Recognition of the Multi-class Schizophrenia Based on the Resting-State EEG Network Topology.

The clinical therapy of schizophrenia (SCZ) replies on the corresponding accurate and reliable recognition. Although efforts have been paid, the diagnosis of SCZ is still roughly subjective, it is thus urgent to search for related objective physiological parameters. Motivated by the great potential of resting-state networks in underling the brain deficits among different SCZ groups, in this study, we then developed a multi-class feature extraction approach that could effectively extract the spatial network topology and facilitate the recognition of the SCZ, by combining a network structure based supervised learning with an ensemble co-decision strategy. The results demonstrated that the multi-class spatial pattern of the network (MSPN) features outperformed the other conventional electrophysiological features, such as relative power spectrums and network properties, and achieved the highest classification accuracy of 71.58% in the alpha band. These findings did validate that the resting-state MSPN is a promising tool for the clinical assessment of the SCZ.

Predicting individual decision-making responses based on single-trial EEG.

Decision-making plays an essential role in the interpersonal interactions and cognitive processing of individuals. There has been increasing interest in being able to predict an individual's decision-making response (i.e., acceptance or rejection). We proposed an electroencephalogram (EEG)-based computational intelligence framework to predict individual responses. Specifically, the discriminative spatial network pattern (DSNP), a supervised learning approach, was applied to single-trial EEG data to extract the DSNP feature from the single-trial brain network. A linear discriminate analysis (LDA) trained on the DSNP features was then used to predict the individual response trial-by-trial. To verify the performance of the proposed DSNP, we recruited two independent subject groups, and recorded the EEGs using two types of EEG systems. The performances of the trial-by-trial predictors achieved an accuracy of 0.88 ±â€¯0.09 for the first dataset, and 0.90 ±â€¯0.10 for the second dataset. These trial-by-trial prediction performances suggested that individual responses could be predicted trial-by-trial by using the specific pattern of single-trial EEG networks, and our proposed method has the potential to establish the biologically inspired artificial intelligence decision system.

Separated Channel Attention Convolutional Neural Network (SC-CNN-Attention) to Identify ADHD in Multi-Site Rs-fMRI Dataset.

The accurate identification of an attention deficit hyperactivity disorder (ADHD) subject has remained a challenge for both neuroscience research and clinical diagnosis. Unfortunately, the traditional methods concerning the classification model and feature extraction usually depend on the single-channel model and static measurements (i.e., functional connectivity, FC) in the small, homogenous single-site dataset, which is limited and may cause the loss of intrinsic information in functional MRI (fMRI). In this study, we proposed a new two-stage network structure by combing a separated channel convolutional neural network (SC-CNN) with an attention-based network (SC-CNN-attention) to discriminate ADHD and healthy controls on a large-scale multi-site database (5 sites and n = 1019). To utilize both intrinsic temporal feature and the interactions of temporal dependent in whole-brain resting-state fMRI, in the first stage of our proposed network structure, a SC- CNN is used to learn the temporal feature of each brain region, and an attention network in the second stage is adopted to capture temporal dependent features among regions and extract fusion features. Using a "leave-one-site-out" cross-validation framework, our proposed method obtained a mean classification accuracy of 68.6% on five different sites, which is higher than those reported in previous studies. The classification results demonstrate that our proposed network is robust to data variants and is also replicated across sites. The combination of the SC-CNN with the attention network is powerful to capture the intrinsic fMRI information to discriminate ADHD across multi-site resting-state fMRI data.

Microshell Arrays Enhanced Sensitivity in Detection of Specific Antibody for Reduced Graphene Oxide Optical Sensor.

Protein-protein interactions play an important role in the investigation of biomolecules. In this paper, we reported on the use of a reduced graphene oxide microshell (RGOM)-based optical biosensor for the determination of goat anti-rabbit IgG. The biosensor was prepared through a self-assembly of monolayers of monodisperse polystyrene microspheres, combined with a high-temperature reduction, in order to decorate the RGOM with rabbit IgG. The periodic microshells allowed a simpler functionalization and modification of RGOM with bioreceptor units, than reduced graphene oxide (RGO). With additional antibody-antigen binding, the RGOM-based biosensor achieved better real-time and label-free detection. The RGOM-based biosensor presented a more satisfactory response to goat anti-rabbit IgG than the RGO-based biosensor. This method is promising for immobilizing biomolecules on graphene surfaces and for the fabrication of biosensors with enhanced sensitivity.

Temperature-induced labelling of Fluo-3 AM selectively yields brighter nucleus in adherent cells.

Fluo-3 is widely used to study cell calcium. Two traditional approaches: (1) direct injection and (2) Fluo-3 acetoxymethyl ester (AM) loading, often bring conflicting results in cytoplasmic calcium ([Ca(2+)]c) and nuclear calcium ([Ca(2+)]n) imaging. AM loading usually yields a darker nucleus than in cytoplasm, while direct injection always induces a brighter nucleus which is more responsive to [Ca(2+)]n detection. In this work, we detailedly investigated the effects of loading and de-esterification temperatures on the fluorescence intensity of Fluo-3 in response to [Ca(2+)]n and [Ca(2+)]c in adherent cells, including osteoblast, HeLa and BV2 cells. Interestingly, it showed that fluorescence intensity of nucleus in osteoblast cells was about two times larger than that of cytoplasm when cells were loaded with Fluo-3 AM at 4 °C and allowed a subsequent step for de-esterification at 20 °C. Brighter nuclei were also acquired in HeLa and BV2 cells using the same experimental condition. Furthermore, loading time and adhesion quality of cells had effect on fluorescence intensity. Taken together, cold loading and room temperature de-esterification treatment of Fluo-3 AM selectively yielded brighter nucleus in adherent cells.

Sleep stages classification by fusing the time-related synchronization analysis and brain activations.

Sleep staging plays an important role in the diagnosis and treatment of clinical sleep disorders. The sleep staging standard defines every 30 seconds as a sleep period, which may mean that there exist similar brain activity patterns during the same sleep period. Thus, in this work, we propose a novel time-related synchronization analysis framework named time-related multimodal sleep scoring model (TRMSC) to explore the potential time-related patterns of sleeping. In the proposed TRMSC, the time-related synchronization analysis is first conducted on the single channel electrophysiological signal, i.e., Electroencephalogram (EEG) and Electrooculogram (EOG), to explore the time-related patterns, and the spectral activation features are also extracted by spectrum analysis to obtain the multimodal features. With the extracted multimodal features, the feature fusion and selection strategy is utilized to obtain the optimal feature set and achieve robust sleep staging. To verify the effectiveness of the proposed TRMSC, sleep staging experiments were conducted on the Sleep-EDF dataset, and the experimental results indicate that the proposed TRMSC has achieved better performance than other existing strategies, which proves that the time-related synchronization features can make up for the shortcomings of traditional spectrum-based strategies and achieve a higher classification accuracy. The proposed TRMSC model may be helpful for portable sleep analyzers and provide a new analytical method for clinical sleeping research.

EEG based emotion recognition by hierarchical bayesian spectral regression framework.

Spectral regression (SR), a graph-based learning regression model, can be used to extract features from graphs to realize efficient dimensionality reduction. However, due to the SR method remains a regularized least squares problem and being defined in L2-norm space, the effect of artifacts in EEG signals cannot be efficiently resisted. In this work, to further improve the robustness of the graph-based regression models, we propose to utilize the prior distribution estimation in the Bayesian framework and develop a robust hierarchical Bayesian spectral regression framework (named HB-SR), which is designed with the hierarchical Bayesian ensemble strategies. In the proposed HB-SR, the impact of noises can be effectively reduced by the adaptive adjustment approach in model parameters with the data-driven manner. Specifically, in the current work, three different distributions have been elaborately designed to enhance the universality of the proposed HB-SR, i.e., Gaussian distribution, Laplace distribution, and Student-t distribution. To objectively evaluate the performance of the HB-SR framework, we conducted both simulation studies and emotion recognition experiments based on emotional EEG signals. Experimental results have consistently indicated that compared with other existing spectral regression methods, the proposed HB-SR can effectively suppress the influence of noises and achieve robust EEG emotion recognition.

A hybrid graph network model for ASD diagnosis based on resting-state EEG signals.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder and early diagnosis is crucial for effective treatment. Stable and effective biomarkers are essential for understanding the underlying causes of the disorder and improving diagnostic accuracy. Electroencephalography (EEG) signals have proven to be reliable biomarkers for diagnosing ASD. Extracting stable connectivity patterns from EEG signals helps ensure robustness in ASD diagnostic systems. In this study, we propose a hybrid graph convolutional network framework called Rest-HGCN, which utilizes resting-state EEG signals to capture differential patterns of brain connectivity between normal children and ASD patients using graph learning strategies. The Rest-HGCN combines brain network analysis techniques and data-driven strategies to extract discriminative graph features from resting-state EEG signals. By automatically extracting differential graph patterns from these signals, the Rest-HGCN achieves reliable ASD diagnosis. To evaluate the performance of Rest-HGCN, we conducted ASD diagnosis experiments using k-fold cross-validation on the public ABC-CT resting EEG dataset. The proposed Rest-HGCN model achieved accuracies of 87.12 % and 85.32 % in single-subject and cross-experiment analyses, respectively. The results suggest that Rest-HGCN can effectively capture discriminant graph patterns from resting EEG signals and achieve robust ASD diagnosis. This may provide an effective and convenient tool for clinical ASD diagnosis.

An Efficient Graph Learning System for Emotion Recognition Inspired by the Cognitive Prior Graph of EEG Brain Network.

Benefiting from the high-temporal resolution of electroencephalogram (EEG), EEG-based emotion recognition has become one of the hotspots of affective computing. For EEG-based emotion recognition systems, it is crucial to utilize state-of-the-art learning strategies to automatically learn emotion-related brain cognitive patterns from emotional EEG signals, and the learned stable cognitive patterns effectively ensure the robustness of the emotion recognition system. In this work, to realize the efficient decoding of emotional EEG, we propose a graph learning system Graph Convolutional Network framework with Brain network initial inspiration and Fused attention mechanism (BF-GCN) inspired by the brain cognitive mechanism to automatically learn graph patterns from emotional EEG and improve the performance of EEG emotion recognition. In the proposed BF-GCN, three graph branches, i.e., cognition-inspired functional graph branch, data-driven graph branch, and fused common graph branch, are first elaborately designed to automatically learn emotional cognitive graph patterns from emotional EEG signals. And then, the attention mechanism is adopted to further capture the brain activation graph patterns that are related to emotion cognition to achieve an efficient representation of emotional EEG signals. Essentially, the proposed BF-CGN model is a cognition-inspired graph learning neural network model, which utilizes the spectral graph filtering theory in the automatic learning and extracting of emotional EEG graph patterns. To evaluate the performance of the BF-GCN graph learning system, we conducted subject-dependent and subject-independent experiments on two public datasets, i.e., SEED and SEED-IV. The proposed BF-GCN graph learning system has achieved 97.44% (SEED) and 89.55% (SEED-IV) in subject-dependent experiments, and the results in subject-independent experiments have achieved 92.72% (SEED) and 82.03% (SEED-IV), respectively. The state-of-the-art performance indicates that the proposed BF-GCN graph learning system has a robust performance in EEG-based emotion recognition, which provides a promising direction for affective computing.

Effective Emotion Recognition by Learning Discriminative Graph Topologies in EEG Brain Networks.

Multichannel electroencephalogram (EEG) is an array signal that represents brain neural networks and can be applied to characterize information propagation patterns for different emotional states. To reveal these inherent spatial graph features and increase the stability of emotion recognition, we propose an effective emotion recognition model that performs multicategory emotion recognition with multiple emotion-related spatial network topology patterns (MESNPs) by learning discriminative graph topologies in EEG brain networks. To evaluate the performance of our proposed MESNP model, we conducted single-subject and multisubject four-class classification experiments on two public datasets, MAHNOB-HCI and DEAP. Compared with existing feature extraction methods, the MESNP model significantly enhances the multiclass emotional classification performance in the single-subject and multisubject conditions. To evaluate the online version of the proposed MESNP model, we designed an online emotion monitoring system. We recruited 14 participants to conduct the online emotion decoding experiments. The average online experimental accuracy of the 14 participants was 84.56%, indicating that our model can be applied in affective brain-computer interface (aBCI) systems. The offline and online experimental results demonstrate that the proposed MESNP model effectively captures discriminative graph topology patterns and significantly improves emotion classification performance. Moreover, the proposed MESNP model provides a new scheme for extracting features from strongly coupled array signals.

An adaptive joint CCA-ICA method for ocular artifact removal and its application to emotion classification.

BACKGROUND: The quality of Electroencephalogram (EEG) signals is critical for revealing the neural mechanism of emotions. However, ocular artifacts decreased the signal to noise ratio (SNR) and covered the inherent cognitive component of EEGs, which pose a great challenge in neuroscience research. NEW METHOD: We proposed a novel unsupervised learning algorithm to adaptively remove the ocular artifacts by combining canonical correlation analysis (CCA), independent component analysis (ICA), higher-order statistics, empirical mode decomposition (EMD), and wavelet denoising techniques. Specifically, the combination of CCA and ICA aimed to improve the quality of source separation, while the higher-order statistics further located the source of ocular artifacts. Subsequently, these noised sources were further corrected by EMD and wavelet denoising to improve SNR of EEG signals. RESULTS: We evaluated the performance of our proposed method with simulation studies and real EEG applications. The results of simulation study showed our proposed method could significantly improve the quality of signals under almost all noise conditions compared to four state-of-art methods. Consistently, the experiments of real EEG applications showed that the proposed methods could efficiently restrict the components of ocular artifacts and preserve the inherent information of cognition processing to improve the reliability of related analysis such as power spectral density (PSD) and emotion recognition. COMPARISON WITH EXISTING METHODS: Our proposed model outperforms the comparative methods in EEG recovery, which further improve the application performance such as PSD analysis and emotion recognition. CONCLUSIONS: The superior performance of our proposed method suggests that it is promising for removing ocular artifacts from EEG signals, which offers an efficient EEG preprocessing technology for the development of brain computer interface such as emotion recognition.

Granger Causal Inference Based on Dual Laplacian Distribution and Its Application to MI-BCI Classification.

Granger causality-based effective brain connectivity provides a powerful tool to probe the neural mechanism for information processing and the potential features for brain computer interfaces. However, in real applications, traditional Granger causality is prone to the influence of outliers, such as inevitable ocular artifacts, resulting in unreasonable brain linkages and the failure to decipher inherent cognition states. In this work, motivated by constructing the sparse causality brain networks under the strong physiological outlier noise conditions, we proposed a dual Laplacian Granger causality analysis (DLap-GCA) by imposing Laplacian distributions on both model parameters and residuals. In essence, the first Laplacian assumption on residuals will resist the influence of outliers in electroencephalogram (EEG) on causality inference, and the second Laplacian assumption on model parameters will sparsely characterize the intrinsic interactions among multiple brain regions. Through simulation study, we quantitatively verified its effectiveness in suppressing the influence of complex outliers, the stable capacity for model estimation, and sparse network inference. The application to motor-imagery (MI) EEG further reveals that our method can effectively capture the inherent hemispheric lateralization of MI tasks with sparse patterns even under strong noise conditions. The MI classification based on the network features derived from the proposed approach shows higher accuracy than other existing traditional approaches, which is attributed to the discriminative network structures being captured in a timely manner by DLap-GCA even under the single-trial online condition. Basically, these results consistently show its robustness to the influence of complex outliers and the capability of characterizing representative brain networks for cognition information processing, which has the potential to offer reliable network structures for both cognitive studies and future brain-computer interface (BCI) realization.

Dynamic networks of P300-related process.

P300 as an effective biomarker to index attention and memory has been widely used for brain-computer interface, cognitive evaluation, and clinical diagnosis. To evoke clear P300, an oddball paradigm consisting of two types of stimuli, i.e., infrequent target stimuli and frequent standard stimuli, is usually used. However, to simply and quickly explore the P300-related process, previous studies predominately focused on the target condition but ignored the fusion of target and standard conditions, as well as the difference of brain networks between them. Therefore, in this study, we used the hidden Markov model to investigate the fused multi-conditional electroencephalogram dataset of P300, aiming to effectively identify the underlying brain networks and explore the difference between conditions. Specifically, the inferred networks, including their transition sequences and spatial distributions, were scrutinized first. Then, we found that the difference between target and standard conditions was mainly concentrated in two phases. One was the stimulation phase that mainly related to the cortical activities of the postcentral gyrus and superior parietal lobule, and the other corresponded to the response phase that involved the activities of superior and medial frontal gyri. This might be attributed to distinct cognitive functions, as the stimulation phase is associated with visual information integration whereas the response phase involves stimulus discrimination and behavior control. Taken together, the current work explored dynamic networks underlying the P300-related process and provided a complementary understanding of distinct P300 conditions, which may contribute to the design of P300-related brain-machine systems.

L1-norm based time-varying brain neural network and its application to dynamic analysis for motor imagery.

Objective.Electroencephalogram (EEG)-based motor imagery (MI) brain-computer interface offers a promising way to improve the efficiency of motor rehabilitation and motor skill learning. In recent years, the power of dynamic network analysis for MI classification has been proved. In fact, its usability mainly depends on the accurate estimation of brain connection. However, traditional dynamic network estimation strategies such as adaptive directed transfer function (ADTF) are designed in the L2-norm. Usually, they estimate a series of pseudo connections caused by outliers, which results in biased features and further limits its online application. Thus, how to accurately infer dynamic causal relationship under outlier influence is urgent.Approach.In this work, we proposed a novel ADTF, which solves the dynamic system in the L1-norm space (L1-ADTF), so as to restrict the outlier influence. To enhance its convergence, we designed an iteration strategy with the alternating direction method of multipliers, which could be used for the solution of the dynamic state-space model restricted in the L1-norm space. Furthermore, we compared L1-ADTF to traditional ADTF and its dual extension across both simulation and real EEG experiments.Main results.A quantitative comparison between L1-ADTF and other ADTFs in simulation studies demonstrates that fewer bias errors and more desirable dynamic state transformation patterns can be captured by the L1-ADTF. Application to real MI EEG datasets seriously noised by ocular artifacts also reveals the efficiency of the proposed L1-ADTF approach to extract the time-varying brain neural network patterns, even when more complex noises are involved.Significance.The L1-ADTF may not only be capable of tracking time-varying brain network state drifts robustly but may also be useful in solving a wide range of dynamic systems such as trajectory tracking problems and dynamic neural networks.

Electroencephalographic Network Topologies Predict Antidepressant Responses in Patients With Major Depressive Disorder.

Medication therapy seems to be an effective treatment for major depressive disorder (MDD). However, although the efficacies of various medicines are equal or similar on average, they vary widely among individuals. Therefore, an understanding of methods for the timely evaluation of short-term therapeutic response and prediction of symptom improvement after a specific course of medication at the individual level at the initial stage of treatment is very important. In our present study, we sought to identify a neurobiological signature of the response to short-term antidepressant treatment. Related brain network analysis was applied in resting-state electroencephalogram (EEG) datasets from patients with MDD. The corresponding EEG networks were constructed accordingly and then quantitatively measured to predict the efficacy after eight weeks of medication, as well as to distinguish the therapeutic responders from non-responders. The results of our present study revealed that the corresponding resting-state EEG networks became significantly weaker after one week of treatment, and the eventual medication efficacy was reliably predicted using the changes in those network properties within the one-week medication regimen. Moreover, the corresponding resting-state networks at baseline were also proven to precisely distinguish those responders from other individuals with an accuracy of 96.67% when using the spatial network topologies as the discriminative features. These findings consistently provide a deeper neurobiological understanding of antidepressant treatment and a reliable and quantitative approach for personalized treatment of MDD.

Corrections to "Identification of the General Anesthesia Induced Loss of Consciousness by Cross Fuzzy Entropy-Based Brain Network".

In the above article [1], to track the loss of consciousness (LOC) induced by general anesthesia (GA), we first developed the multi-channel cross fuzzy entropy method to construct the time- varying networks, whose temporal fluctuations were then explored and quantitatively evaluated. Since time-varying network topologies were found to fluctuate from long-range frontal-occipital to short-range prefrontal-frontal connectivity during the LOC period, a new parameter, i.e., the long-range connectivity (LRC) that measured the number of frontal-occipital connectivity, was accordingly calculated and then investigated between the coherence (COH) and cross fuzzy entropy (C-FuzzyEn) approaches, as displayed in Fig. 1. The distinct time-varying fluctuations of both approaches were indeed found within this period, where only C-FuzzyEn effectively captured the consciousness fluctuation induced by the GA.

Identification of the General Anesthesia Induced Loss of Consciousness by Cross Fuzzy Entropy-Based Brain Network.

Although the spatiotemporal complexity and network connectivity are clarified to be disrupted during the general anesthesia (GA) induced unconsciousness, it remains to be difficult to exactly monitor the fluctuation of consciousness clinically. In this study, to track the loss of consciousness (LOC) induced by GA, we first developed the multi-channel cross fuzzy entropy method to construct the time-varying networks, whose temporal fluctuations were then explored and quantitatively evaluated. Thereafter, an algorithm was further proposed to detect the time onset at which patients lost their consciousness. The results clarified during the resting state, relatively stable fuzzy fluctuations in multi-channel network architectures and properties were found; by contrast, during the LOC period, the disrupted frontal-occipital connectivity occurred at the early stage, while at the later stage, the inner-frontal connectivity was identified. When specifically exploring the early LOC stage, the uphill of the clustering coefficients and the downhill of the characteristic path length were found, which might help resolve the propofol-induced consciousness fluctuation in patients. Moreover, the developed detection algorithm was validated to have great capacity in exactly capturing the time point (in seconds) at which patients lost consciousness. The findings demonstrated that the time-varying cross-fuzzy networks help decode the GA and are of great significance for developing anesthesia depth monitoring technology clinically.

EEG Based Emotion Recognition by Combining Functional Connectivity Network and Local Activations.

OBJECTIVE: Spectral power analysis plays a predominant role in electroencephalogram-based emotional recognition. It can reflect activity differences among multiple brain regions. In addition to activation difference, different emotions also involve different large-scale network during related information processing. In this paper, both information propagation patterns and activation difference in the brain were fused to improve the performance of emotional recognition. METHODS: We constructed emotion-related brain networks with phase locking value and adopted a multiple feature fusion approach to combine the compensative activation and connection information for emotion recognition. RESULTS: Recognition results on three public emotional databases demonstrated that the combined features are superior to either single feature based on power distribution or network character. Furthermore, the conducted feature fusion analysis revealed the common characters between activation and connection patterns involved in the positive, neutral, and negative emotions for information processing. SIGNIFICANCE: The proposed feasible combination of both information propagation patterns and activation difference in the brain is meaningful for developing the effective human-computer interaction systems by adapting to human emotions in the real world applications.

Measuring the Non-linear Directed Information Flow in Schizophrenia by Multivariate Transfer Entropy.

People living with schizophrenia (SCZ) experience severe brain network deterioration. The brain is constantly fizzling with non-linear causal activities measured by electroencephalogram (EEG) and despite the variety of effective connectivity methods, only few approaches can quantify the direct non-linear causal interactions. To circumvent this problem, we are motivated to quantitatively measure the effective connectivity by multivariate transfer entropy (MTE) which has been demonstrated to be able to capture both linear and non-linear causal relationships effectively. In this work, we propose to construct the EEG effective network by MTE and further compare its performance with the Granger causal analysis (GCA) and Bivariate transfer entropy (BVTE). The simulation results quantitatively show that MTE outperformed GCA and BVTE under varied signal-to-noise conditions, edges recovered, sensitivity, and specificity. Moreover, its applications to the P300 task EEG of healthy controls (HC) and SCZ patients further clearly show the deteriorated network interactions of SCZ, compared to that of the HC. The MTE provides a novel tool to potentially deepen our knowledge of the brain network deterioration of the SCZ.

Multiple calcium patterns of rat osteoblasts under fluidic shear stress.

The intracellular calcium ([Ca2+ ]i ) response induced by external forces can be diverse and complex. Using primary osteoblasts from Wistar rats, we found multiple patterns of [Ca2+ ]i responses induced by fluidic shear stress (Fss), including homogeneous non-oscillation and heterogeneous oscillations. These multiple-patterned [Ca2+ ]i responses could be influenced by Fss intensity, cell density, and cell differentiation. Our real-time measurements with free calcium, ATP, ATP without calcium, suramin, apyrase, and thapsigargin confirmed homogeneous [Ca2+ ]i patterns and/or heterogeneous [Ca2+ ]i oscillations with respect to the combined degree of external Ca2+ influx, and intracellular Ca2+ release. Our theoretical model supported diverse Fss-induced calcium activities as well. We concluded that a singular factor of Ca2+ influx or release dominated to produce smooth homogeneous patterns, but combined factors produced oscillatory heterogeneous patterns. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2039-2051, 2018.