The evolving privacy and security concerns for genomic data analysis and sharing as observed from the iDASH competition.

Concerns regarding inappropriate leakage of sensitive personal information as well as unauthorized data use are increasing with the growth of genomic data repositories. Therefore, privacy and security of genomic data have become increasingly important and need to be studied. With many proposed protection techniques, their applicability in support of biomedical research should be well understood. For this purpose, we have organized a community effort in the past 8 years through the integrating data for analysis, anonymization and sharing consortium to address this practical challenge. In this article, we summarize our experience from these competitions, report lessons learned from the events in 2020/2021 as examples, and discuss potential future research directions in this emerging field.

Benchmarking blockchain-based gene-drug interaction data sharing methods: A case study from the iDASH 2019 secure genome analysis competition blockchain track.

BACKGROUND: Blockchain distributed ledger technology is just starting to be adopted in genomics and healthcare applications. Despite its increased prevalence in biomedical research applications, skepticism regarding the practicality of blockchain technology for real-world problems is still strong and there are few implementations beyond proof-of-concept. We focus on benchmarking blockchain strategies applied to distributed methods for sharing records of gene-drug interactions. We expect this type of sharing will expedite personalized medicine. BASIC PROCEDURES: We generated gene-drug interaction test datasets using the Clinical Pharmacogenetics Implementation Consortium (CPIC) resource. We developed three blockchain-based methods to share patient records on gene-drug interactions: Query Index, Index Everything, and Dual-Scenario Indexing. MAIN FINDINGS: We achieved a runtime of about 60 s for importing 4,000 gene-drug interaction records from four sites, and about 0.5 s for a data retrieval query. Our results demonstrated that it is feasible to leverage blockchain as a new platform to share data among institutions. PRINCIPAL CONCLUSIONS: We show the benchmarking results of novel blockchain-based methods for institutions to share patient outcomes related to gene-drug interactions. Our findings support blockchain utilization in healthcare, genomic and biomedical applications. The source code is publicly available at https://github.com/tsungtingkuo/genedrug.

Cancer3D 2.0: interactive analysis of 3D patterns of cancer mutations in cancer subsets.

Our knowledge of cancer genomics exploded in last several years, providing us with detailed knowledge of genetic alterations in almost all cancer types. Analysis of this data gave us new insights into molecular aspects of cancer, most important being the amazing diversity of molecular abnormalities in individual cancers. The most important question in cancer research today is how to classify this diversity to identify subtypes that are most relevant for treatment and outcome prediction for individual patients. The Cancer3D database at http://www.cancer3d.org gives an open and user-friendly way to analyze cancer missense mutations in the context of structures of proteins they are found in and in relation to patients' clinical data. This approach allows users to find novel candidate driver regions for specific subgroups, that often cannot be found when similar analyses are done on the whole gene level and for large, diverse cohorts. Interactive interface allows user to visualize the distribution of mutations in subgroups defined by cancer type and stage, gender and age brackets, patient's ethnicity or vice versa find dominant cancer type, gender or age groups for specific three-dimensional mutation patterns.

Elicitation of Robust Tier 2 Neutralizing Antibody Responses in Nonhuman Primates by HIV Envelope Trimer Immunization Using Optimized Approaches.

The development of stabilized recombinant HIV envelope trimers that mimic the virion surface molecule has increased enthusiasm for a neutralizing antibody (nAb)-based HIV vaccine. However, there is limited experience with recombinant trimers as immunogens in nonhuman primates, which are typically used as a model for humans. Here, we tested multiple immunogens and immunization strategies head-to-head to determine their impact on the quantity, quality, and kinetics of autologous tier 2 nAb development. A bilateral, adjuvanted, subcutaneous immunization protocol induced reproducible tier 2 nAb responses after only two immunizations 8 weeks apart, and these were further enhanced by a third immunization with BG505 SOSIP trimer. We identified immunogens that minimized non-neutralizing V3 responses and demonstrated that continuous immunogen delivery could enhance nAb responses. nAb responses were strongly associated with germinal center reactions, as assessed by lymph node fine needle aspiration. This study provides a framework for preclinical and clinical vaccine studies targeting nAb elicitation.

bNAber: database of broadly neutralizing HIV antibodies.

The discovery of broadly neutralizing antibodies (bNAbs) has provided an enormous impetus to the HIV vaccine research and to entire immunology. The bNAber database at http://bNAber.org provides open, user-friendly access to detailed data on the rapidly growing list of HIV bNAbs, including neutralization profiles, sequences and three-dimensional structures (when available). It also provides an extensive list of visualization and analysis tools, such as heatmaps to analyse neutralization data as well as structure and sequence viewers to correlate bNAbs properties with structural and sequence features of individual antibodies. The goal of the bNAber database is to enable researchers in this field to easily compare and analyse available information on bNAbs thereby supporting efforts to design an effective vaccine for HIV/AIDS. The bNAber database not only provides easy access to data that currently is scattered in the Supplementary Materials sections of individual papers, but also contributes to the development of general standards of data that have to be presented with the discovery of new bNAbs and a universal mechanism of how such data can be shared.

A novel mode of Gleevec binding is revealed by the structure of spleen tyrosine kinase.

Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase required for signaling from immunoreceptors in various hematopoietic cells. Phosphorylation of two tyrosine residues in the activation loop of the Syk kinase catalytic domain is necessary for signaling, a phenomenon typical of tyrosine kinase family members. Syk in vitro enzyme activity, however, does not depend on phosphorylation (activation loop tyrosine --> phenylalanine mutants retain catalytic activity). We have determined the x-ray structure of the unphosphorylated form of the kinase catalytic domain of Syk. The enzyme adopts a conformation of the activation loop typically seen only in activated, phosphorylated tyrosine kinases, explaining why Syk does not require phosphorylation for activation. We also demonstrate that Gleevec (STI-571, Imatinib) inhibits the isolated kinase domains of both unphosphorylated Syk and phosphorylated Abl with comparable potency. Gleevec binds Syk in a novel, compact cis-conformation that differs dramatically from the binding mode observed with unphosphorylated Abl, the more Gleevec-sensitive form of Abl. This finding suggests the existence of two distinct Gleevec binding modes: an extended, trans-conformation characteristic of tight binding to the inactive conformation of a protein kinase and a second compact, cis-conformation characteristic of weaker binding to the active conformation. Finally, the Syk-bound cis-conformation of Gleevec bears a striking resemblance to the rigid structure of the nonspecific, natural product kinase inhibitor staurosporine.

Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator.

Cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding cassette (ABC) transporter that functions as a chloride channel. Nucleotide-binding domain 1 (NBD1), one of two ABC domains in CFTR, also contains sites for the predominant CF-causing mutation and, potentially, for regulatory phosphorylation. We have determined crystal structures for mouse NBD1 in unliganded, ADP- and ATP-bound states, with and without phosphorylation. This NBD1 differs from typical ABC domains in having added regulatory segments, a foreshortened subdomain interconnection, and an unusual nucleotide conformation. Moreover, isolated NBD1 has undetectable ATPase activity and its structure is essentially the same independent of ligand state. Phe508, which is commonly deleted in CF, is exposed at a putative NBD1-transmembrane interface. Our results are consistent with a CFTR mechanism, whereby channel gating occurs through ATP binding in an NBD1-NBD2 nucleotide sandwich that forms upon displacement of NBD1 regulatory segments.