Zeyu Gao

Yao Mu, Tianxing Chen, Shijia Peng et al.

In the rapidly advancing field of robotics, dual-arm coordination and complex object manipulation are essential capabilities for developing advanced autonomous systems. However, the scarcity of diverse, high-quality demonstration data and real-world-aligned evaluation benchmarks severely limits such development. To address this, we introduce RoboTwin, a generative digital twin framework that uses 3D generative foundation models and large language models to produce diverse expert datasets and provide a real-world-aligned evaluation platform for dual-arm robotic tasks. Specifically, RoboTwin creates varied digital twins of objects from single 2D images, generating realistic and interactive scenarios. It also introduces a spatial relation-aware code generation framework that combines object annotations with large language models to break down tasks, determine spatial constraints, and generate precise robotic movement code. Our framework offers a comprehensive benchmark with both simulated and real-world data, enabling standardized evaluation and better alignment between simulated training and real-world performance. We validated our approach using the open-source COBOT Magic Robot platform. Policies pre-trained on RoboTwin-generated data and fine-tuned with limited real-world samples improve the success rate of over 70% for single-arm tasks and over 40% for dual-arm tasks compared to models trained solely on real-world data. This significant improvement demonstrates RoboTwin's potential to enhance the development and evaluation of dual-arm robotic manipulation systems. Project Page: https://robotwin-benchmark.github.io/early-version/.

William McGough, Thomas Buddenkotte, Stephan Ursprung et al.

This study introduces an automated pipeline for renal cancer (RC) detection in non-contrast computed tomography (NCCT). In the development of our pipeline, we test three detections models: a shape model, a 2D-, and a 3D axial-sample model. Training (n=1348) and testing (n=64) data were gathered from open sources (KiTS23, Abdomen1k, CT-ORG) and Cambridge University Hospital (CUH). Results from cross-validation and testing revealed that the 2D axial sample model had the highest small ($\leq$40mm diameter) RC detection area under the curve (AUC) of 0.804. Our pipeline achieves 61.9\% sensitivity and 92.7\% specificity for small kidney cancers on unseen test data. Our results are much more accurate than previous attempts to automatically detect small renal cancers in NCCT, the most likely imaging modality for RC screening. This pipeline offers a promising advance that may enable screening for kidney cancers.

Wenyu Zhu, Hao Wang, Yuchen Zhou et al.

Binary Code Embedding (BCE) has important applications in various reverse engineering tasks such as binary code similarity detection, type recovery, control-flow recovery and data-flow analysis. Recent studies have shown that the Transformer model can comprehend the semantics of binary code to support downstream tasks. However, existing models overlooked the prior knowledge of assembly language. In this paper, we propose a novel Transformer-based approach, namely kTrans, to generate knowledge-aware binary code embedding. By feeding explicit knowledge as additional inputs to the Transformer, and fusing implicit knowledge with a novel pre-training task, kTrans provides a new perspective to incorporating domain knowledge into a Transformer framework. We inspect the generated embeddings with outlier detection and visualization, and also apply kTrans to 3 downstream tasks: Binary Code Similarity Detection (BCSD), Function Type Recovery (FTR) and Indirect Call Recognition (ICR). Evaluation results show that kTrans can generate high-quality binary code embeddings, and outperforms state-of-the-art (SOTA) approaches on downstream tasks by 5.2%, 6.8%, and 12.6% respectively. kTrans is publicly available at: https://github.com/Learner0x5a/kTrans-release

Zeyu Gao, Yao Mu, Chen Chen et al.

End-to-end autonomous driving provides a feasible way to automatically maximize overall driving system performance by directly mapping the raw pixels from a front-facing camera to control signals. Recent advanced methods construct a latent world model to map the high dimensional observations into compact latent space. However, the latent states embedded by the world model proposed in previous works may contain a large amount of task-irrelevant information, resulting in low sampling efficiency and poor robustness to input perturbations. Meanwhile, the training data distribution is usually unbalanced, and the learned policy is challenging to cope with the corner cases during the driving process. To solve the above challenges, we present a SEMantic Masked recurrent world model (SEM2), which introduces a semantic filter to extract key driving-relevant features and make decisions via the filtered features, and is trained with a multi-source data sampler, which aggregates common data and multiple corner case data in a single batch, to balance the data distribution. Extensive experiments on CARLA show our method outperforms the state-of-the-art approaches in terms of sample efficiency and robustness to input permutations.

Zeyu Gao, Hao Wang, Yuchen Zhou et al.

As software becomes increasingly complex and prone to vulnerabilities, automated vulnerability detection is critically important, yet challenging. Given the significant successes of large language models (LLMs) in various tasks, there is growing anticipation of their efficacy in vulnerability detection. However, a quantitative understanding of their potential in vulnerability detection is still missing. To bridge this gap, we introduce a comprehensive vulnerability benchmark VulBench. This benchmark aggregates high-quality data from a wide range of CTF (Capture-the-Flag) challenges and real-world applications, with annotations for each vulnerable function detailing the vulnerability type and its root cause. Through our experiments encompassing 16 LLMs and 6 state-of-the-art (SOTA) deep learning-based models and static analyzers, we find that several LLMs outperform traditional deep learning approaches in vulnerability detection, revealing an untapped potential in LLMs. This work contributes to the understanding and utilization of LLMs for enhanced software security.

Yao Mu, Tianxing Chen, Zanxin Chen et al.

In the rapidly advancing field of robotics, dual-arm coordination and complex object manipulation are essential capabilities for developing advanced autonomous systems. However, the scarcity of diverse, high-quality demonstration data and real-world-aligned evaluation benchmarks severely limits such development. To address this, we introduce RoboTwin, a generative digital twin framework that uses 3D generative foundation models and large language models to produce diverse expert datasets and provide a real-world-aligned evaluation platform for dual-arm robotic tasks. Specifically, RoboTwin creates varied digital twins of objects from single 2D images, generating realistic and interactive scenarios. It also introduces a spatial relation-aware code generation framework that combines object annotations with large language models to break down tasks, determine spatial constraints, and generate precise robotic movement code. Our framework offers a comprehensive benchmark with both simulated and real-world data, enabling standardized evaluation and better alignment between simulated training and real-world performance. We validated our approach using the open-source COBOT Magic Robot platform. Policies pre-trained on RoboTwin-generated data and fine-tuned with limited real-world samples demonstrate significant potential for enhancing dual-arm robotic manipulation systems by improving success rates by over 70% for single-arm tasks and over 40% for dual-arm tasks compared to models trained solely on real-world data.

Pargorn Puttapirat, Haichuan Zhang, Jingyi Deng et al.

Transition from conventional to digital pathology requires a new category of biomedical informatic infrastructure which could facilitate delicate pathological routine. Pathological diagnoses are sensitive to many external factors and is known to be subjective. Only systems that can meet strict requirements in pathology would be able to run along pathological routines and eventually digitized the study area, and the developed platform should comply with existing pathological routines and international standards. Currently, there are a number of available software tools which can perform histopathological tasks including virtual slide viewing, annotating, and basic image analysis, however, none of them can serve as a digital platform for pathology. Here we describe OpenHI2, an enhanced version Open Histopathological Image platform which is capable of supporting all basic pathological tasks and file formats; ready to be deployed in medical institutions on a standard server environment or cloud computing infrastructure. In this paper, we also describe the development decisions for the platform and propose solutions to overcome technical challenges so that OpenHI2 could be used as a platform for histopathological images. Further addition can be made to the platform since each component is modularized and fully documented. OpenHI2 is free, open-source, and available at https://gitlab.com/BioAI/OpenHI.

Kun Wu, Chengkai Hou, Jiaming Liu et al.

In this paper, we introduce RoboMIND (Multi-embodiment Intelligence Normative Data for Robot Manipulation), a dataset containing 107k demonstration trajectories across 479 diverse tasks involving 96 object classes. RoboMIND is collected through human teleoperation and encompasses comprehensive robotic-related information, including multi-view observations, proprioceptive robot state information, and linguistic task descriptions. To ensure data consistency and reliability for imitation learning, RoboMIND is built on a unified data collection platform and a standardized protocol, covering four distinct robotic embodiments: the Franka Emika Panda, the UR5e, the AgileX dual-arm robot, and a humanoid robot with dual dexterous hands. Our dataset also includes 5k real-world failure demonstrations, each accompanied by detailed causes, enabling failure reflection and correction during policy learning. Additionally, we created a digital twin environment in the Isaac Sim simulator, replicating the real-world tasks and assets, which facilitates the low-cost collection of additional training data and enables efficient evaluation. To demonstrate the quality and diversity of our dataset, we conducted extensive experiments using various imitation learning methods for single-task settings and state-of-the-art Vision-Language-Action (VLA) models for multi-task scenarios. By leveraging RoboMIND, the VLA models achieved high manipulation success rates and demonstrated strong generalization capabilities. To the best of our knowledge, RoboMIND is the largest multi-embodiment teleoperation dataset collected on a unified platform, providing large-scale and high-quality robotic training data. Our project is at https://x-humanoid-robomind.github.io/.

Fan Luo, Zeyu Gao, Xinhao Luo et al.

Spiking Neural Networks (SNNs), with their brain-inspired spatiotemporal dynamics and spike-driven computation, have emerged as promising energy-efficient alternatives to Artificial Neural Networks (ANNs). However, existing SNNs typically replicate inputs directly or aggregate them into frames at fixed intervals. Such strategies lead to neurons receiving nearly identical stimuli across time steps, severely limiting the model's expressive power, particularly in complex tasks like object detection. In this work, we propose the Temporal Dynamics Enhancer (TDE) to strengthen SNNs' capacity for temporal information modeling. TDE consists of two modules: a Spiking Encoder (SE) that generates diverse input stimuli across time steps, and an Attention Gating Module (AGM) that guides the SE generation based on inter-temporal dependencies. Moreover, to eliminate the high-energy multiplication operations introduced by the AGM, we propose a Spike-Driven Attention (SDA) to reduce attention-related energy consumption. Extensive experiments demonstrate that TDE can be seamlessly integrated into existing SNN-based detectors and consistently outperforms state-of-the-art methods, achieving mAP50-95 scores of 57.7% on the static PASCAL VOC dataset and 47.6% on the neuromorphic EvDET200K dataset. In terms of energy consumption, the SDA consumes only 0.240 times the energy of conventional attention modules.

Wen Wen, Tieliang Gong, Yunjiao Zhang et al.

Continual learning (CL) has emerged as a dominant paradigm for acquiring knowledge from sequential tasks while avoiding catastrophic forgetting. Although many CL methods have been proposed to show impressive empirical performance, the theoretical understanding of their generalization behavior remains limited, particularly for replay-based approaches. In this paper, we establish a unified theoretical framework for replay-based CL, deriving a series of information-theoretic bounds that explicitly characterize how the memory buffer interacts with the current task to affect generalization. Specifically, our hypothesis-based bounds reveal that utilizing the limited exemplars of previous tasks alongside the current task data, rather than exhaustive replay, facilitates improved generalization while effectively mitigating catastrophic forgetting. Furthermore, our prediction-based bounds yield tighter and computationally tractable upper bounds of the generalization gap through the use of low-dimensional variables. Our analysis is general and broadly applicable to a wide range of learning algorithms, exemplified by stochastic gradient Langevin dynamics (SGLD) as a representative method. Comprehensive experimental evaluations demonstrate the effectiveness of our derived bounds in capturing the generalization dynamics in replay-based CL settings.

Daniël Boeke, Cedrik Blommestijn, Rebecca N. Wray et al.

Recurrence risk estimation in clear cell renal cell carcinoma (ccRCC) is essential for guiding postoperative surveillance and treatment. The Leibovich score remains widely used for stratifying distant recurrence risk but offers limited patient-level resolution and excludes imaging information. This study evaluates multimodal recurrence prediction by integrating preoperative computed tomography (CT) and postoperative histopathology whole-slide images (WSIs). A modular deep learning framework with pretrained encoders and Cox-based survival modeling was tested across unimodal, late fusion, and intermediate fusion setups. In a real-world ccRCC cohort, WSI-based models consistently outperformed CT-only models, underscoring the prognostic strength of pathology. Intermediate fusion further improved performance, with the best model (TITAN-CONCH with ResNet-18) approaching the adjusted Leibovich score. Random tie-breaking narrowed the gap between the clinical baseline and learned models, suggesting discretization may overstate individualized performance. Using simple embedding concatenation, radiology added value primarily through fusion. These findings demonstrate the feasibility of foundation model-based multimodal integration for personalized ccRCC risk prediction. Future work should explore more expressive fusion strategies, larger multimodal datasets, and general-purpose CT encoders to better match pathology modeling capacity.

Xuhang Chen, Ihsane Olakorede, Stefan Yu Bögli et al.

Artefacts compromise clinical decision-making in the use of medical time series. Pulsatile waveforms offer probabilities for accurate artefact detection, yet most approaches rely on supervised manners and overlook patient-level distribution shifts. To address these issues, we introduce a generalised label-free framework, GenClean, for real-time artefact cleaning and leverage an in-house dataset of 180,000 ten-second arterial blood pressure (ABP) samples for training. We first investigate patient-level generalisation, demonstrating robust performances under both intra- and inter-patient distribution shifts. We further validate its effectiveness through challenging cross-disease cohort experiments on the MIMIC-III database. Additionally, we extend our method to photoplethysmography (PPG), highlighting its applicability to diverse medical pulsatile signals. Finally, its integration into ICM+, a clinical research monitoring software, confirms the real-time feasibility of our framework, emphasising its practical utility in continuous physiological monitoring. This work provides a foundational step toward precision medicine in improving the reliability of high-resolution medical time series analysis

Jiangbo Shi, Chang Jia, Zeyu Gao et al.

Nuclei segmentation is a fundamental task in digital pathology analysis and can be automated by deep learning-based methods. However, the development of such an automated method requires a large amount of data with precisely annotated masks which is hard to obtain. Training with weakly labeled data is a popular solution for reducing the workload of annotation. In this paper, we propose a novel meta-learning-based nuclei segmentation method which follows the label correction paradigm to leverage data with noisy masks. Specifically, we design a fully conventional meta-model that can correct noisy masks using a small amount of clean meta-data. Then the corrected masks can be used to supervise the training of the segmentation model. Meanwhile, a bi-level optimization method is adopted to alternately update the parameters of the main segmentation model and the meta-model in an end-to-end way. Extensive experimental results on two nuclear segmentation datasets show that our method achieves the state-of-the-art result. It even achieves comparable performance with the model training on supervised data in some noisy settings.

Jialun Wu, Anyu Mao, Xinrui Bao et al.

Digital pathology plays a crucial role in the development of artificial intelligence in the medical field. The digital pathology platform can make the pathological resources digital and networked, and realize the permanent storage of visual data and the synchronous browsing processing without the limitation of time and space. It has been widely used in various fields of pathology. However, there is still a lack of an open and universal digital pathology platform to assist doctors in the management and analysis of digital pathological sections, as well as the management and structured description of relevant patient information. Most platforms cannot integrate image viewing, annotation and analysis, and text information management. To solve the above problems, we propose a comprehensive and extensible platform PIMIP. Our PIMIP has developed the image annotation functions based on the visualization of digital pathological sections. Our annotation functions support multi-user collaborative annotation and multi-device annotation, and realize the automation of some annotation tasks. In the annotation task, we invited a professional pathologist for guidance. We introduce a machine learning module for image analysis. The data we collected included public data from local hospitals and clinical examples. Our platform is more clinical and suitable for clinical use. In addition to image data, we also structured the management and display of text information. So our platform is comprehensive. The platform framework is built in a modular way to support users to add machine learning modules independently, which makes our platform extensible.

Jialun Wu, Yang Liu, Zeyu Gao et al.

Constructing large-scaled medical knowledge graphs can significantly boost healthcare applications for medical surveillance, bring much attention from recent research. An essential step in constructing large-scale MKG is extracting information from medical reports. Recently, information extraction techniques have been proposed and show promising performance in biomedical information extraction. However, these methods only consider limited types of entity and relation due to the noisy biomedical text data with complex entity correlations. Thus, they fail to provide enough information for constructing MKGs and restrict the downstream applications. To address this issue, we propose Biomedical Information Extraction, a hybrid neural network to extract relations from biomedical text and unstructured medical reports. Our model utilizes a multi-head attention enhanced graph convolutional network to capture the complex relations and context information while resisting the noise from the data. We evaluate our model on two major biomedical relationship extraction tasks, chemical-disease relation and chemical-protein interaction, and a cross-hospital pan-cancer pathology report corpus. The results show that our method achieves superior performance than baselines. Furthermore, we evaluate the applicability of our method under a transfer learning setting and show that BioIE achieves promising performance in processing medical text from different formats and writing styles.

Jialun Wu, Zeyu Gao, Haichuan Zhang et al.

Personalized diagnoses have not been possible due to sear amount of data pathologists have to bear during the day-to-day routine. This lead to the current generalized standards that are being continuously updated as new findings are reported. It is noticeable that these effective standards are developed based on a multi-source heterogeneous data, including whole-slide images and pathology and clinical reports. In this study, we propose a framework that combines pathological images and medical reports to generate a personalized diagnosis result for individual patient. We use nuclei-level image feature similarity and content-based deep learning method to search for a personalized group of population with similar pathological characteristics, extract structured prognostic information from descriptive pathology reports of the similar patient population, and assign importance of different prognostic factors to generate a personalized pathological diagnosis result. We use multi-source heterogeneous data from TCGA (The Cancer Genome Atlas) database. The result demonstrate that our framework matches the performance of pathologists in the diagnosis of renal cell carcinoma. This framework is designed to be generic, thus could be applied for other types of cancer. The weights could provide insights to the known prognostic factors and further guide more precise clinical treatment protocols.

Anyu Mao, Jialun Wu, Xinrui Bao et al.

Pathological diagnosis is the gold standard for cancer diagnosis, but it is labor-intensive, in which tasks such as cell detection, classification, and counting are particularly prominent. A common solution for automating these tasks is using nucleus segmentation technology. However, it is hard to train a robust nucleus segmentation model, due to several challenging problems, the nucleus adhesion, stacking, and excessive fusion with the background. Recently, some researchers proposed a series of automatic nucleus segmentation methods based on point annotation, which can significant improve the model performance. Nevertheless, the point annotation needs to be marked by experienced pathologists. In order to take advantage of segmentation methods based on point annotation, further alleviate the manual workload, and make cancer diagnosis more efficient and accurate, it is necessary to develop an automatic nucleus detection algorithm, which can automatically and efficiently locate the position of the nucleus in the pathological image and extract valuable information for pathologists. In this paper, we propose a W-shaped network for automatic nucleus detection. Different from the traditional U-Net based method, mapping the original pathology image to the target mask directly, our proposed method split the detection task into two sub-tasks. The first sub-task maps the original pathology image to the binary mask, then the binary mask is mapped to the density mask in the second sub-task. After the task is split, the task's difficulty is significantly reduced, and the network's overall performance is improved.

Jialun Wu, Haichuan Zhang, Zeyu Gao et al.

Diagnostic pathology, which is the basis and gold standard of cancer diagnosis, provides essential information on the prognosis of the disease and vital evidence for clinical treatment. Tumor region detection, subtype and grade classification are the fundamental diagnostic indicators for renal cell carcinoma (RCC) in whole-slide images (WSIs). However, pathological diagnosis is subjective, differences in observation and diagnosis between pathologists is common in hospitals with inadequate diagnostic capacity. The main challenge for developing deep learning based RCC diagnostic system is the lack of large-scale datasets with precise annotations. In this work, we proposed a deep learning-based framework for analyzing histopathological images of patients with renal cell carcinoma, which has the potential to achieve pathologist-level accuracy in diagnosis. A deep convolutional neural network (InceptionV3) was trained on the high-quality annotated dataset of The Cancer Genome Atlas (TCGA) whole-slide histopathological image for accurate tumor area detection, classification of RCC subtypes, and ISUP grades classification of clear cell carcinoma subtypes. These results suggest that our framework can help pathologists in the detection of cancer region and classification of subtypes and grades, which could be applied to any cancer type, providing auxiliary diagnosis and promoting clinical consensus.

Zeyu Gao, Bangyang Hong, Xianli Zhang et al.

Histological subtype of papillary (p) renal cell carcinoma (RCC), type 1 vs. type 2, is an essential prognostic factor. The two subtypes of pRCC have a similar pattern, i.e., the papillary architecture, yet some subtle differences, including cellular and cell-layer level patterns. However, the cellular and cell-layer level patterns almost cannot be captured by existing CNN-based models in large-size histopathological images, which brings obstacles to directly applying these models to such a fine-grained classification task. This paper proposes a novel instance-based Vision Transformer (i-ViT) to learn robust representations of histopathological images for the pRCC subtyping task by extracting finer features from instance patches (by cropping around segmented nuclei and assigning predicted grades). The proposed i-ViT takes top-K instances as input and aggregates them for capturing both the cellular and cell-layer level patterns by a position-embedding layer, a grade-embedding layer, and a multi-head multi-layer self-attention module. To evaluate the performance of the proposed framework, experienced pathologists are invited to selected 1162 regions of interest from 171 whole slide images of type 1 and type 2 pRCC. Experimental results show that the proposed method achieves better performance than existing CNN-based models with a significant margin.

Zeyu Gao, Jiangbo Shi, Xianli Zhang et al.

The grade of clear cell renal cell carcinoma (ccRCC) is a critical prognostic factor, making ccRCC nuclei grading a crucial task in RCC pathology analysis. Computer-aided nuclei grading aims to improve pathologists' work efficiency while reducing their misdiagnosis rate by automatically identifying the grades of tumor nuclei within histopathological images. Such a task requires precisely segment and accurately classify the nuclei. However, most of the existing nuclei segmentation and classification methods can not handle the inter-class similarity property of nuclei grading, thus can not be directly applied to the ccRCC grading task. In this paper, we propose a Composite High-Resolution Network for ccRCC nuclei grading. Specifically, we propose a segmentation network called W-Net that can separate the clustered nuclei. Then, we recast the fine-grained classification of nuclei to two cross-category classification tasks, based on two high-resolution feature extractors (HRFEs) which are proposed for learning these two tasks. The two HRFEs share the same backbone encoder with W-Net by a composite connection so that meaningful features for the segmentation task can be inherited for the classification task. Last, a head-fusion block is applied to generate the predicted label of each nucleus. Furthermore, we introduce a dataset for ccRCC nuclei grading, containing 1000 image patches with 70945 annotated nuclei. We demonstrate that our proposed method achieves state-of-the-art performance compared to existing methods on this large ccRCC grading dataset.

Zeyu Gao, Pargorn Puttapirat, Jiangbo Shi et al.

Obtaining a large amount of labeled data in medical imaging is laborious and time-consuming, especially for histopathology. However, it is much easier and cheaper to get unlabeled data from whole-slide images (WSIs). Semi-supervised learning (SSL) is an effective way to utilize unlabeled data and alleviate the need for labeled data. For this reason, we proposed a framework that employs an SSL method to accurately detect cancerous regions with a novel annotation method called Minimal Point-Based annotation, and then utilize the predicted results with an innovative hybrid loss to train a classification model for subtyping. The annotator only needs to mark a few points and label them are cancer or not in each WSI. Experiments on three significant subtypes of renal cell carcinoma (RCC) proved that the performance of the classifier trained with the Min-Point annotated dataset is comparable to a classifier trained with the segmentation annotated dataset for cancer region detection. And the subtyping model outperforms a model trained with only diagnostic labels by 12% in terms of f1-score for testing WSIs.

Jiangbo Shi, Zeyu Gao, Haichuan Zhang et al.

Pathological is crucial to cancer diagnosis. Usually, Pathologists draw their conclusion based on observed cell and tissue structure on histology slides. Rapid development in machine learning, especially deep learning have established robust and accurate classifiers. They are being used to analyze histopathological slides and assist pathologists in diagnosis. Most machine learning systems rely heavily on annotated data sets to gain experiences and knowledge to correctly and accurately perform various tasks such as classification and segmentation. This work investigates different granularity of annotations in histopathological data set including image-wise, bounding box, ellipse-wise, and pixel-wise to verify the influence of annotation in pathological slide on deep learning models. We design corresponding experiments to test classification and segmentation performance of deep learning models based on annotations with different annotation granularity. In classification, state-of-the-art deep learning-based classifiers perform better when trained by pixel-wise annotation dataset. On average, precision, recall and F1-score improves by 7.87%, 8.83% and 7.85% respectively. Thus, it is suggested that finer granularity annotations are better utilized by deep learning algorithms in classification tasks. Similarly, semantic segmentation algorithms can achieve 8.33% better segmentation accuracy when trained by pixel-wise annotations. Our study shows not only that finer-grained annotation can improve the performance of deep learning models, but also help extracts more accurate phenotypic information from histopathological slides. Intelligence systems trained on granular annotations may help pathologists inspecting certain regions for better diagnosis. The compartmentalized prediction approach similar to this work may contribute to phenotype and genotype association studies.