Motion Sensor-Based Detection of Outlier Days Supporting Continuous Health Assessment for Single Older Adults.

The aging population has resulted in interest in remote monitoring of elderly individuals' health and well being. This paper describes a simple unsupervised monitoring system that can automatically detect if an elderly individual's pattern of presence deviates substantially from the recent past. The proposed system uses a small set of low-cost motion sensors and analyzes the produced data to establish an individual's typical presence pattern. Then, the algorithm uses a distance function to determine whether the individual's observed presence for each day significantly deviates from their typical pattern. Empirically, the algorithm is validated on both synthetic data and data collected by installing our system in the residences of three older individuals. In the real-world setting, the system detected, respectively, five, four, and one deviating days in the three locations. The deviating days detected by the system could result from a health issue that requires attention. The information from the system can aid caregivers in assessing the subject's health status and allows for a targeted intervention. Although the system can be refined, we show that otherwise hidden but relevant events (e.g., fall incident and irregular sleep patterns) are detected and reported to the caregiver.

A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery.

Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2+, CLEC5Ahigh, MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.

Combined Analysis of Metabolomes, Proteomes, and Transcriptomes of Hepatitis C Virus-Infected Cells and Liver to Identify Pathways Associated With Disease Development.

BACKGROUND & AIMS: The mechanisms of hepatitis C virus (HCV) infection, liver disease progression, and hepatocarcinogenesis are only partially understood. We performed genomic, proteomic, and metabolomic analyses of HCV-infected cells and chimeric mice to learn more about these processes. METHODS: Huh7.5.1dif (hepatocyte-like cells) were infected with culture-derived HCV and used in RNA sequencing, proteomic, metabolomic, and integrative genomic analyses. uPA/SCID (urokinase-type plasminogen activator/severe combined immunodeficiency) mice were injected with serum from HCV-infected patients; 8 weeks later, liver tissues were collected and analyzed by RNA sequencing and proteomics. Using differential expression, gene set enrichment analyses, and protein interaction mapping, we identified pathways that changed in response to HCV infection. We validated our findings in studies of liver tissues from 216 patients with HCV infection and early-stage cirrhosis and paired biopsy specimens from 99 patients with hepatocellular carcinoma, including 17 patients with histologic features of steatohepatitis. Cirrhotic liver tissues from patients with HCV infection were classified into 2 groups based on relative peroxisome function; outcomes assessed included Child-Pugh class, development of hepatocellular carcinoma, survival, and steatohepatitis. Hepatocellular carcinomas were classified according to steatohepatitis; the outcome was relative peroxisomal function. RESULTS: We quantified 21,950 messenger RNAs (mRNAs) and 8297 proteins in HCV-infected cells. Upon HCV infection of hepatocyte-like cells and chimeric mice, we observed significant changes in levels of mRNAs and proteins involved in metabolism and hepatocarcinogenesis. HCV infection of hepatocyte-like cells significantly increased levels of the mRNAs, but not proteins, that regulate the innate immune response; we believe this was due to the inhibition of translation in these cells. HCV infection of hepatocyte-like cells increased glucose consumption and metabolism and the STAT3 signaling pathway and reduced peroxisome function. Peroxisomes mediate ß-oxidation of very long-chain fatty acids; we found intracellular accumulation of very long-chain fatty acids in HCV-infected cells, which is also observed in patients with fatty liver disease. Cells in livers from HCV-infected mice had significant reductions in levels of the mRNAs and proteins associated with peroxisome function, indicating perturbation of peroxisomes. We found that defects in peroxisome function were associated with outcomes and features of HCV-associated cirrhosis, fatty liver disease, and hepatocellular carcinoma in patients. CONCLUSIONS: We performed combined transcriptome, proteome, and metabolome analyses of liver tissues from HCV-infected hepatocyte-like cells and HCV-infected mice. We found that HCV infection increases glucose metabolism and the STAT3 signaling pathway and thereby reduces peroxisome function; alterations in the expression levels of peroxisome genes were associated with outcomes of patients with liver diseases. These findings provide insights into liver disease pathogenesis and might be used to identify new therapeutic targets.

Module Analysis Captures Pancancer Genetically and Epigenetically Deregulated Cancer Driver Genes for Smoking and Antiviral Response.

The availability of increasing volumes of multi-omics profiles across many cancers promises to improve our understanding of the regulatory mechanisms underlying cancer. The main challenge is to integrate these multiple levels of omics profiles and especially to analyze them across many cancers. Here we present AMARETTO, an algorithm that addresses both challenges in three steps. First, AMARETTO identifies potential cancer driver genes through integration of copy number, DNA methylation and gene expression data. Then AMARETTO connects these driver genes with co-expressed target genes that they control, defined as regulatory modules. Thirdly, we connect AMARETTO modules identified from different cancer sites into a pancancer network to identify cancer driver genes. Here we applied AMARETTO in a pancancer study comprising eleven cancer sites and confirmed that AMARETTO captures hallmarks of cancer. We also demonstrated that AMARETTO enables the identification of novel pancancer driver genes. In particular, our analysis led to the identification of pancancer driver genes of smoking-induced cancers and 'antiviral' interferon-modulated innate immune response. SOFTWARE AVAILABILITY: AMARETTO is available as an R package at https://bitbucket.org/gevaertlab/pancanceramaretto.

miR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesis.

BACKGROUND AND AIMS: HCV infection is a leading risk factor of hepatocellular carcinoma (HCC). However, even after viral clearance, HCC risk remains elevated. HCV perturbs host cell signalling to maintain infection, and derailed signalling circuitry is a key driver of carcinogenesis. Since protein phosphatases are regulators of signalling events, we aimed to identify phosphatases that respond to HCV infection with relevance for hepatocarcinogenesis. METHODS: We assessed mRNA and microRNA (miRNA) expression profiles in primary human hepatocytes, liver biopsies and resections of patients with HCC, and analysed microarray and RNA-seq data from paired liver biopsies of patients with HCC. We revealed changes in transcriptional networks through gene set enrichment analysis and correlated phosphatase expression levels to patient survival and tumour recurrence. RESULTS: We demonstrate that tumour suppressor protein tyrosine phosphatase receptor delta (PTPRD) is impaired by HCV infection in vivo and in HCC lesions of paired liver biopsies independent from tissue inflammation or fibrosis. In liver tissue adjacent to tumour, high PTPRD levels are associated with a dampened transcriptional activity of STAT3, an increase of patient survival from HCC and reduced tumour recurrence after surgical resection. We identified miR-135a-5p as a mechanistic regulator of hepatic PTPRD expression in patients with HCV. CONCLUSIONS: We previously demonstrated that STAT3 is required for HCV infection. We conclude that HCV promotes a STAT3 transcriptional programme in the liver of patients by suppressing its regulator PTPRD via upregulation of miR-135a-5p. Our results show the existence of a perturbed PTPRD-STAT3 axis potentially driving malignant progression of HCV-associated liver disease.

Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis.

We have previously reported the molecular signature of murine pathogenic TH17 cells that induce experimental autoimmune encephalomyelitis (EAE) in animals. Here we show that human peripheral blood IFN-γ+IL-17+ (TH1/17) and IFN-γ-IL-17+ (TH17) CD4+ T cells display distinct transcriptional profiles in high-throughput transcription analyses. Compared to TH17 cells, TH1/17 cells have gene signatures with marked similarity to mouse pathogenic TH17 cells. Assessing 15 representative signature genes in patients with multiple sclerosis, we find that TH1/17 cells have elevated expression of CXCR3 and reduced expression of IFNG, CCL3, CLL4, GZMB, and IL10 compared to healthy controls. Moreover, higher expression of IL10 in TH17 cells is found in clinically stable vs. active patients. Our results define the molecular signature of human pro-inflammatory TH17 cells, which can be used to both identify pathogenic TH17 cells and to measure the effect of treatment on TH17 cells in human autoimmune diseases.

Improving the accuracy of existing camera based fall detection algorithms through late fusion.

Fall incidents remain an important health hazard for older adults. Fall detection systems can reduce the consequences of a fall incident by insuring that timely aid is given. Currently fall detection algorithms however suffer a reduction in accuracy when introduced in real-life situations. In this paper a late fusion technique is proposed that will improve the accuracy of existing fall detection systems. It combines the confidence levels of different single camera fall detection systems. Four different aggregation methods are compared to each other based on the Area Under the Curve (AUC) of precision-recall curves. Calculating the median of the confidence levels of five cameras an increase of 218% in the AUC of the precision-recall-curves is achieved compared to the AUC of the single camera fall detector. These results show that significant improvements can be made to the accuracy of single camera fall detectors in a relatively easy way.

Detection of chewing motion in the elderly using a glasses mounted accelerometer in a real-life environment.

This paper describes a method of detecting an elderly person's chewing motion using a glasses mounted accelerometer. A real-life dataset was collected from 13 elderly adults, aged 65 or older, during meal times in a care facility. A supervised classifier is used to automatically distinguish between epochs of chewing and non-chewing activity. Results are compared to a lab dataset of 5 young to middle-aged adults captured in previous work. K-Nearest Neighbor, Random Forest and Support Vector Machine classifiers are evaluated. All are able to achieve similar performance, with the Support Vector Machine performing the best with an F1-score of 0.73.

Bridging the gap between real-life data and simulated data by providing a highly realistic fall dataset for evaluating camera-based fall detection algorithms.

Fall incidents are an important health hazard for older adults. Automatic fall detection systems can reduce the consequences of a fall incident by assuring that timely aid is given. The development of these systems is therefore getting a lot of research attention. Real-life data which can help evaluate the results of this research is however sparse. Moreover, research groups that have this type of data are not at liberty to share it. Most research groups thus use simulated datasets. These simulation datasets, however, often do not incorporate the challenges the fall detection system will face when implemented in real-life. In this Letter, a more realistic simulation dataset is presented to fill this gap between real-life data and currently available datasets. It was recorded while re-enacting real-life falls recorded during previous studies. It incorporates the challenges faced by fall detection algorithms in real life. A fall detection algorithm from Debard et al. was evaluated on this dataset. This evaluation showed that the dataset possesses extra challenges compared with other publicly available datasets. In this Letter, the dataset is discussed as well as the results of this preliminary evaluation of the fall detection algorithm. The dataset can be downloaded from www.kuleuven.be/advise/datasets.

Developing a system that can automatically detect health changes using transfer times of older adults.

BACKGROUND: As gait speed and transfer times are considered to be an important measure of functional ability in older adults, several systems are currently being researched to measure this parameter in the home environment of older adults. The data resulting from these systems, however, still needs to be reviewed by healthcare workers which is a time-consuming process. METHODS: This paper presents a system that employs statistical process control techniques (SPC) to automatically detect both positive and negative trends in transfer times. Several SPC techniques, Tabular cumulative sum (CUSUM) chart, Standardized CUSUM and Exponentially Weighted Moving Average (EWMA) chart were evaluated. The best performing method was further optimized for the desired application. After this, it was validated on both simulated data and real-life data. RESULTS: The best performing method was the Exponentially Weighted Moving Average control chart with the use of rational subgroups and a reinitialization after three alarm days. The results from the simulated data showed that positive and negative trends are detected within 14 days after the start of the trend when a trend is 28 days long. When the transition period is shorter, the number of days before an alert is triggered also diminishes. If for instance an abrupt change is present in the transfer time an alert is triggered within two days after this change. On average, only one false alarm is triggered every five weeks. The results from the real-life dataset confirm those of the simulated dataset. CONCLUSIONS: The system presented in this paper is able to detect both positive and negative trends in the transfer times of older adults, therefore automatically triggering an alarm when changes in transfer times occur. These changes can be gradual as well as abrupt.

A targeted functional RNA interference screen uncovers glypican 5 as an entry factor for hepatitis B and D viruses.

UNLABELLED: Chronic hepatitis B and D infections are major causes of liver disease and hepatocellular carcinoma worldwide. Efficient therapeutic approaches for cure are absent. Sharing the same envelope proteins, hepatitis B virus and hepatitis delta virus use the sodium/taurocholate cotransporting polypeptide (a bile acid transporter) as a receptor to enter hepatocytes. However, the detailed mechanisms of the viral entry process are still poorly understood. Here, we established a high-throughput infectious cell culture model enabling functional genomics of hepatitis delta virus entry and infection. Using a targeted RNA interference entry screen, we identified glypican 5 as a common host cell entry factor for hepatitis B and delta viruses. CONCLUSION: These findings advance our understanding of virus cell entry and open new avenues for curative therapies. As glypicans have been shown to play a role in the control of cell division and growth regulation, virus-glypican 5 interactions may also play a role in the pathogenesis of virus-induced liver disease and cancer.

Automated walking aid detector based on indoor video recordings.

Due to the rapidly aging population, developing automated home care systems is a very important step in taking care of elderly people. This will enable us to automatically monitor the health of senior citizens in their own living environment and prevent problems before they happen. One of the challenging tasks is to actively monitor walking habits of elderlies, who alternate between the use of different walking aids, and to combine this with automated fall risk assessment systems. We propose a camera based system that uses object categorization techniques to robustly detect walking aids, like a walker, in order to improve the classification of the fall risk. By automatically integrating the application specific scenery knowledge like camera position and used walker type, we succeed in detecting walking aids within a single frame with an accuracy of 68% for trajectory A and 38% for trajectory B. Furthermore, compared to current state of the art detection systems, we use a rather limited set of training data to achieve this accuracy and thus create a system that is easily adaptable for other applications. Moreover, we applied spatial constraints between detections to optimize the object detection output and to limit the amount of false positive detections. Finally, we evaluate the output on a walking sequence base, leading up to a 92.3% correct classification rate of walking sequences. It can be noted that adapting this approach to other walking aids, like a walking cane, is quite straightforward and opens up the door for many future applications.

Automatic detection of health changes using statistical process control techniques on measured transfer times of elderly.

It has been shown that gait speed and transfer times are good measures of functional ability in elderly. However, data currently acquired by systems that measure either gait speed or transfer times in the homes of elderly people require manual reviewing by healthcare workers. This reviewing process is time-consuming. To alleviate this burden, this paper proposes the use of statistical process control methods to automatically detect both positive and negative changes in transfer times. Three SPC techniques: tabular CUSUM, standardized CUSUM and EWMA, known for their ability to detect small shifts in the data, are evaluated on simulated transfer times. This analysis shows that EWMA is the best-suited method with a detection accuracy of 82% and an average detection time of 9.64 days.

Accelerometry-based home monitoring for detection of nocturnal hypermotor seizures based on novelty detection.

Nocturnal home monitoring of epileptic children is often not feasible due to the cumbersome manner of seizure monitoring with the standard method of video/EEG-monitoring. We propose a method for hypermotor seizure detection based on accelerometers attached to the extremities. From the acceleration signals, multiple temporal, frequency, and wavelet-based features are extracted. After determining the features with the highest discriminative power, we classify movement events in epileptic and nonepileptic movements. This classification is only based on a nonparametric estimate of the probability density function of normal movements. Such approach allows us to build patient-specific models to classify movement data without the need for seizure data that are rarely available. If, in the test phase, the probability of a data point (event) is lower than a threshold, this event is considered to be an epileptic seizure; otherwise, it is considered as a normal nocturnal movement event. The mean performance over seven patients gives a sensitivity of 95.24% and a positive predictive value of 60.04%. However, there is a noticeable interpatient difference.

Detecting rare events using extreme value statistics applied to epileptic convulsions in children.

OBJECTIVE: Nocturnal home monitoring of epileptic children is often not feasible due to the cumbersome manner of seizure detection with the standard method of video electroencephalography monitoring. The goal of this paper is to propose a method for hypermotor seizure detection based on accelerometers that are attached to the extremities. METHODS: Supervised methods that are commonly used in literature need annotation of data and hence require expert (neurologist) interaction resulting in a substantial cost. In this paper an unsupervised method is proposed that uses extreme value statistics and seizure detection based on a model of normal behavior that is estimated using all recorded and unlabeled data. In this way the expensive interaction can be avoided. RESULTS: When applying this method to a labeled dataset, acquired from 7 patients, all hypermotor seizures are detected in 5 of the 7 patients with an average positive predictive value (PPV) of 53%. For evaluating the performance on an unlabeled dataset, seizure events are presented to the system as normal movement events. Since hypermotor seizures are rare compared to normal movements, the very few abnormal events have a negligible effect on the quality of the model. In this way, it was possible to evaluate the system for 3 of the 7 patients when 3% of the training set was composed of seizure events. This resulted in sensitivity scores of 80%, 22% and 90% and a PPV of 89%, 21% and 44% respectively. These scores are comparable with a state-of-the-art supervised machine learning based approach which requires a labeled dataset. CONCLUSIONS: A person-dependent epileptic seizure detection method has been designed that requires little human interaction. In contrast to traditional machine learning approaches, the imbalance of the dataset does not cause substantial difficulties.

Validation of the kinect for gait analysis using the GAITRite walkway.

Accurate, non-intrusive and straightforward techniques for gait quality analysis can provide important information concerning the fall risk of a person. For this purpose an algorithm was developed which can measure step length and step time using the Kinect depth image. The validity of the measured step length and time is determined using the GAITRite walkway as a ground truth. The results of this validation confirm that the Kinect is well-suited for determining general parameters of a walking sequence (a Spearmans Correlation Coefficient (SCC) of 0.94 for average step length and 0.75 for average step time per walk), but we furthermore show that determining accurate results for single steps is more difficult (SCC of 0.74 for step length and 0.43 for step time for each step), making it harder to measure more complex gait parameters such as e.g. gait symmetry.