Comparing generative and retrieval-based chatbots in answering patient questions regarding age-related macular degeneration and diabetic retinopathy.

BACKGROUND/AIMS: To compare the performance of generative versus retrieval-based chatbots in answering patient inquiries regarding age-related macular degeneration (AMD) and diabetic retinopathy (DR). METHODS: We evaluated four chatbots: generative models (ChatGPT-4, ChatGPT-3.5 and Google Bard) and a retrieval-based model (OcularBERT) in a cross-sectional study. Their response accuracy to 45 questions (15 AMD, 15 DR and 15 others) was evaluated and compared. Three masked retinal specialists graded the responses using a three-point Likert scale: either 2 (good, error-free), 1 (borderline) or 0 (poor with significant inaccuracies). The scores were aggregated, ranging from 0 to 6. Based on majority consensus among the graders, the responses were also classified as 'Good', 'Borderline' or 'Poor' quality. RESULTS: Overall, ChatGPT-4 and ChatGPT-3.5 outperformed the other chatbots, both achieving median scores (IQR) of 6 (1), compared with 4.5 (2) in Google Bard, and 2 (1) in OcularBERT (all p ≤8.4×10-3). Based on the consensus approach, 83.3% of ChatGPT-4's responses and 86.7% of ChatGPT-3.5's were rated as 'Good', surpassing Google Bard (50%) and OcularBERT (10%) (all p ≤1.4×10-2). ChatGPT-4 and ChatGPT-3.5 had no 'Poor' rated responses. Google Bard produced 6.7% Poor responses, and OcularBERT produced 20%. Across question types, ChatGPT-4 outperformed Google Bard only for AMD, and ChatGPT-3.5 outperformed Google Bard for DR and others. CONCLUSION: ChatGPT-4 and ChatGPT-3.5 demonstrated superior performance, followed by Google Bard and OcularBERT. Generative chatbots are potentially capable of answering domain-specific questions outside their original training. Further validation studies are still required prior to real-world implementation.

Management of corneal neovascularization: Current and emerging therapeutic approaches.

Corneal neovascularization (CoNV) is a sight-threatening condition affecting an estimated 1.4 million people per year, and the incidence is expected to rise. It is a complication of corneal pathological diseases such as infective keratitis, chemical burn, corneal limbal stem cell deficiency, mechanical trauma, and immunological rejection after keratoplasties. CoNV occurs due to a disequilibrium in proangiogenic and antiangiogenic mediators, involving a complex system of molecular interactions. Treatment of CoNV is challenging, and no therapy thus far has been curative. Anti-inflammatory agents such as corticosteroids are the mainstay of treatment due to their accessibility and well-studied safety profile. However, they have limited effectiveness and are unable to regress more mature neovascularization. With the advent of advanced imaging modalities and an expanding understanding of its pathogenesis, contemporary treatments targeting a wide array of molecular mechanisms and surgical options are gaining traction. This review aims to summarize evidence regarding conventional and emerging therapeutic options for CoNV.

ArCH: improving the performance of clonal hematopoiesis variant calling and interpretation.

MOTIVATION: The acquisition of somatic mutations in hematopoietic stem and progenitor stem cells with resultant clonal expansion, termed clonal hematopoiesis (CH), is associated with increased risk of hematologic malignancies and other adverse outcomes. CH is generally present at low allelic fractions, but clonal expansion and acquisition of additional mutations leads to hematologic cancers in a small proportion of individuals. With high depth and high sensitivity sequencing, CH can be detected in most adults and its clonal trajectory mapped over time. However, accurate CH variant calling is challenging due to the difficulty in distinguishing low frequency CH mutations from sequencing artifacts. The lack of well-validated bioinformatic pipelines for CH calling may contribute to lack of reproducibility in studies of CH. RESULTS: Here, we developed ArCH, an Artifact filtering Clonal Hematopoiesis variant calling pipeline for detecting single nucleotide variants and short insertions/deletions by combining the output of four variant calling tools and filtering based on variant characteristics and sequencing error rate estimation. ArCH is an end-to-end cloud-based pipeline optimized to accept a variety of inputs with customizable parameters adaptable to multiple sequencing technologies, research questions, and datasets. Using deep targeted sequencing data generated from six acute myeloid leukemia patient tumor: normal dilutions, 31 blood samples with orthogonal validation, and 26 blood samples with technical replicates, we show that ArCH improves the sensitivity and positive predictive value of CH variant detection at low allele frequencies compared to standard application of commonly used variant calling approaches. AVAILABILITY AND IMPLEMENTATION: The code for this workflow is available at: https://github.com/kbolton-lab/ArCH.

Rationale and protocol paper for the Asia Pacific Network for inherited eye diseases.

PURPOSE: There are major gaps in our knowledge of hereditary ocular conditions in the Asia-Pacific population, which comprises approximately 60% of the world's population. Therefore, a concerted regional effort is urgently needed to close this critical knowledge gap and apply precision medicine technology to improve the quality of lives of these patients in the Asia-Pacific region. DESIGN: Multi-national, multi-center collaborative network. METHODS: The Research Standing Committee of the Asia-Pacific Academy of Ophthalmology and the Asia-Pacific Society of Eye Genetics fostered this research collaboration, which brings together renowned institutions and experts for inherited eye diseases in the Asia-Pacific region. The immediate priority of the network will be inherited retinal diseases (IRDs), where there is a lack of detailed characterization of these conditions and in the number of established registries. RESULTS: The network comprises 55 members from 35 centers, spanning 12 countries and regions, including Australia, China, India, Indonesia, Japan, South Korea, Malaysia, Nepal, Philippines, Singapore, Taiwan, and Thailand. The steering committee comprises ophthalmologists with experience in consortia for eye diseases in the Asia-Pacific region, leading ophthalmologists and vision scientists in the field of IRDs internationally, and ophthalmic geneticists. CONCLUSIONS: The Asia Pacific Inherited Eye Disease (APIED) network aims to (1) improve genotyping capabilities and expertise to increase early and accurate genetic diagnosis of IRDs, (2) harmonise deep phenotyping practices and utilization of ontological terms, and (3) establish high-quality, multi-user, federated disease registries that will facilitate patient care, genetic counseling, and research of IRDs regionally and internationally.

Popular large language model chatbots' accuracy, comprehensiveness, and self-awareness in answering ocular symptom queries.

In light of growing interest in using emerging large language models (LLMs) for self-diagnosis, we systematically assessed the performance of ChatGPT-3.5, ChatGPT-4.0, and Google Bard in delivering proficient responses to 37 common inquiries regarding ocular symptoms. Responses were masked, randomly shuffled, and then graded by three consultant-level ophthalmologists for accuracy (poor, borderline, good) and comprehensiveness. Additionally, we evaluated the self-awareness capabilities (ability to self-check and self-correct) of the LLM-Chatbots. 89.2% of ChatGPT-4.0 responses were 'good'-rated, outperforming ChatGPT-3.5 (59.5%) and Google Bard (40.5%) significantly (all p < 0.001). All three LLM-Chatbots showed optimal mean comprehensiveness scores as well (ranging from 4.6 to 4.7 out of 5). However, they exhibited subpar to moderate self-awareness capabilities. Our study underscores the potential of ChatGPT-4.0 in delivering accurate and comprehensive responses to ocular symptom inquiries. Future rigorous validation of their performance is crucial to ensure their reliability and appropriateness for actual clinical use.

Mechanisms and clinical relevance of the bidirectional relationship of viral infections with metabolic diseases.

Viruses have been present during all evolutionary steps on earth and have had a major effect on human history. Viral infections are still among the leading causes of death. Another public health concern is the increase of non-communicable metabolic diseases in the last four decades. In this Review, we revisit the scientific evidence supporting the presence of a strong bidirectional feedback loop between several viral infections and metabolic diseases. We discuss how viruses might lead to the development or progression of metabolic diseases and conversely, how metabolic diseases might increase the severity of a viral infection. Furthermore, we discuss the clinical relevance of the current evidence on the relationship between viral infections and metabolic disease and the present and future challenges that should be addressed by the scientific community and health authorities.

Dysfunctional Autophagy, Proteostasis, and Mitochondria as a Prelude to Age-Related Macular Degeneration.

Retinal pigment epithelial (RPE) cell dysfunction is a key driving force of AMD. RPE cells form a metabolic interface between photoreceptors and choriocapillaris, performing essential functions for retinal homeostasis. Through their multiple functions, RPE cells are constantly exposed to oxidative stress, which leads to the accumulation of damaged proteins, lipids, nucleic acids, and cellular organelles, including mitochondria. As miniature chemical engines of the cell, self-replicating mitochondria are heavily implicated in the aging process through a variety of mechanisms. In the eye, mitochondrial dysfunction is strongly associated with several diseases, including age-related macular degeneration (AMD), which is a leading cause of irreversible vision loss in millions of people globally. Aged mitochondria exhibit decreased rates of oxidative phosphorylation, increased reactive oxygen species (ROS) generation, and increased numbers of mitochondrial DNA mutations. Mitochondrial bioenergetics and autophagy decline during aging because of insufficient free radical scavenger systems, the impairment of DNA repair mechanisms, and reductions in mitochondrial turnover. Recent research has uncovered a much more complex role of mitochondrial function and cytosolic protein translation and proteostasis in AMD pathogenesis. The coupling of autophagy and mitochondrial apoptosis modulates the proteostasis and aging processes. This review aims to summarise and provide a perspective on (i) the current evidence of autophagy, proteostasis, and mitochondrial dysfunction in dry AMD; (ii) current in vitro and in vivo disease models relevant to assessing mitochondrial dysfunction in AMD, and their utility in drug screening; and (iii) ongoing clinical trials targeting mitochondrial dysfunction for AMD therapeutics.

Measuring Caspase Activity Using a Fluorometric Assay or Flow Cytometry.

The activation of cysteine proteases, known as caspases, remains an important process in multiple forms of cell death. Caspases are critical initiators and executioners of apoptosis, the most studied form of programmed cell death. Apoptosis occurs during developmental processes and is a necessary event in tissue homeostasis. Pyroptosis is another form of cell death that utilizes caspases and is a critical process in activating the immune system through the activation of the inflammasome, which results in the release of members of the interleukin-1 (IL-1) family. To assess caspase activity, target substrates can be assessed. However, sensitivity can be an issue when examining single cells or low-level activity. We demonstrate how a fluorogenic substrate can be used with a population-based assay or single-cell assay by flow cytometry. With proper controls, different amino acid sequences can be used to identify which caspases are active. Using these assays, the simultaneous loss of the inhibitors of apoptosis proteins upon tumor necrosis factor (TNF) stimulation has been identified, which primarily induces apoptosis in macrophages rather than other forms of cell death.

Understanding National Nonprofit Data Environments.

We develop the concept of the nonprofit data environment as all data collected and reported in a country resulting from law implemented into practice. We map data environments across 20 countries and propose explanations for differences between the information nongovernmental organizations report (collected) and what is made publicly available (reported). Domestic factors including regime type, civil society autonomy, and regulatory quality increase the amount of information collected and released publicly. Exposure to international political forces, including aid flows and globalization, increases the gap, which runs counter to expectations of greater openness with global engagement. Our findings point to the need for a better understanding of patterns in non-profit organizations (NPOs) data environments; while all governments collect information, countries with similar legal codes have widely varying data environments. This matters for NPOs as their ability to learn and improve depends on access to quality data and coincides with a feared global political backlash.

Analysis of the pachychoroid phenotype in an Asian population: methodology and baseline study population characteristics.

AIM: To describe the clinical characteristics in a cohort of patients with the pachychoroid phenotype and to evaluate the association of ocular and systemic factors with type of complications observed. METHODS: We report baseline findings from a prospective observational study which recruited subjects with subfoveal choroidal thickness (SFCT) of ≥300 µm on spectral-domain optical coherence tomography (OCT). Multimodal imaging was used to classify eyes as uncomplicated pachychoroid (UP) or pachychoroid disease with pachychoroid pigment epitheliopathy (PPE), central serous chorioretinopathy (CSC) or pachychoroid neovasculopathy (PNV) subtypes. RESULTS: Among 181 eyes of 109 participants (mean age 60.6 years, 33 (30.3%) female, 95 (7.2%) Chinese), 38 eyes (21.0%) had UP. Of 143 eyes (79.0%) with pachychoroid disease, 82 (45.3%), 41 (22.7%) and 20 (11.0%) had PPE, CSC and PNV, respectively. Addition of autofluorescence and OCT angiography to structural OCT led to reclassification of 31 eyes to a more severe category. Systemic and ocular factors evaluated, including SFCT, were not associated with disease severity. Comparison of PPE, CSC and PNV eyes showed no significant difference in OCT features of retinal pigment epithelial (RPE) dysfunction, but disruption of the ellipsoid zone (PPE 30.5% vs CSC 70.7% vs PNV 60%, p<0.001) and thinning of inner nuclear/inner plexiform layers (PPE 7.3% vs CSC 36.6% vs PNV 35%, p<0.001) were more frequent in CSC and PNV eyes. CONCLUSIONS: These cross-sectional associations suggest pachychoroid disease manifestations may reflect progressive decompensation from the choroid to the RPE then retinal layers. Planned follow-up of this cohort will be beneficial in clarifying the natural history of the pachychoroid phenotype.

Moving Toward Findable, Accessible, Interoperable, Reusable Practices in Epidemiologic Research.

Data sharing is essential for reproducibility of epidemiologic research, replication of findings, pooled analyses in consortia efforts, and maximizing study value to address multiple research questions. However, barriers related to confidentiality, costs, and incentives often limit the extent and speed of data sharing. Epidemiological practices that follow Findable, Accessible, Interoperable, Reusable (FAIR) principles can address these barriers by making data resources findable with the necessary metadata, accessible to authorized users, and interoperable with other data, to optimize the reuse of resources with appropriate credit to its creators. We provide an overview of these principles and describe approaches for implementation in epidemiology. Increasing degrees of FAIRness can be achieved by moving data and code from on-site locations to remote, accessible ("Cloud") data servers, using machine-readable and nonproprietary files, and developing open-source code. Adoption of these practices will improve daily work and collaborative analyses and facilitate compliance with data sharing policies from funders and scientific journals. Achieving a high degree of FAIRness will require funding, training, organizational support, recognition, and incentives for sharing research resources, both data and code. However, these costs are outweighed by the benefits of making research more reproducible, impactful, and equitable by facilitating the reuse of precious research resources by the scientific community.

GWAS Explorer: an open-source tool to explore, visualize, and access GWAS summary statistics in the PLCO Atlas.

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is a prospective cohort study of nearly 155,000 U.S. volunteers aged 55-74 at enrollment in 1993-2001. We developed the PLCO Atlas Project, a large resource for multi-trait genome-wide association studies (GWAS), by genotyping participants with available DNA and genomic consent. Genotyping on high-density arrays and imputation was performed, and GWAS were conducted using a custom semi-automated pipeline. Association summary statistics were generated from a total of 110,562 participants of European, African and Asian ancestry. Application programming interfaces (APIs) and open-source software development kits (SKDs) enable exploring, visualizing and open data access through the PLCO Atlas GWAS Explorer website, promoting Findable, Accessible, Interoperable, and Re-usable (FAIR) principles. Currently the GWAS Explorer hosts association data for 90 traits and >78,000,000 genomic markers, focusing on cancer and cancer-related phenotypes. New traits will be posted as association data becomes available. The PLCO Atlas is a FAIR resource of high-quality genetic and phenotypic data with many potential reuse opportunities for cancer research and genetic epidemiology.

Magnetic resonance imaging of disorders with white matter changes in children and adolescents: a pictorial essay.

White matter changes are seen in a spectrum of disorders in children and adolescents. Understanding their distribution and appearance helps to reach diagnoses in daily radiologic practice. This pictorial essay will outline the magnetic resonance imaging (MRI) appearances of diseases with white matter changes including demyelinating diseases, dysmyelinating disorders/leukodystrophies, infections, autoimmune diseases, vascular causes, mitochondrial disorders and neurocutaneous syndromes, along with a brief overview of clinical aspects of the diseases such as typical age of presentation, etiology, symptoms and signs and treatment options. This article highlights important features in common white matter diseases in children and adolescents.

Membrane Protein Modification Modulates Big and Small Extracellular Vesicle Biodistribution and Tumorigenic Potential in Breast Cancers In Vivo.

Extracellular vesicles (EVs) are released by cells to mediate intercellular communication under pathological and physiological conditions. While small EVs (sEVs; <100-200 nm, exosomes) are intensely investigated, the properties and functions of medium and large EVs (big EVs (bEVs); >200 nm, microvesicles) are less well explored. Here, bEVs and sEVs are identified as distinct EV populations, and it is determined that bEVs are released in a greater bEV:sEV ratio in the aggressive human triple-negative breast cancer (TNBC) subtype. PalmGRET, bioluminescence-resonance-energy-transfer (BRET)-based EV reporter, reveals dose-dependent EV biodistribution at nonlethal and physiological EV dosages, as compared to lipophilic fluorescent dyes. Remarkably, the bEVs and sEVs exhibit unique biodistribution profiles, yet individually promote in vivo tumor growth in a syngeneic immunocompetent TNBC breast tumor murine model. The bEVs and sEVs share mass-spectrometry-identified tumor-progression-associated EV surface membrane proteins (tpEVSurfMEMs), which include solute carrier family 29 member 1, Cd9, and Cd44. tpEVSurfMEM depletion attenuates EV lung organotropism, alters biodistribution, and reduces protumorigenic potential. This study identifies distinct in vivo property and function of bEVs and sEVs in breast cancer, which suggest the significant role of bEVs in diseases, diagnostic and therapeutic applications.

Treat and extend regimen for diabetic macular oedema-a systematic review and meta-analysis.

PURPOSE: Various treatment regimens are currently practiced in the treatment of CI-DMO (centre-involving diabetic macular oedema). In recent years, there has been a growing body of evidence supporting a treat and extend (T&E) regimen for DMO which offers the promise of comparable visual and anatomical outcomes while reducing injection burden. This meta-analysis was hence performed to evaluate the aforementioned outcomes in the treatment of DMO. Ten studies met the inclusion criteria. METHODS: A search of PubMed, MEDLINE, Current Contents, and Cochrane Central Register of Controlled Trials (CENTRAL) databases was performed. We employed the terms 'treat AND extend AND (diabetic AND macular AND edema OR oedema)' to ensure a comprehensive search. The search workflow adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. RESULTS: The pooled analysis of the mean number of injections in 1 year for T&E-aflibercept (AFL), T&E-ranibizumab (RBZ) and collectively was 9.1 (95% CI: 7.63-10.63), 10.0 (95% CI: 9.55-10.47) and 9.6 (95% CI: 8.62-10.49), respectively. Improvements in vision at 1 year for T&E-AFL, T&E-RBZ and collectively were 6.26 (95% CI: 3.24-9.29), 7.14 (95% CI: 4.76-9.52) and 7.08 (95% CI: 5.32-8.84) letters, respectively. The improvements in central subfield thickness at 1 year for T&E-AFL, T&E-RBZ and collectively were 131.94 (95% CI: 100.29-163.60), 108.64 (95% CI: 82.82-134.46) and 121.32 (95% CI: 102.89-139.75) microns, respectively. CONCLUSION: The meta-analysis of T&E for DMO did not show a clear advantage in reducing the number of injections compared to landmark clinical trials with pro-re-nata (PRN) treatment regimens in the first year of treatment with limited gains in visual and anatomical outcomes. However, the T&E approach offers the potential for fewer patient visits, thereby reducing treatment burden. Longer term studies on T&E with a standardised protocol would be required to assess the longevity of the vision gain in the first year despite a likely reduced treatment burden compared to the PRN trials.

Epstein Barr virus-mediated transformation of B cells from XIAP-deficient patients leads to increased expression of the tumor suppressor CADM1.

X-linked lymphoproliferative disease (XLP) is either caused by loss of the SLAM-associated protein (SAP; XLP-1) or the X-linked inhibitor of apoptosis (XIAP; XLP-2). In both instances, infection with the oncogenic human Epstein Barr virus (EBV) leads to pathology, but EBV-associated lymphomas only emerge in XLP-1 patients. Therefore, we investigated the role of XIAP during B cell transformation by EBV. Using humanized mice, IAP inhibition in EBV-infected mice led to a loss of B cells and a tendency to lower viral titers and lymphomagenesis. Loss of memory B cells was also observed in four newly described patients with XIAP deficiency. EBV was able to transform their B cells into lymphoblastoid cell lines (LCLs) with similar growth characteristics to patient mothers' LCLs in vitro and in vivo. Gene expression analysis revealed modest elevated lytic EBV gene transcription as well as the expression of the tumor suppressor cell adhesion molecule 1 (CADM1). CADM1 expression on EBV-infected B cells might therefore inhibit EBV-associated lymphomagenesis in patients and result in the absence of EBV-associated malignancies in XLP-2 patients.

PLCOjs, a FAIR GWAS web SDK for the NCI Prostate, Lung, Colorectal and Ovarian Cancer Genetic Atlas project.

MOTIVATION: The Division of Cancer Epidemiology and Genetics (DCEG) and the Division of Cancer Prevention (DCP) at the National Cancer Institute (NCI) have recently generated genome-wide association study (GWAS) data for multiple traits in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Genomic Atlas project. The GWAS included 110 000 participants. The dissemination of the genetic association data through a data portal called GWAS Explorer, in a manner that addresses the modern expectations of FAIR reusability by data scientists and engineers, is the main motivation for the development of the open-source JavaScript software development kit (SDK) reported here. RESULTS: The PLCO GWAS Explorer resource relies on a public stateless HTTP application programming interface (API) deployed as the sole backend service for both the landing page's web application and third-party analytical workflows. The core PLCOjs SDK is mapped to each of the API methods, and also to each of the reference graphic visualizations in the GWAS Explorer. A few additional visualization methods extend it. As is the norm with web SDKs, no download or installation is needed and modularization supports targeted code injection for web applications, reactive notebooks (Observable) and node-based web services. AVAILABILITY AND IMPLEMENTATION: code at https://github.com/episphere/plco; project page at https://episphere.github.io/plco.

Navigating communication between conventional medicine and traditional Chinese medicine: a case study of cancer patients in Hong Kong.

BACKGROUND: Traditional Chinese medicine (TCM) is a growing phenomenon worldwide. Despite its historical role in Chinese society, however, few studies have explored the nature of communication among patients with cancer who receive TCM care in addition to conventional medicine. If TCM practitioners acquire adequate knowledge to understand the needs and communication issues for their patients with cancer, particularly those who are simultaneously receiving conventional medicine, this will lead to better quality of care and clinical outcomes, such as high patient satisfaction and treatment compliance. OBJECTIVES: To fill this knowledge gap, this study explored the nature of communication among patients with cancer in Hong Kong who receive TCM treatment in addition to conventional medicine. PARTICIPANTS: We conducted in-depth interviews with 20 patients, 5 oncologists and 5 TCM practitioners to elicit their views on TCM treatments. METHOD: We adopted a qualitative approach using an interpretative phenomenological analysis. RESULTS: Based on the themes that emerged from our interview transcripts, we outlined communication priorities when advising patients with cancer who are receiving both TCM and conventional medical care. We developed a framework to train TCM practitioners to better integrate their patients' conventional medical history when delivering patient care. CONCLUSIONS: Our study findings inform communication priorities when caring for patients who opt for TCM care in addition to conventional treatments. In addition, they provide useful information for developing future clinical research studies to explore integrated approaches between TCM and conventional medicine in treating patients with cancer.

Development and evaluation of short form of constitution in Chinese medicine questionnaire: a national epidemiological survey data of 21 948 case.

OBJECTIVE: To develop the best short form of constitution in Chinese medicine questionnaire (CCMQ) and evaluate its psychometric properties in Chinese population. METHODS: A total of 21 948 subjects were used to refine the short form. Correlation coefficient, exploratory factor analysis (EFA) and Cronbach's alpha coefficient were used to analyze and select items to form the short form. Separate sample of 205 subjects were collected to further evaluate the short from. EFA, confirmatory factor analysis (CFA), item-scale correlation, discriminant validity, internal consistency reliability and split-half reliability were carried out to evaluate the short form. RESULTS: The short form CCMQ included 26 items. Seven common factors of characteristic root > 1 were extracted to explain 58.488% of the total variation. Result of CFA was consistent with the 9-factors structure. The mean differences of Blood-stasis body constitution and Qi-stagnation body constitution had statistical significance in body mass index differentiation. Cronbach's alpha coefficient of short form CCMQ was 0.863. The split-half reliability of total scale was 0.813, and each scale was 0.568-0.770. The item-scale correlations ranged from 0.620-0.849. CONCLUSION: The short form CCMQ consisted of 26 items with good psychometric properties. The short form should be recommended for the measurement of health of Chinese population in any clinical trial.

Protein interaction networks define the genetic architecture of preterm birth.

The likely genetic architecture of complex diseases is that subgroups of patients share variants in genes in specific networks sufficient to express a shared phenotype. We combined high throughput sequencing with advanced bioinformatic approaches to identify such subgroups of patients with variants in shared networks. We performed targeted sequencing of patients with 2 or 3 generations of preterm birth on genes, gene sets and haplotype blocks that were highly associated with preterm birth. We analyzed the data using a multi-sample, protein-protein interaction (PPI) tool to identify significant clusters of patients associated with preterm birth. We identified shared protein interaction networks among preterm cases in two statistically significant clusters, p < 0.001. We also found two small control-dominated clusters. We replicated these data on an independent, large birth cohort. Separation testing showed significant similarity scores between the clusters from the two independent cohorts of patients. Canonical pathway analysis of the unique genes defining these clusters demonstrated enrichment in inflammatory signaling pathways, the glucocorticoid receptor, the insulin receptor, EGF and B-cell signaling, These results support a genetic architecture defined by subgroups of patients that share variants in genes in specific networks and pathways which are sufficient to give rise to the disease phenotype.