being studied for potential applications in a variety of biomedical fields, such as site-directed drug delivery, tumor-targeted imaging, and anticancer drug development. In the present study, we observed that SWCNTs could significantly induce cell death of human ovarian cancer OVCAR3 cells. More importantly, we demonstrated that SWCNTs could sensitize OVCAR3 cells to the chemotherapeutic compound paclitaxel (PTX), resulting increased cell death. Mechanistic investigations suggested that SWCNTs provoked cell death in the absence or presence of PTX mainly via apoptosis. Taken together, our results suggest that SWCNTs contribute to regulating the chemosensitivity of ovarian cancer cells to the anticancer drug. Co-exposure of SWCNTs and chemotherapeutic drugs might thus stand for a promising approach to improve the cancer treatment.

The high-dimensional pattern classification methods, e.g., support vector machines (SVM), have been widely investigated for analysis of structural and functional brain images (such as magnetic resonance imaging (MRI)) to assist the diagnosis of Alzheimer's disease (AD) including its prodromal stage, i.e., mild cognitive impairment (MCI). Most existing classification methods extract features from neuroimaging data and then construct a single classifier to perform classification. However, due to noise and small sample size of neuroimaging data, it is challenging to train only a global classifier that can be robust enough to achieve good classification performance. In this paper, instead of building a single global classifier, we propose a local patch-based subspace ensemble method which builds multiple individual classifiers based on different subsets of local patches and then combines them for more accurate and robust classification. Specifically, to capture the local spatial consistency, each brain image is partitioned into a number of local patches and a subset of patches is randomly selected from the patch pool to build a weak classifier. Here, the sparse representation-based classifier (SRC) method, which has shown to be effective for classification of image data (e.g., face), is used to construct each weak classifier. Then, multiple weak classifiers are combined to make the final decision. We evaluate our method on 652 subjects (including 198 AD patients, 225 MCI and 229 normal controls) from Alzheimer's Disease Neuroimaging Initiative (ADNI) database using MR images. The experimental results show that our method achieves an accuracy of 90.8% and an area under the ROC curve (AUC) of 94.86% for AD classification and an accuracy of 87.85% and an AUC of 92.90% for MCI classification, respectively, demonstrating a very promising performance of our method compared with the state-of-the-art methods for AD/MCI classification using MR images., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Different imaging modalities provide essential complementary information that can be used to enhance our understanding of brain disorders. This study focuses on integrating multiple imaging modalities to identify individuals at risk for mild cognitive impairment (MCI). MCI, often an early stage of Alzheimer's disease (AD), is difficult to diagnose due to its very mild or insignificant symptoms of cognitive impairment. Recent emergence of brain network analysis has made characterization of neurological disorders at a whole-brain connectivity level possible, thus providing new avenues for brain diseases classification. Employing multiple-kernel Support Vector Machines (SVMs), we attempt to integrate information from diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rs-fMRI) for improving classification performance. Our results indicate that the multimodality classification approach yields statistically significant improvement in accuracy over using each modality independently. The classification accuracy obtained by the proposed method is 96.3%, which is an increase of at least 7.4% from the single modality-based methods and the direct data fusion method. A cross-validation estimation of the generalization performance gives an area of 0.953 under the receiver operating characteristic (ROC) curve, indicating excellent diagnostic power. The multimodality classification approach hence allows more accurate early detection of brain abnormalities with greater sensitivity., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Many machine learning and pattern classification methods have been applied to the diagnosis of Alzheimer's disease (AD) and its prodromal stage, i.e., mild cognitive impairment (MCI). Recently, rather than predicting categorical variables as in classification, several pattern regression methods have also been used to estimate continuous clinical variables from brain images. However, most existing regression methods focus on estimating multiple clinical variables separately and thus cannot utilize the intrinsic useful correlation information among different clinical variables. On the other hand, in those regression methods, only a single modality of data (usually only the structural MRI) is often used, without considering the complementary information that can be provided by different modalities. In this paper, we propose a general methodology, namely multi-modal multi-task (M3T) learning, to jointly predict multiple variables from multi-modal data. Here, the variables include not only the clinical variables used for regression but also the categorical variable used for classification, with different tasks corresponding to prediction of different variables. Specifically, our method contains two key components, i.e., (1) a multi-task feature selection which selects the common subset of relevant features for multiple variables from each modality, and (2) a multi-modal support vector machine which fuses the above-selected features from all modalities to predict multiple (regression and classification) variables. To validate our method, we perform two sets of experiments on ADNI baseline MRI, FDG-PET, and cerebrospinal fluid (CSF) data from 45 AD patients, 91 MCI patients, and 50 healthy controls (HC). In the first set of experiments, we estimate two clinical variables such as Mini Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), as well as one categorical variable (with value of 'AD', 'MCI' or 'HC'), from the baseline MRI, FDG-PET, and CSF data. In the second set of experiments, we predict the 2-year changes of MMSE and ADAS-Cog scores and also the conversion of MCI to AD from the baseline MRI, FDG-PET, and CSF data. The results on both sets of experiments demonstrate that our proposed M3T learning scheme can achieve better performance on both regression and classification tasks than the conventional learning methods., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Mild cognitive impairment (MCI) is difficult to diagnose due to its subtlety. Recent emergence of advanced network analysis techniques utilizing resting-state functional Magnetic Resonance Imaging (rs-fMRI) has made the understanding of neurological disorders more comprehensively at a whole-brain connectivity level. However, inferring effective brain connectivity from fMRI data is a challenging task, particularly when the ultimate goal is to obtain good control-patient classification performance. Incorporating sparsity into connectivity modeling can potentially produce results that are biologically more meaningful since most biologically networks are formed by a relatively few number of connections. However, this constraint, when applied at an individual level, will degrade classification performance due to inter-subject variability. To address this problem, we consider a constrained sparse linear regression model associated with the least absolute shrinkage and selection operator (LASSO). Specifically, we introduced sparsity into brain connectivity via l1-norm penalization, and ensured consistent non-zero connections across subjects via l2-norm penalization. Our results demonstrate that the constrained sparse network gives better classification performance than the conventional correlation-based network, indicating its greater sensitivity to early stage brain pathologies.

In recent studies of Alzheimer's disease (AD), it has increasing attentions in identifying mild cognitive impairment (MCI) converters (MCI-C) from MCI non-converters (MCI-NC). Note that MCI is a prodromal stage of AD, with possibility to convert to AD. Most traditional methods for MCI conversion prediction learn information only from MCI subjects (including MCI-C and MCI-NC), not from other related subjects, e.g., AD and normal controls (NC), which can actually aid the classification between MCI-C and MCI-NC. In this paper, we propose a novel domain-transfer learning method for MCI conversion prediction. Different from most existing methods, we classify MCI-C and MCI-NC with aid from the domain knowledge learned with AD and NC subjects as auxiliary domain to further improve the classification performance. Our method contains two key components: (1) the cross-domain kernel learning for transferring auxiliary domain knowledge, and (2) the adapted support vector machine (SVM) decision function construction for cross-domain and auxiliary domain knowledge fusion. Experimental results on the Alzheimer's Disease neuroimaging initiative (ADNI) database show that the proposed method can significantly improve the classification performance between MCI-C and MCI-NC, with aid of domain knowledge learned from AD and NC subjects.

microRNAs (miRNAs) are involved in controlling tumor behaviors either as oncogenes or tumor suppressors. To elucidate the role of miRNAs in the regulation of tumor initiation, we delineated the microRNA expression signature characterizing the properties of tumor-initiating cells for breast cancer. A group of miRNAs were differentially expressed in MDA-MB-231 and SUM1315 cells (with a high proportion of breast cancer tumor-initiating cells, CD44(+)CD24(-/low) subpopulation) compared to MCF-7 cells (only a small proportion of CD44(+)CD24(-/low) cells). Among the differentially expressed miRNAs common to MDA-MB-231 and SUM1315, approximately 46% of them are suggested to regulate the 'stemness' of stem cells or progenitor cells. Taken together, these findings suggested that miRNAs contribute to the maintenance of tumor-initiating properties and indicate the potential value of the miRNA expression signature in characterizing or predicting the features (including metastasis) of breast cancer.

In spite of great advances in conventional cancer diagnosis and treatment, the early recognition and characterization for various cancers remain a technological bottleneck. The combined characteristics of board absorption and narrow emission make quantum dots (QDs) desirable fluorescent labels for cancer imaging and other applications in the biomedical field. In the current study, to the best of our knowledge, we first evidenced the preferential accumulation of QDs in cytoplasm of breast cancer cells. QDs therefore reveal considerable potentials in both tumor imaging and therapeutic application.

Accurate prediction of clinical changes of mild cognitive impairment (MCI) patients, including both qualitative change (i.e., conversion to Alzheimer's disease (AD)) and quantitative change (i.e., cognitive scores) at future time points, is important for early diagnosis of AD and for monitoring the disease progression. In this paper, we propose to predict future clinical changes of MCI patients by using both baseline and longitudinal multimodality data. To do this, we first develop a longitudinal feature selection method to jointly select brain regions across multiple time points for each modality. Specifically, for each time point, we train a sparse linear regression model by using the imaging data and the corresponding clinical scores, with an extra 'group regularization' to group the weights corresponding to the same brain region across multiple time points together and to allow for selection of brain regions based on the strength of multiple time points jointly. Then, to further reflect the longitudinal changes on the selected brain regions, we extract a set of longitudinal features from the original baseline and longitudinal data. Finally, we combine all features on the selected brain regions, from different modalities, for prediction by using our previously proposed multi-kernel SVM. We validate our method on 88 ADNI MCI subjects, with both MRI and FDG-PET data and the corresponding clinical scores (i.e., MMSE and ADAS-Cog) at 5 different time points. We first predict the clinical scores (MMSE and ADAS-Cog) at 24-month by using the multimodality data at previous time points, and then predict the conversion of MCI to AD by using the multimodality data at time points which are at least 6-month ahead of the conversion. The results on both sets of experiments show that our proposed method can achieve better performance in predicting future clinical changes of MCI patients than the conventional methods.

Sparse learning has recently received increasing attentions in neuroimaging research such as brain disease diagnosis and progression. Most existing studies focus on cross-sectional analysis, i.e., learning a sparse model based on single time-point of data. However, in some brain imaging applications, multiple time-points of data are often available, thus longitudinal analysis can be performed to better uncover the underlying disease progression patterns. In this paper, we propose a novel temporally-constrained group sparse learning method aiming for longitudinal analysis with multiple time-points of data. Specifically, for each time-point, we train a sparse linear regression model by using the imaging data and the corresponding responses, and further use the group regularization to group the weights corresponding to the same brain region across different time-points together. Moreover, to reflect the smooth changes between adjacent time-points of data, we also include two smoothness regularization terms into the objective function, i.e., one fused smoothness term which requires the differences between two successive weight vectors from adjacent time-points should be small, and another output smoothness term which requires the differences between outputs of two successive models from adjacent time-points should also be small. We develop an efficient algorithm to solve the new objective function with both group-sparsity and smoothness regularizations. We validate our method through estimation of clinical cognitive scores using imaging data at multiple time-points which are available in the Alzheimer's disease neuroimaging initiative (ADNI) database.

Neuroimage analysis based on machine learning technologies has been widely employed to assist the diagnosis of brain diseases such as Alzheimer's disease and its prodromal stage--mild cognitive impairment. One of the major problems in brain image analysis involves learning the most relevant features from a huge set of raw imaging features, which are far more numerous than the training samples. This makes the tasks of both disease classification and interpretation extremely challenging. Sparse coding via L1 regularization, such as Lasso, can provide an effective way to select the most relevant features for alleviating the curse of dimensionality and achieving more accurate classification. However, the selected features may distribute randomly throughout the whole brain, although in reality disease-induced abnormal changes often happen in a few contiguous regions. To address this issue, we investigate a tree-guided sparse coding method to identify grouped imaging features in the brain regions for guiding disease classification and interpretation. Spatial relationships of the image structures are imposed during sparse coding with a tree-guided regularization. Our experimental results on the ADNI dataset show that the tree-guided sparse coding method not only achieves better classification accuracy, but also allows for more meaningful diagnosis of brain diseases compared with the conventional L1-regularized LASSO.

In this paper, we present a group sparsity constrained patch based label propagation method for multi-atlas automatic brain labeling. The proposed method formulates the label propagation process as a graph-based theoretical framework, where each voxel in the input image is linked to each candidate voxel in each atlas image by an edge in the graph. The weight of the edge is estimated based on a sparse representation framework to identify a limited number of candidate voxles whose local image patches can best represent the local image patch of each voxel in the input image. The group sparsity constraint to capture the dependency among candidate voxels with the same anatomical label is also enforced. It is shown that based on the edge weight estimated by the proposed method, the anatomical label for each voxel in the input image can be estimated more accurately by the label propagation process. Moreover, we extend our group sparsity constrained patch based label propagation framework to the reproducing kernel Hilbert space (RKHS) to capture the nonlinear similarity of patches among different voxels and construct the sparse representation in high dimensional feature space. The proposed method was evaluated on the NA0-NIREP database for automatic human brain anatomical labeling. It was also compared with several state-of-the-art multi-atlas based brain labeling algorithms. Experimental results demonstrate that our method consistently achieves the highest segmentation accuracy among all methods used for comparison.

Effective and accurate diagnosis of Alzheimer's disease (AD), as well as its prodromal stage (i.e., mild cognitive impairment (MCI)), has attracted more and more attention recently. So far, multiple biomarkers have been shown to be sensitive to the diagnosis of AD and MCI, i.e., structural MR imaging (MRI) for brain atrophy measurement, functional imaging (e.g., FDG-PET) for hypometabolism quantification, and cerebrospinal fluid (CSF) for quantification of specific proteins. However, most existing research focuses on only a single modality of biomarkers for diagnosis of AD and MCI, although recent studies have shown that different biomarkers may provide complementary information for the diagnosis of AD and MCI. In this paper, we propose to combine three modalities of biomarkers, i.e., MRI, FDG-PET, and CSF biomarkers, to discriminate between AD (or MCI) and healthy controls, using a kernel combination method. Specifically, ADNI baseline MRI, FDG-PET, and CSF data from 51AD patients, 99 MCI patients (including 43 MCI converters who had converted to AD within 18 months and 56 MCI non-converters who had not converted to AD within 18 months), and 52 healthy controls are used for development and validation of our proposed multimodal classification method. In particular, for each MR or FDG-PET image, 93 volumetric features are extracted from the 93 regions of interest (ROIs), automatically labeled by an atlas warping algorithm. For CSF biomarkers, their original values are directly used as features. Then, a linear support vector machine (SVM) is adopted to evaluate the classification accuracy, using a 10-fold cross-validation. As a result, for classifying AD from healthy controls, we achieve a classification accuracy of 93.2% (with a sensitivity of 93% and a specificity of 93.3%) when combining all three modalities of biomarkers, and only 86.5% when using even the best individual modality of biomarkers. Similarly, for classifying MCI from healthy controls, we achieve a classification accuracy of 76.4% (with a sensitivity of 81.8% and a specificity of 66%) for our combined method, and only 72% even using the best individual modality of biomarkers. Further analysis on MCI sensitivity of our combined method indicates that 91.5% of MCI converters and 73.4% of MCI non-converters are correctly classified. Moreover, we also evaluate the classification performance when employing a feature selection method to select the most discriminative MR and FDG-PET features. Again, our combined method shows considerably better performance, compared to the case of using an individual modality of biomarkers., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD), is difficult to diagnose due to the subtlety of cognitive impairment. Recent emergence of reliable network characterization techniques based on diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rs-fMRI) has made the understanding of neurological disorders at a whole-brain connectivity level possible, providing new avenues for brain classification. Taking a multi-kernel SVM, we attempt to integrate these two imaging modalities for improving classification performance. Our results indicate that the multimodality classification approach performs better than the single modality approach, with statistically significant improvement in accuracy. It was also found that the prefrontal cortex, orbitofrontal cortex, temporal pole, anterior and posterior cingulate gyrus, precuneus, amygdala, thalamus, parahippocampal gyrus and insula regions provided the most discriminant features for classification, in line with the results reported in previous studies. The multimodality classification approach allows more accurate early detection of brain abnormalities with larger sensitivity, and is important for treatment management of potential AD patients.

Label fusion is a key step in multi-atlas based segmentation, which combines labels from multiple atlases to make the final decision. However, most of the current label fusion methods consider each voxel equally and independently during label fusion. In our point of view, however, different voxels act different roles in the way that some voxels might have much higher confidence in label determination than others, i.e., because of their better alignment across all registered atlases. In light of this, we propose a sequential label fusion framework for multi-atlas based image segmentation by hierarchically using the voxels with high confidence to guide the labeling procedure of other challenging voxels (whose registration results among deformed atlases are not good enough) to afford more accurate label fusion. Specifically, we first measure the corresponding labeling confidence for each voxel based on the k-nearest-neighbor rule, and then perform label fusion sequentially according to the estimated labeling confidence on each voxel. In particular, for each label fusion process, we use not only the propagated labels from atlases, but also the estimated labels from the neighboring voxels with higher labeling confidence. We demonstrate the advantage of our method by deploying it to the two popular label fusion algorithms, i.e., majority voting and local weighted voting. Experimental results show that our sequential label fusion method can consistently improve the performance of both algorithms in terms of segmentation/labeling accuracy.

The goal of semisupervised kernel matrix learning (SS-KML) is to learn a kernel matrix on all the given samples on which just a little supervised information, such as class label or pairwise constraint, is provided. Despite extensive research, the performance of SS-KML still leaves some space for improvement in terms of effectiveness and efficiency. For example, a recent pairwise constraints propagation (PCP) algorithm has formulated SS-KML into a semidefinite programming (SDP) problem, but its computation is very expensive, which undoubtedly restricts PCPs scalability in practice. In this paper, a novel algorithm, called kernel propagation (KP), is proposed to improve the comprehensive performance in SS-KML. The main idea of KP is first to learn a small-sized sub-kernel matrix (named seed-kernel matrix) and then propagate it into a larger-sized full-kernel matrix. Specifically, the implementation of KP consists of three stages: 1) separate the supervised sample (sub)set X(l) from the full sample set X; 2) learn a seed-kernel matrix on X(l) through solving a small-scale SDP problem; and 3) propagate the learnt seed-kernel matrix into a full-kernel matrix on X . Furthermore, following the idea in KP, we naturally develop two conveniently realizable out-of-sample extensions for KML: one is batch-style extension, and the other is online-style extension. The experiments demonstrate that KP is encouraging in both effectiveness and efficiency compared with three state-of-the-art algorithms and its related out-of-sample extensions are promising too.

Traditional pattern recognition involves two tasks: clustering learning and classification learning. Clustering result can enhance the generalization ability of classification learning, while the class information can improve the accuracy of clustering learning. Hence, both learning methods can complement each other. To fuse the advantages of both learning methods together, many existing algorithms have been developed in a sequential fusing way by first optimizing the clustering criterion and then the classification criterion associated with the obtained clustering results. However, such kind of algorithms naturally fails to achieve the simultaneous optimality for two criteria, and thus has to sacrifice either the clustering performance or the classification performance. To overcome that problem, in this paper, we present a multiobjective simultaneous learning framework (MSCC) for both clustering and classification learning. MSCC utilizes multiple objective functions to formulate the clustering and classification problems, respectively, and more importantly, it employs the Bayesian theory to make these functions all only dependent on a set of the same parameters, i.e., clustering centers which play a role of the bridge connecting the clustering and classification learning. By simultaneously optimizing the clustering centers embedded in these functions, not only the effective clustering performance but also the promising classification performance can be simultaneously attained. Furthermore, from the multiple Pareto-optimality solutions obtained in MSCC, we can get an interesting observation that there is complementarity to great extent between clustering and classification learning processes. Empirical results on both synthetic and real data sets demonstrate the effectiveness and potential of MSCC.

The matrix, as an extended pattern representation to the vector, has proven to be effective in feature extraction. However, the subsequent classifier following the matrix-pattern- oriented feature extraction is generally still based on the vector pattern representation (namely, MatFE + VecCD), where it has been demonstrated that the effectiveness in classification just attributes to the matrix representation in feature extraction. This paper looks at the possibility of applying the matrix pattern representation to both feature extraction and classifier design. To this end, we propose a so-called fully matrixized approach, i.e., the matrix-pattern-oriented feature extraction followed by the matrix-pattern-oriented classifier design (MatFE + MatCD). To more comprehensively validate MatFE + MatCD, we further consider all the possible combinations of feature extraction (FE) and classifier design (CD) on the basis of patterns represented by matrix and vector respectively, i.e., MatFE + MatCD, MatFE + VecCD, just the matrix-pattern-oriented classifier design (MatCD), the vector-pattern-oriented feature extraction followed by the matrix-pattern-oriented classifier design (VecFE + MatCD), the vector-pattern-oriented feature extraction followed by the vector-pattern-oriented classifier design (VecFE + VecCD) and just the vector-pattern-oriented classifier design (VecCD). The experiments on the combinations have shown the following: 1) the designed fully matrixized approach (MatFE + MatCD) has an effective and efficient performance on those patterns with the prior structural knowledge such as images; and 2) the matrix gives us an alternative feasible pattern representation in feature extraction and classifier designs, and meanwhile provides a necessary validation for "ugly duckling" and "no free lunch" theorems.

Fuzzy c-means clustering (FCM) with spatial constraints (FCM_S) is an effective algorithm suitable for image segmentation. Its effectiveness contributes not only to the introduction of fuzziness for belongingness of each pixel but also to exploitation of spatial contextual information. Although the contextual information can raise its insensitivity to noise to some extent, FCM_S still lacks enough robustness to noise and outliers and is not suitable for revealing non-Euclidean structure of the input data due to the use of Euclidean distance (L2 norm). In this paper, to overcome the above problems, we first propose two variants, FCM_S1 and FCM_S2, of FCM_S to aim at simplifying its computation and then extend them, including FCM_S, to corresponding robust kernelized versions KFCM_S, KFCM_S1 and KFCM_S2 by the kernel methods. Our main motives of using the kernel methods consist in: inducing a class of robust non-Euclidean distance measures for the original data space to derive new objective functions and thus clustering the non-Euclidean structures in data; enhancing robustness of the original clustering algorithms to noise and outliers, and still retaining computational simplicity. The experiments on the artificial and real-world datasets show that our proposed algorithms, especially with spatial constraints, are more effective.