ISA-TAB-Nano: A Specification for Sharing Nanomaterial Research Data in Spreadsheet-based Format
© Thomas et al.; licensee BioMed Central Ltd. 2013
Received: 12 April 2012
Accepted: 11 December 2012
Published: 14 January 2013
Background and motivation
The high-throughput genomics communities have been successfully using standardized spreadsheet-based formats to capture and share data within labs and among public repositories. The nanomedicine community has yet to adopt similar standards to share the diverse and multi-dimensional types of data (including metadata) pertaining to the description and characterization of nanomaterials. Owing to the lack of standardization in representing and sharing nanomaterial data, most of the data currently shared via publications and data resources are incomplete, poorly-integrated, and not suitable for meaningful interpretation and re-use of the data. Specifically, in its current state, data cannot be effectively utilized for the development of predictive models that will inform the rational design of nanomaterials.
We have developed a specification called ISA-TAB-Nano, which comprises four spreadsheet-based file formats for representing and integrating various types of nanomaterial data. Three file formats (Investigation, Study, and Assay files) have been adapted from the established ISA-TAB specification; while the Material file format was developed de novo to more readily describe the complexity of nanomaterials and associated small molecules. In this paper, we have discussed the main features of each file format and how to use them for sharing nanomaterial descriptions and assay metadata.
The ISA-TAB-Nano file formats provide a general and flexible framework to record and integrate nanomaterial descriptions, assay data (metadata and endpoint measurements) and protocol information. Like ISA-TAB, ISA-TAB-Nano supports the use of ontology terms to promote standardized descriptions and to facilitate search and integration of the data. The ISA-TAB-Nano specification has been submitted as an ASTM work item to obtain community feedback and to provide a nanotechnology data-sharing standard for public development and adoption.
As we enter the National Nanotechnology Initiative’s second decade , the early concerns regarding rapid product development without extensive regulatory review have shifted to today’s modest commercialization rate and pursuit of plausible risk assessments. Responsible development of nanotechnology will be influenced strongly by the public’s perception of both promise and risk coupled with the expectation that there are responsible parties addressing any remaining uncertainty [2, 3]. Meeting this expectation requires effective multidisciplinary communication that often involves the exchange of complex datasets. The responsible development of nanotechnology products will be empirically-driven, grounded on effective informatics  for a variety of purposes; e.g., discussing ecotoxicity data with a regulator or modeling environmental fate for the purpose of setting appropriate disposal instructions or regulating the design of nanoparticles for an effective biological application.
A cross-cutting need in the nanotechnology community is the development of standards to support both meaningful data submission to public repositories and information exchange among investigators . In order to move toward the rational design of nanomaterials for biomedical and other applications, it is critical to recognize and exploit the nanomaterial physicochemical properties that drive biological behavior. Data mining and computer simulation are essential for deriving this information; however, the datasets needed to support such modeling and computational studies are sparse and stored across a variety of nanotechnology repositories and resources. The lack of standardized data formats and the non-uniformity of information reported have proven to be significant barriers to effective and meaningful data sharing and re-use. We have addressed this problem by developing a spreadsheet-based data exchange format specification, called ISA-TAB-Nano, which provides a general framework for representing and integrating diverse types of data related to the description and characterization of nanomaterials. As noted by Dr. Francis Collins, open access to technologies, tools, and databases has become increasingly critical for accelerating biological discovery [6, 7]. Open access databases necessitate open standards for representing the information to be exchanged. A number of nanomaterials resources are now becoming available leading to an opportune moment to introduce an open standard for nanomedicine. In this paper, we discuss the main features of ISA-TAB-Nano file formats and how they can be used to represent and share nanomaterial data.
Data exchange formats and their uses
The ability to share data meaningfully among investigators from separate biomedical disciplines is a challenge [8–11]. In order to understand and use experimental data generated by another investigator, one must have sufficiently detailed information about how the data were generated, using mutually understood terminology. These requirements can be facilitated through a shared data exchange format that captures information between two laboratories or between investigators and public repositories. Many XML-based and spreadsheet-based data exchange formats have been successfully developed and adopted across the biomedical community; examples include the SBML – Systems Biology Markup Language ; BioPAX – Biological Pathway Exchange ; MAGE-ML – Microarray and Gene Expression Markup Language ; MAGE-TAB – Microarray Gene Expression Tabular ; and ISA-TAB – Investigation/Study/Assay Tabular [16–18].
Compared to XML-based formats, spreadsheet-based formats offer the advantage that they can be created, viewed, and edited by the investigator using software (e.g., Excel) that is broadly available and familiar to most researchers. The most widely adopted spreadsheet-based formats of biological data are MAGE-TAB  and ISA-TAB [16–18]. MAGE-TAB supports the capture and exchange of microarray data in accordance with the minimal information standards adopted in this field . It was developed in response to the need for a format that could be created and used by laboratories lacking the dedicated bioinformatics personnel necessary to support its predecessor XML-based MAGE-ML format. The ease of use of MAGE-TAB has facilitated its broad adoption across the microarray community and it is supported by several public repositories (ArrayExpress , caArray , the Stanford Microarray Database ) and analysis tools (e.g., GenePattern , Bioconductor ). In addition, data from The Cancer Genome Atlas Project (TCGA) are made available in MAGE-TAB format. Based on the wide acceptance of MAGE-TAB, a generalization of this format (ISA-TAB) was developed to support the broader community need for a common format to support the exchange of data about ‘omics studies employing a combination of methodologies (e.g., genomics, transcriptomics, proteomics). Multiple public and private repositories are now ISA-TAB compliant  and an open-source tool suite has been developed to support the use of this format [16–18].
The need for a data exchange format to share nanomaterial data
Information describing the chemical composition and three-dimensional (3D) structure of nanomaterials is often represented in an unstructured fashion, with no standardized way to associate this information with the assay data from characterization studies. Nanomaterials are diverse: chemical composition, size, geometry, morphology and surface chemistry all play important roles in determining the biological properties of resulting nanomaterials. Complex nanomaterials are often multi-component systems formulated with small molecules for specific biomedical applications such as drug delivery, imaging, and detection of diseases. Such complex formulations make the representation of exact chemical composition, physical structure, and properties very challenging and very necessary.
Nanomaterial analysis requires knowledge of the characterization experiment details so that the results can be accurately and interpreted. Nanomaterial interactions with biological systems are complex and, accordingly, associated data are often generated at multiple levels of detail. The properties of nanomaterials are analyzed based on the data available from different characterization studies, such as in vitro and in vivo analysis of biological activities and abiotic studies of physicochemical properties. Each characterization itself involves a wide range of variables using different types of assays, which can also vary depending on the endpoint measured, technology used, and the protocol applied. Furthermore, even minor variations in the chemical composition, assay protocols and conditions, and time point of analysis (the elapsed time since the nanomaterial was synthesized), can give rise to different characterization results. Currently, most of the measurements on nanomaterial properties depend on non-standardized protocols and diverse instrumentation technology types. Experimental results are dependent on protocol details that are not consistently captured or reported . For example, measurements of certain parameters, such as size, are dependent on the instrumentation and the sample preparation method; this information needs to be captured in the form of metadata to fully interpret such measurements.
To address the challenges associated with the sharing and re-use of nanomaterial data, we have developed the ISA-TAB-Nano specification, a standard format for representing and sharing data pertaining to the description and characterization of nanomaterials. ISA-TAB-Nano is intended to facilitate the submission and exchange of assay metadata and nanomaterial descriptions, along with other information (raw/derived data, image data, protocol information), among individual researchers and to/from nanotechnology online resources. We expect that ISA-TAB-Nano will provide organizations with a standard approach to representing nanomaterial data that will enable researchers to share nanomaterial information effectively and to make cross-material comparisons.
In 2008, the Nanotechnology Working Group (Nano WG) was established as part of National Cancer Institute (NCI) cancer Biomedical Informatics Grid (caBIG®) program, to support the informatics needs of nanomedicine researchers. Today, the group has over 20 active participants who represent a broad range of expertise and come from academic, industrial, government agency and other institutions. Beginning in March 2010, a sub-group of the Nano WG began developing a specification to facilitate the exchange of nanomaterial data amongst research labs and with public repositories of nanoparticle information. An important goal of this effort from the outset was to use and extend concepts from the caBIG® Life Sciences Domain Analysis Model  while using the NanoParticle Ontology  and other ontologies as terminology sources. Recognizing that nanoparticle assays have many of the same challenges as microarray assays, the Nano WG looked to the microarray community for lessons learned. The ISA-TAB standard [16, 18] forms the basis for our ISA-TAB-Nano format because of its flexibility in supporting several different types of assays of interest including physicochemical, in vitro, and in vivo assays.
The ISA-TAB-Nano file formats were evaluated using several nanomaterial datasets from the cancer Nanotechnology Laboratory Portal (caNanoLab)  and individual researchers with applications ranging from biomedicine to nanotoxicology. This diversity allowed for format refinement and enabled support for a broad range of interests. Test case studies were conducted and feedback was provided to the ISA-TAB-Nano development team. Example datasets are available from the ISA-TAB-Nano website at https://wiki.nci.nih.gov/x/HgiG.
Basis of ISA-TAB-Nano
The ISA-TAB-Nano specification is based on the ISA-TAB specification [16–18, 25]. ISA-TAB defines three file formats for sharing the metadata associated with ‘omics (e.g., proteomics, genomics, metabolomics, and transcriptomics) – based experiments. The three files are called Investigation file, Study file, and Assay file. Non-standard (user-defined) file formats such as image files, spreadsheet files containing raw/derived data, and protocol documents, can also be referenced in appropriate fields within the Investigation, Study, and Assay files. By providing a standard format for representing the metadata related to each ‘omics experiment, the ISA-TAB file formats facilitate the integration and sharing of ‘omics data in a meaningful and standardized way.
The ISA-TAB Study file is used to record information about the source and characteristics of a subject (sample) under study as well as the different treatment protocols that are applied to prepare the samples for the analysis (assay). The subject under study could be an organism, a sample taken out of the organism, or any other sample. The Assay files are used to record the assay metadata along with references to the names (or URIs) of the raw/derived data and image files. In the ISA-TAB framework, the type of assay is determined by the endpoint of measurement and by the technology (technique) used to measure that endpoint. Therefore, a single study (of a given sample) can comprise several types of assays. The Investigation file serves to relate the different types of assays to their corresponding studies. In particular, the Investigation file is used to record reference information about each Study file and Assay file; point of contact; publications; the parameters, instruments, software, and reagents of a protocol; the factors of the study (a factor is defined as any independent variable that is varied in an experiment to investigate its effect on the subject under study) and the terminology sources referred to in the Investigation, Study and Assay files.
Biospecimens versus material samples
An important extension to ISA-TAB required to support nanomaterials came from the need to distinguish samples derived from biological sources (e.g., from cell lines, tissues, body fluids, etc.) and samples derived from non-biological sources (e.g., nanoparticle formulations, small molecule drug, etc.). Hence, for the ISA-TAB-Nano specification, we consider a sample derived from biological sources as a biological specimen or biospecimen material type, while referencing samples derived from non-biological sources as material samples.
The ISA-TAB Study file can be used to describe the source and characteristics of biological specimens, however, it is not suitable for describing nanomaterials. In this work, we have designed a “Material” file format for describing nanomaterials. In general, this file format is applicable for describing any material sample, nanoscale or otherwise, as discussed later. Hence, in ISA-TAB-Nano, the concept of a sample (as used in ISA-TAB specification) is extended to distinguish between biological specimens and material samples by incorporating information about the latter into the Material file.
Scope of a ISA-TAB-Nano Material file
The Material file is designed to capture information related to the description of nanomaterials. Typically, the description of a nanomaterial is complex and includes different types of information (name, type, characteristics) related to the whole nanomaterial and its individual chemical components. A typical example is that of a nanoparticle formulation [5, 28], which can be generally described as a multi-component system containing chemical components that may be distinguished as nanoparticles, chemical constituents of the nanoparticle, functionalizing agents, and components of the medium in which the nanoparticles may be suspended. These chemical components can be described and identified based on their molecular structure, biochemical role, and function . The types of information needed to describe nanoparticles and their formulations include specification of the linkages existing between the different components of the formulation (e.g., encapsulation, entrapment, amide linkages, etc.); the physical state of the formulation (e.g., emulsion, solid, hydrogel, etc.); the properties (physical, chemical, and functional) of each chemical component; the intended functions and applications of the nanoparticle; the nanoparticle design principles (or rationale); and the type of stimulus that may be required for activating a specific function of the nanoparticle (e.g., magnetic field, ultrasound, pH change, etc.) . All of these types of information were taken into account when developing the specification for the ISA-TAB-Nano Material file format.
Results and discussion
The ISA-TAB-Nano specification makes use of the ISA-TAB Investigation, Study, and Assay files to record and share the assay metadata. In addition to sharing the assay metadata, we also want to share the endpoint measurements and description (chemical composition, characteristics) of both nanomaterials and small molecules (e.g., drugs, imaging agents). To accommodate this additional information, we have made extensions to ISA-TAB. In particular, the ISA-TAB Study file is suited for recording the source and characteristics of biological specimens and for specifying any treatments performed on them. However, the Study file is not designed to represent information about the chemical composition and characteristics of material samples (nanomaterials, drugs, imaging agents, and other small molecules). To represent this information, we have introduced a fourth ISA-TAB-Nano file called the Material file. We use the Material file to describe material samples while using the ISA-TAB Study file to describe biospecimens. We have modified the definitions of some of the field names in the ISA-TAB Investigation, Study, and Assay files and added new fields names to expand the scope of information that needs to be shared using the ISA-TAB-Nano specification. Detailed information of the field names and definitions of each file format can be found in Supporting Information. For more detailed information about the structure and contents of the ISA-TAB files, the reader may refer to the ISA-TAB specification . The rules for naming the four file formats defined in the ISA-TAB-Nano specification are i_xxxx.txt for the Investigation file, s_xxxx.txt for the Study file, a_xxxx.txt for the Assay file, and m_xxxx.txt for the Material file, where ‘xxxx’ denotes a unique string.
The following sections describe the different components of the ISA-TAB-Nano files. Supporting Information provides additional materials to supplement the manuscript discussion, including a summary of extensions to the ISA-TAB format, the standard specification, and examples.
Types of information shared using ISA-TAB-Nano files
Types of information entered in the four ISA-TAB-Nano files
Types of information entered in each ISA-TAB-Nano file
Reference information about each investigation, study, assay, protocol, Study file, and Assay file.
Names and attributes of protocols used for preparing samples for analysis; source and characteristics of biospecimens.
Values of measured endpoint variables and references to external data files for each analyzed sample.
Descriptions of the material sample and its structural parts and chemical components; linkage descriptions between chemical components; reference information about external material data files.
Sharing material sample description
In the ISA-TAB-Nano framework, all material samples are viewed as formulations having one or more chemical components (e.g., nanoparticles, small molecules, solvent medium, etc.). The ISA-TAB-Nano material file has been designed for recording descriptions of various types of formulations, ranging from a simple chemical compound to a complex multi-component nanoparticle formulation.
The layout of the ISA-TAB-Nano Material file is same as that of the Study and Assay files, wherein the field names are arranged as columns and material sample information is entered as rows. Columns in the ISA-TAB-Nano Material file provide information on the material and its components, the relationship between materials and components, and any associated data files, as mentioned in Table 1.
Using the ISA-TAB-Nano Material file to describe a material sample and its components
Using the ISA-TAB-Nano Material file to describe linkages in a material sample
Using the ISA-TAB-Nano Material file to record information about external files that provide additional information about the material sample
The Material file is also used to record the name or URI of external files that contain additional information about the material sample. Examples include image files displaying the chemical structures of molecules, or documents (e.g., spreadsheet, Word, PDF, etc.) that contain detailed descriptions of the sample. The example given in Figure 4 references one file called “magnevist.jpg” that contains an image of the molecular structure of Magnevist®.
In practice, one ISA-TAB-Nano Material file should be created for each material sample in a study. When using the format “m_xxxx.txt” to name the Material files, the string “xxxx” should exactly match the string used in the Material Source Name field of the sample’s Material file. For example, we would name the Material file of samples LAB-1 and LAB-2 as m_LAB-1.txt and m_LAB-2.txt, respectively.
Sharing assay information
Different types of assays are performed to measure the physicochemical, in vitro, and in vivo properties of material samples. We can identify the type of each assay based on the measured endpoint, measurand, and technique used. For example, if an assay is related to a size characterization study, the endpoint could be “size” and the technique could be “dynamic light scattering (DLS)”, or “scanning electron microscopy (SEM)”, or other relevant technique. The corresponding assay types are “size by DLS assay”, “size by SEM”, etc. Assays of the same type may be performed using different protocols, by different people, at different dates, and under different experimental conditions. To interpret the characterization results of a material sample meaningfully, we need to have information about the assay type; biospecimen information (if it is a bioassay); protocol descriptions; dates of synthesis and analysis of the material sample; the measured endpoint variables; as well as the protocol variables of the experiment. Based on the ISA-TAB specification, variables that are kept constant in an assay experiment are termed “parameters”, while variables that are changed for studying their effects on the measured endpoint values are termed “study factors”.
Representing physiochemical characterization data of material samples using ISA-TAB-Nano files
In a physicochemical characterization study, one measures the properties of a material sample and studies how these properties are affected by the study factors. Typically, one prepares several dilutions of same material sample and may even suspend each sample in different test media to achieve solution conditions suitable for performing a specific assay. Therefore, each analyzed sample may have its own identifier while its (source) material sample to be characterized has a different identifier (the Material Source Name).
In the ISA-TAB Study file, a column Source Name is used to define the source of a biospecimen. ISA-TAB-Nano extends the ISA-TAB Study file by adding a column called Material Source Name REF to refer the source name of the material sample, given in the Material Source Name column of the sample’s Material file. Thus, as shown in Figure 5, the first column of the Study file (Material Source Name REF) represents the identifier of the material sample that is to be characterized. The second column contains the name of the protocol applied to prepare each individual biospecimen or material sample for the analysis. After the protocol column, we create columns to capture the attributes of the protocol including the name of the person who performed the protocol, the date when the protocol was applied, and the values of each parameter in the protocol. After these, we add two more columns to record the sample name (identifier) and its material type.
The first column of the Assay file is used to enter the biospecimen or material sample names under the header name Sample Name (see Figure 6) – note that these names should match the names entered in the Sample Name column of the Study file. The names of the assay and protocol are entered in the next two columns. As in the Study file, we also create columns to capture the attributes of each protocol, including investigator, date, and parameter values. We also create columns for entering the values of each factor value and measurement value variables, followed by columns to record the URIs or names of associated data files, as shown in Figure 6.
The values for the parameters, factors, and measurements can be qualified by a unit of measurement and a statistical type (if applicable) using column headers Unit and Statistic, respectively, in both the Study as well as in the Assay files (see Figure 5 and Figure 6). Note that the Measurement Value [<measurement name>] and Statistic columns are newly added by the ISA-TAB-Nano specification. If terms from an ontology are used as valid values in any of the columns of the Study and Assay files, it is necessary to enter the term’s identifier and source ontology name in adjacent columns named as Term Accession Number and Term Source REF, respectively (not shown in the Figure 5 and Figure 6). One may choose to enter the factor values either in the Study file and/or in the Assay file, as appropriate to the actual experimental procedure(s). Furthermore, to enter any additional type of information in the Study or Assay file, one may create a column with header name, Comment [<string>], as specified by ISA-TAB.
Types of information entered in the eleven sections of the ISA-TAB-Nano Investigation file
Sections of Investigation file
Types of information entered in each section
Ontology Source Reference
Information about the ontologies referenced in the ISA-TAB-Nano files.
Investigation title and description.
Point(s) of contact for the whole investigation.
References to publications of an investigation.
Information about each study and its associated Study file.
Study Design Descriptors
Type of study design.
Point(s) of contact for a study.
References to publications of a study.
Information about each assay and its associated Assay file.
Names of factor variables and types.
Information about each protocol.
Note that the ontologies or controlled vocabularies referenced in any of the ISA-TAB-Nano files must be declared in the Ontology Reference section of the Investigation file (noted in Table 2). The Investigation file can also contain information about publications and point of contact associated with an investigation or a specific study within the investigation (also noted in Table 2). For more details on the Investigation file, we refer the reader to the ISA-TAB specification  and ASTM ISA-TAB-Nano specification .
Representing material sample in vitro and in vivocharacterization data of material samples using ISA-TAB-Nano files
Integrated view of ISA-TAB-Nano files and external referenced documents
Validation of ISA-TAB-Nano files
A key feature of ISA-TAB-Nano (and the parent ISA-TAB format) is that it can be readily created and edited with any spreadsheet software, without the need for specialized bioinformatics support. However, this also creates challenges because such software does not enforce validation rules for ISA-TAB-Nano files. One possible solution to this problem is to adapt the suite of open source tools provided by the ISA-TAB community [16–18], such as: (1) ISACreator, which provides a graphical user interface for entering in data into ISA-TAB files; (2) ISAValidator, which assesses the validity of ISA-TAB files; (3) ISAConverter, which converts an ISA-TAB file to one of several other formats if so desired, (4) ISAConfigurator, which creates the XML files that define specialized versions of ISA-TAB, and (5) bioinvindex, which is a database for storing ISA-TAB files. These tools are part of our future plans to be tested for editing and validating ISA-TAB-Nano files.
XML-based validation is also of interest and would involve developing an ISA-TAB-Nano XML schema based on the ISA-TAB-Nano specification such that any ISA-TAB-Nano XML file converted from the ISA-TAB-Nano files can be formally validated against the XML schema. Having an XML-based validation service would also enable software systems to import and export validated ISA-TAB-Nano files to and from distributed nanotechnology resources.
In this paper, we have provided an overview of ISA-TAB-Nano, a spreadsheet-based exchange format for information pertaining to the description and characterization of nanomaterials. The ISA-TAB-Nano specification extends the ISA-TAB specification that was designed for sharing all types of ‘omics data. Specifically, ISA-TAB-Nano leverages the three primary ISA-TAB file formats - Investigation file, the Study file, and the Assay file - to represent the metadata related to the characterization of nanomaterials. To capture the measurement data, ISA-TAB-Nano specifies new fields in the Investigation file and in the Assay file. In addition, ISA-TAB-Nano includes a new file format, the Material file, to capture the description of nanomaterials and chemical substances (drugs, imaging agents, etc.) that are characterized in an assay. The ISA-TAB-Nano specification was recently submitted as an ASTM work item to obtain community feedback and to promote ISA-TAB-Nano as a voluntary consensus standard for the nanotechnology community. Additionally, we hope that the ISA-TAB-Nano standard will be adopted by journals and other organizations to ensure a uniform representation of information that is too often “lost” in a prose Methods section and cannot be easily extracted for re-use.
Many of the ISA-TAB extensions developed for ISA-TAB-Nano could also be used for studies of other types of complex materials or formulations. In particular, the “Material” file addition is likely to be useful outside of the nanotechnology realm for a broader range of samples with complex composition or structural characteristics.
Key to promoting the successful adoption of ISA-TAB-Nano will be the availability of resources to facilitate the creation and validation of these files. Our adherence to the parent ISA-TAB specification will allow the ready adaptation of the ISA Tools [16–18] to support the extended framework, an anticipated next step for this project. The ability easily select ontology terms when populating the files is critical to the ultimate goal of integrating these data across disparate resources. The ISA-TAB and ISA-TAB-Nano specifications support the use of any ontology or controlled vocabulary; in this domain, preferred ontologies include NanoParticle Ontology (NPO) , Chemical Entities of Biological Interest (ChEBI) , Gene Ontology (GO) , NCI thesaurus (NCIt) , and Unit Ontology (UO) . The Nano WG continues to expand the NanoParticle Ontology (NPO) to support the needs of ISA-TAB-Nano, and is considering various methods and tools for facilitating the use of ontology terms in ISA-TAB-Nano files. (Additional files 1, 2 and 3).
We would like to thank Susanna-Assunta Sansone and Philippe Rocca-Serra, for taking time to provide their expertise on ISA-TAB during the various stages of ISA-TAB-Nano development. We would also like to thank the anonymous reviewers for their helpful comments and suggestions. N.A.B. and D.G.T. acknowledge support from the NIH NCI caBIG® Working Group, Pacific Northwest National Laboratory HHS sector LDRD funds, as well as NIH grants U54 HG004028 (National Center for Biomedical Ontology), U01 NS073457, and R01 GM069702. S.L.H. would like to acknowledge support from NIEHS Environmental Health Sciences Center P30 ES03850, National Institute of Environmental Health Sciences ES016896-01, and the Air Force Research Laboratory FA8650-05-1-5041 under an agreement with the Oregon Nanoscience and Microtechnologies Institute/Safer Nanomaterials and Nanomanufacturing Initiative. D.P. acknowledges support for funding from Stanford CCNE-TR/CCNE-T (NIH U54 CA119367) and National Center for Biomedical Ontology (NIH U54 CA151459). The views, opinions, and content in this article are those of the authors and do not necessarily represent the views, opinions, or policies of their respective employers or organizations. Mention of company names or products does not constitute endorsement.
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