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• Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation

  Despite recent advances, the dynamics of genome architecture and chromatin function during human cell differentiation and its potential reorganization upon neoplastic transformation remains poorly characterized. Here, we integrate in situ Hi-C and nine additional omic layers to define and biologically characterize the dynamic changes in three-dimensional (3D) genome architecture across normal B cell differentiation and in neoplastic cells from different subtypes of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) patients. Beyond conventional active (A) and inactive (B) compartments, an integrative analysis of Hi-C data uncovers a highly-dynamic intermediate compartment enriched in poised and polycomb-repressed chromatin. During B cell development, we detect that 28% of the compartments change at defined maturation stages and mostly involve the intermediate compartment. The transition from naive to germinal center B cells is associated with widespread chromatin activation, which mostly reverts into the naive state upon further maturation of germinal center cells into memory B cells. The analysis of CLL and MCL neoplastic cells points both to entity and subtype-specific alterations in chromosome organization. Remarkably, we observe that large chromatin blocks containing key disease-specific genes alter their 3D genome organization. These include the inactivation of a 2Mb region containing the EBF1 gene in CLL and the activation of a 6.1Mb region containing the SOX11 gene in clinically aggressive MCL. This study indicates that 3D genome interactions are extensively modulated during normal B cell differentiation and that the genome of B cell neoplasias acquires a tumor-specific 3D genome architecture.

  Study EGAS00001004763

• A higher ctDNA fraction decreases survival in regorafenib-treated metastatic colorectal cancer patients

  The predictive effect of circulating tumor DNA (ctDNA) in colorectal cancer (CRC) treatment is still highly discussed. The primary objective of this study was to investigate a possible prognostic/predictive value of ctDNA under regorafenib treatment. This prospective multicenter translational biomarker phase II pilot study enrolled 30 metastatic CRC patients (67% men, 33% women) treated with regorafenib. ctDNA was assessed in plasma before treatment start and at defined time points during administration. Measurement of tumor fraction as well as mutation and copy number analysis of CRC driver genes were performed by next generation sequencing approaches. Multivariate analyses for survival and treatment efficacy were adjusted to age, gender and ECOG. Disease control rate was 30%. Median tumor fraction at baseline was 18.5% (0-49.9). Mutations in CRC driver genes or genes involved in angiogenesis were identified in 25 patients (83.3%). KRAS mutations were detected in 13 out of 14 KRAS positive tumors, in three patients without KRAS mutation in the respective tumor acquired mutations as a consequence of prior anti-EGFR treatment were detected. In a subset of patients, novel occurring mutations or focal amplifications were detected. A tumor fraction of 5% and higher at baseline was significantly associated with a decreased OS (p=0.022; HHR 3.110 (95%CI: 1.2-8.2). ctDNA is detectable in a high proportion of mCRC patients. Higher ctDNA levels are associated with survival among regorafenib treatment. Moreover, our data highlight the benefit of a combined evaluation of mutations and somatic copy number alterations (SCNA) in advanced cancer patients.

  Study EGAS00001004491

• Evaluation of EBUS-TBNA Aspirates from Advanced NSCLC for Comprehensive Sequencing Platforms Including Whole Genome Sequencing

  Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is often the only source of tumor tissue from patients with advanced, inoperable lung cancer. EBUS-TBNA aspirates are used for the diagnosis, staging, and genomic testing to inform therapy options. Here we extracted DNA and RNA from 220 EBUS-TBNA aspirates to evaluate their suitability for whole genome (WGS), whole exome (WES), and comprehensive panel sequencing. For a subset of 40 cases, the same nucleic acid extraction was sequenced using WGS, WES, and the TruSight Oncology 500 assay. Genomic features were compared between sequencing platforms and compared with those reported by clinical testing. A total of 204 aspirates (92.7%) had sufficient DNA (100 ng) for comprehensive panel sequencing, and 109 aspirates (49.5%) had sufficient material for WGS. Comprehensive sequencing platforms detected all seven clinically reported tier 1 actionable mutations, an additional three (7%) tier 1 mutations, six (15%) tier 2–3 mutations, and biomarkers of potential immunotherapy benefit (tumor mutation burden and microsatellite instability). As expected, WGS was more suited for the detection and discovery of emerging novel biomarkers of treatment response. WGS could be performed in half of all EBUS-TBNA aspirates, which points to the enormous potential of EBUS-TBNA as source material for large, well-curated discovery-based studies for novel and more effective predictors of treatment response. Comprehensive panel sequencing is possible in the vast majority of fresh EBUS-TBNA aspirates and enhances the detection of actionable mutations over current clinical testing.

  Study EGAS00001007708

• NIH RECOVER-Pediatric: Understanding the Long-Term Impact of COVID on Children and Families

  The NIH Researching COVID to Enhance Recovery (RECOVER) initiative comprises a set of three combined retrospective and prospective, longitudinal and observational meta-cohort studies with nested case-control studies designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection (PASC or Post-COVID syndrome) in a diverse study population representative of the general COVID-19 population in the US. Enrolled patients, with and without known SARS-CoV-2 infection, will be observed for clinical signs and symptoms of PASC and will be assessed for risk and resiliency factors and potential mediating factors associated with the severity and progression of PASC. The objective of the RECOVER initiative is to enhance knowledge of recovery from SARS-CoV-2 infections in order to support development of novel diagnostic and therapeutic interventions. Overarching scientific objectives are as follows:Characterize the incidence and prevalence of sequelae of SARS-CoV-2 infection.Characterize the spectrum of clinical symptoms, subclinical organ dysfunction, natural history, and distinct phenotypes identified as sequelae of SARS-CoV-2 infection. Define the biological mechanisms underlying pathogenesis of the sequelae of SARS-CoV-2 infection. The RECOVER observational studies comprise three cohorts across the lifespan (adult, pediatric, and tissue pathology (autopsy)). The data collection and data analysis plans for each cohort have been harmonized to use common data elements where feasible. Brief descriptions of each cohort are provided in the following paragraphs: 1) NIH RECOVER: A Multi-site Observational Study of Post-Acute Sequelae of SARS-CoV-2 Infection in Adults (see phs003463)The RECOVER adult cohort study is a combined retrospective and prospective, longitudinal, observational meta-cohort of individuals who will enter the cohort with and without SARS-CoV-2 infection and at varying stages before and after infection. Individuals with and without SARS-CoV-2 infection, and with or without PASC symptoms, will be followed to identify risk factors and occurrence of PASC. This study will be conducted in the United States and subjects will be recruited through inpatient, outpatient, and community-based settings. Study data including age, demographics, social determinants of health, medical history, vaccination history, details of acute SARS-CoV-2 infection, overall health and physical function, and PASC symptom screen will be reported by subjects or collected from the electronic health record using a case report form at specified intervals. Biologic specimens will be collected at specified intervals, with some tests performed in local clinical laboratories and others performed by centralized research centers or banked in the Biospecimen Repository. Advanced clinical examinations and radiologic examinations will be performed at local study sites with cross-site standardization. 2) A Multi-Center Observational Study: The RECOVER Post Acute Sequelae of SARS-CoV-2 (PASC) Pediatric Cohort Study (this study)The RECOVER pediatric study is a combined retrospective and prospective, longitudinal, observational meta-cohort of individuals ages newborn-25 years who will enter the cohort with and without SARS-CoV-2 infection at varying stages before and after infection. Individuals with and without SARS-CoV-2 infection and with or without PASC symptoms will be followed to identify risk factors and occurrence of PASC. This study recruit participants inpatient, outpatient, and community-based settings in the United States. Study data including age, demographics, social determinants of health, medical history, vaccination history, details of acute SARS-CoV-2 infection, overall health and physical function, and PASC symptoms will be reported by participants or collected from the electronic health record using a case report form at specified intervals. Biologic specimens will be collected at specified intervals, with some tests performed in local clinical laboratories and others performed by centralized research centers or banked in the Biospecimen Repository. Advanced clinical and radiologic examinations will be performed at local study sites with cross-site standardization. 3) NIH RECOVER: A Multi-site Pathology Study of Post-Acute Sequelae of SARS-CoV-2 Infection The RECOVER tissue pathology study is a cross-sectional study designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection in a diverse population representative of the general COVID-19 population in the US. The autopsy study will characterize the pathology of PASC in (i) non-hospitalized patients who die 30 days or later from symptom onset of COVID-19, and (ii) hospitalized patients who die 30 days or later after discharge from a hospitalization for COVID-19. The study will include decedents who had previously fully recovered from SARS-CoV-2 infection (i.e., >30 days from onset in non-hospitalized, or >30 days from discharge in hospitalized patients), and decedents who meet clinical criteria of PASC as defined by the recent World Health Organization publication (see Section 5.4 below). The autopsy study will also explore the pathology of acute SARS-CoV-2 infection in a smaller subset of patients who died 15-30 days from symptom onset. This protocol defines the common set of clinical data elements, autopsy procedures for tissue collection, core measures, pathology protocols, shared pathology tissues, data elements, and methodology. Each investigator site is expected to perform autopsies on the decedents to address the pathophysiology of the potential long-term effects of SARS-CoV-2 infection on human health. The Consortium analysis plan aims to address research questions by incorporating: 1) tissue obtained from autopsies performed at each Phase II participant's site; and 2) tissue available from other pathology investigators/autopsy sites within the Consortium.

  Study phs003461

• NIH RECOVER: A Multi-Site Observational Study of Post-Acute Sequelae of SARS-CoV-2 Infection in Adults

  The NIH Researching COVID to Enhance Recovery (RECOVER) initiative comprises a set of three combined retrospective and prospective, longitudinal, observational meta-cohort studies with nested case-control studies designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection (PASC or Post-COVID syndrome) in a diverse study population representative of the general COVID-19 population in the US. Enrolled patients with and without known SARS-CoV-2 infection will be observed for clinical signs and symptoms of PASC and will be assessed for risk and resiliency factors and potential mediating factors associated with the severity and progression of PASC. The objective of the RECOVER initiative is to enhance knowledge of recovery from SARS-CoV-2 infections in order to support development of novel diagnostic and therapeutic interventions. Overarching scientific objectives are as follows: Characterize the incidence and prevalence of sequelae of SARS-CoV-2 infection. Characterize the spectrum of clinical symptoms, subclinical organ dysfunction, natural history, and distinct phenotypes identified as sequelae of SARS-CoV-2 infection.Define the biological mechanisms underlying pathogenesis of the sequelae of SARS-CoV-2 infection. The RECOVER observational studies comprise three cohorts across the lifespan (adult, pediatric, and tissue pathology (autopsy)). The data collection and data analysis plans for each cohort have been harmonized to use common data elements where feasible. Brief descriptions of each cohort are provided in the following paragraphs:1) NIH RECOVER: A Multi-site Observational Study of Post-Acute Sequelae of SARS-CoV-2 Infection in Adults (this study)The RECOVER adult cohort study is a combined retrospective and prospective, longitudinal, observational meta-cohort of individuals who will enter the cohort with and without SARS-CoV-2 infection and at varying stages before and after infection. Individuals with and without SARS-CoV-2 infection and with or without PASC symptoms will be followed to identify risk factors and occurrence of PASC. This study will be conducted in the United States and subjects will be recruited through inpatient, outpatient, and community-based settings. Study data including age, demographics, social determinants of health, medical history, vaccination history, details of acute SARS-CoV-2 infection, overall health and physical function, and PASC symptom screen will be reported by subjects or collected from the electronic health record using a case report form at specified intervals. Biologic specimens will be collected at specified intervals, with some tests performed in local clinical laboratories and others performed by centralized research centers or banked in the Biospecimen Repository. Advanced clinical examinations and radiologic examinations will be performed at local study sites with cross-site standardization. A summary of information available by request in the RECOVER Adult Cohort (this study) can be reviewed via the "Adult Cohort Dataset Release Notes" and the "REDCap Codebook for the Adult Cohort" documents.2) The RECOVER Post Acute Sequelae of SARS-CoV-2 (PASC) Pediatric Cohort Study: A Multi-Center Observational Study (data not yet released)The RECOVER pediatric study is a combined retrospective and prospective, longitudinal, observational meta-cohort of individuals ages newborn-25 years who will enter the cohort with and without SARS-CoV-2 infection at varying stages before and after infection. Individuals with and without SARS-CoV-2 infection and with or without PASC symptoms will be followed to identify risk factors and occurrence of PASC. This study recruit participants inpatient, outpatient, and community-based settings in the United States. Study data including age, demographics, social determinants of health, medical history, vaccination history, details of acute SARS-CoV-2 infection, overall health and physical function, and PASC symptoms will be reported by participants or collected from the electronic health record using a case report form at specified intervals. Biologic specimens will be collected at specified intervals, with some tests performed in local clinical laboratories and others performed by centralized research centers or banked in the Biospecimen Repository. Advanced clinical and radiologic examinations will be performed at local study sites with cross-site standardization.3) NIH RECOVER: A Multi-site Pathology Study of Post-Acute Sequelae of SARS-CoV-2 Infection (data not yet released)The RECOVER tissue pathology study is a cross-sectional study designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection in a diverse population representative of the general COVID-19 population in the US. The autopsy study will characterize the pathology of PASC in (i) non-hospitalized patients who die 30 days or later from symptom onset of COVID-19, and (ii) hospitalized patients who die 30 days or later after discharge from a hospitalization for COVID-19. The study will include decedents who had previously fully recovered from SARS-CoV-2 infection (i.e., >30 days from onset in non-hospitalized, or >30 days from discharge in hospitalized patients), and decedents who meet clinical criteria of PASC as defined by the recent World Health Organization publication (see Section 5.4 below). The autopsy study will also explore the pathology of acute SARS-CoV-2 infection in a smaller subset of patients who died 15-30 days from symptom onset. This protocol defines the common set of clinical data elements, autopsy procedures for tissue collection, core measures, pathology protocols, shared pathology tissues, data elements, and methodology. Each investigator site is expected to perform autopsies on the decedents to address the pathophysiology of the potential long-term effects of SARS-CoV-2 infection on human health. The Consortium analysis plan aims to address research questions by incorporating: 1) tissue obtained from autopsies performed at each Phase II participant's site; and 2) tissue available from other pathology investigators/autopsy sites within the Consortium.

  Study phs003463

• How to encrypt files with EGACryptor

  File preparation Due to the processes used at the EGA for file archival the use of non-alphanumeric characters in a filename will cause issues in archival. By convention whitespaces in filenames are to be avoided and should be replaced with the underscore character (_). Before encrypting your files please make sure that any files that will be uploaded to EGA do not use special characters such as # ? ( ) [ ] / \ = + < > : ; " ' , * ^ | &  Crypt4gh EGACryptor Files encrypted with EGACryptor must be uploaded via FTP EGACryptor The EGACryptor v.2.0.0 is a JAVA-based application which enables submitters to produce EGA compliant encrypted files along with files for the encrypted and unencrypted md5sum for each file to be submitted. The application will generate an output folder that will by default mirror the directory structure containing the original files. This output folder can subsequently be uploaded to the EGA FTP staging area via an FTP or Aspera client. Download EgaCryptor Download EgaCryptor Using the EgaCryptor Using the EgaCryptor Encrypting single file Encrypting multiple files Encrypting all files in folder Points to note Troubleshooting Troubleshooting Download EGACryptor The required jar files can be obtained by downloading EgaCrytptor jar file After the file has been downloaded, extraction of the zipped archive is required. The EGACryptor has been built to work with Java Runtime Environments from version 6 and above and with the OpenJDK Environment. Please refer to the relevant resources for installation guidance. Installing the latest version of the OpenJDK will include the JCE files. If your installation of Java JRE is less than 1.8.0_151 will require the manual installation of the JCE Policy Files. You can verify the version of the Java SE Runtime Environment (JRE) installed by using the command: $ java -version If you need to install the JCE please follow the instructions below: Installing the JCE policy files (due to licensing terms and conditions the required policy files must be downloaded direct from the ORACLE website) : Download the unlimited strength JCE policy files (JRE 6 / JRE 7/ JRE 8) Uncompress and extract the downloaded file. This will create a subdirectory called JCE. This directory contains the following files: README.txt, COPYRIGHT.html, local_policy.jar and US_export_policy.jar Install the two policy JAR files by replacing the existing ones in your java home directory. Install the two policy JAR files by replacing the existing ones in your directory. The standard place for JCE jurisdiction policy JAR files is: /lib/security [Unix] or \lib\security [Win32] Notes: refers to the directory where the Java SE Runtime Environment (JRE) was installed. Additional performance enhancements that have been included in the EGACryptor V2.0.0: The ability to parallelise the processing of datasets through the use of the resources on a system. Multicore systems will allow the user to specify n-1 cores for an n-core system. The use of this feature on clusters may speed up the processing of datasets that have large file numbers but consult your local cluster guide to ensure that there are not monopolising resources that are needed by other system users. The default for this process remains single threaded. 3 levels of system usage can be specified. Full usage within the limits detailed above. A limited mode that will ensure that 50% of the system resources are available for other tasks. Maximum mode is limited to 75% of system resources, this allows encryption to be prioritised but allows for the system to be usable for light alternate tasks. Finally there is a throttling mode that allows you to specify the exact number of computational threads to be used. the EGACryptor is able to ingest a structured directory and will output a directory with the same structure containing the encrypted files along with the md5checksums for the plain and encrypted files. The entire output directory can then be uploaded to the EGA for archival. as with the input path, it is now possible to specify the output path. the options have been updated inline with the upgraded functionality. The tool can only be used via the command line. The EGACryptor is designed to perform a single task, encrypting your data, for upload of these files please refer to our uploading guide Using the EgaCryptor Below are the three ways on how the EGACryptor tool can be used: Encrypting a single file : java -jar ../EGA-Cryptor_2_0_0.jar -i example1.bam Encrypting multiple files : java -jar ../EGA-Cryptor_2_0_0.jar -i "example1.bam,example2.bam" Encrypting all the files within a folder java -jar ../EGA-Cryptor_2_0_0.jar -i path/to/target/directory By default the EGACryptor v2 will create a new output directory containing all encrypted files and the relevant checksums within the target directory. If a specific directory is desired this can be specified by using the -o flag. This can be achieved in a similar manner to the following example: java -jar ../EGA-Cryptor_2_0_0.jar -i /path/to/target/directory -o /path/to/output/directory The tool will output three files per input file: file.gpg ( encrypted file ) file.md5( file md5 sum value file ) file.gpg.md5 ( encrypted file md5 sum value file ) All output files must then be uploaded to your submission account using Aspera or FTP. Further documentation on how to upload files: FTP and Aspera. Points to note Remember to provide the path to EgaCryptor.jar and run the command from within the directory the file/s are located. ECryptor writes files to the source directory of your local file system, as a result you must have write-access permissions for the source directory. Troubleshooting If in doubt about the function of the EGACryptor it is recommended to first consult the built-in documentation. This can be accessessed by using the -h flag as stated in the following table. Built-in Commands Table: list of the command line options built into EGA-Cryptor v2.0.0. Command line Option Action --------------------- ----------- -f Set this option to allow application to create maximum threads to utilise full capacity of cores/processors available on machine -h Use this option to view the bult-in help menu * -i File(s) to encrypt. Provide file/folder path or comma separated file path if multiple files in double quotes -l Set this option to allow application to create maximum threads equals to 50% capacity of cores/processors available on machine -m Set this option to allow application to create maximum threads equals to 75% capacity of cores/processors available on machine -o Path of the output file. This is optional. If not provided then output files will be generated in the same path as that of source file (default: output- files) -t Set this option if user wants to control application to create maximum threads as specified. Application will calculate no. of cores/processors available on machine & will create threads accordingly Encryption Errors UnixFileSystem.createFileExclusively (Native Method) The error is thrown by UNIX ("UnixFileSystem.createFileExclusively(Native Method)"). It appears that the user does not have write-access to the file system where the file to be uploaded is located. EGACryptor always writes MD5 checksums into files before uploading them to the server, and these files are created in the same location where the uploaded file itself resides.Solution: address your directory permission issue and re-run the command. Install JCE Unlimited Strength Jurisdiction Policy files The JCE policy unlimited strength jurisdiction files should be installed according to your current java version If you are still facing difficulty with the EGACryptor v.2 after having consulted the documentation please contact the EGA Helpdesk.

  Documentation submission/data/file-preparation/egacryptor

• CIDR: The Role of Rare Coding Variation in Prostate Cancer in Men of African Ancestry - RESPOND Project 2

  In RESPOND Project 2, we seek to identify rare genetic factors that are associated with prostate cancer (PCa) risk and aggressiveness in men of African ancestry (AA). We will conduct exome sequencing of 15,000 prostate cancer cases and 5,000 controls from the RESPOND cohort and the African Ancestry Prostate Cancer Consortium (AAPC) with cases selected based on risk categories: high-risk (stage T3/T4 or Gleason 8+ or PSA&gt;20 ng/ml), intermediate-risk (stage T2b/T2c or Gleason 7 or PSA 10-20 ng/ml) and low-risk disease (stage T1/T2a and Gleason &#8804; 6 and PSA&lt;10 ng/ml). We expect the findings from this Project to significantly advance knowledge of susceptibility to aggressive PCa and racial/ethnic disparities in PCa risk, and to guide the development of future preventive, early detection and prognostic measures for AA men. The first phase of the study will include exome sequence data for approximately 7,500 cases and 5,000 controls from AAPC. The second phase of the study will include exome data for 5,000 cases from RESPOND and AAPC.ACKNOWLEDGMENTS and CONTRIBUTING SITES Multiethnic Cohort (MEC): The MEC and the genotyping in this study were supported by National Institutes of Health (NIH) grants CA63464, CA54281, CA1326792, CA148085, and HG004726. Cancer incidence data for the MEC and Los Angeles Study of Aggressive Prostate Cancer (LAAPC) studies have been collected by the Los Angeles Cancer Surveillance Program of the University of Southern California with federal funds from the National Cancer Institute (NCI)/NIH/Department of Health and Human Services (DHHS) under Contract No. N01-PC-35139, and the California Department of Health Services as part of the state-wide cancer reporting program mandated by California Health and Safety Code Section 103885, and grant 1U58DP000807-3 from the Centers for Disease Control and Prevention (CDC). Ghana Prostate Study (GPS): The Ghana Prostate Study was funded by the Intramural Program of the NCI/NIH/DHHS under Contract No. HHSN261200800001E. Men of African Descent and Carcinoma of the Prostate (MADCaP): We thank all MADCaP study participants. This work is a product of the MADCaP network. This work was supported by NCI/NIH grant U01CA184374 to Timothy Rebbeck and National Institute of General Medical Sciences (NIGMS) MIRA grant R35GM133727 to Joseph Lachance. Additional funding includes a seed grant from the Integrated Cancer Research Center at Georgia Institute of Technology. UGANDA: The UGANDA study was supported by NIH grant R01CA165862. Southern Community Cohort (SCCS) is funded by NIH grant CA092447. SCCS sample preparation was conducted at the Epidemiology Biospecimen Core Lab that is supported in part by the Vanderbilt Ingram Cancer Center (CA68485). Data on SCCS cancer cases were provided by Alabama Statewide Cancer Registry, Kentucky Cancer Registry, Office of Cancer Surveillance at Tennessee Department of Health, Florida Cancer Data System, Central Cancer Registry at North Carolina Division of Public Health, Georgia Comprehensive Cancer Registry, Louisiana Tumor Registry, Mississippi Cancer Registry, South Carolina Central Cancer Registry, Virginia Cancer Registry at Virginia Department of Health, and Cancer Registry at Arkansas Department of Health. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries (NPCR)/Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the NPCR/CDC. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. Karuprostate: The Karuprostate study was supported by the French National Health Directorate and by the Association pour la Recherche sur les Tumeurs de la Prostate. S&#233;verine Ferdinand, Marc Romana. The North Carolina - Louisiana Prostate Cancer Project (PCaP) is carried out as a collaborative study supported by the Department of Defense contract DAMD 17-03-2-0052. The authors thank the staff, advisory committees and research subjects participating in the PCaP study for their important contributions. We would also like to acknowledge the UNC BioSpecimen Facility and the LSUHSC Pathology Lab for our DNA extractions, blood processing, storage and sample disbursement (https://genome.unc.edu/bsp). Gene-Environment Interaction in Prostate Study (GECAP) was supported by NIH grant ES011126. King County Prostate Cancer Study (KCPCS) was supported by NIH grants CA056678, CA082664, and CA092579, with additional support from the Fred Hutchinson Cancer Research Center. We thank the participants in these studies, and Ms. Suzanne Kolb for help with study management. The Los Angeles Study of Aggressive Prostate Cancer (LAAPC) was funded by grant 99-00524V-10258 from the Cancer Research Fund, under Interagency Agreement #97-12013 (University of California contract #98-00924V) with the Department of Health Services Cancer Research Program. Cancer incidence data for the MEC and LAAPC studies have been collected by the Los Angeles Cancer Surveillance Program of the University of Southern California with Federal funds from the NCI/NIH/DHHS under Contract No. N01-PC-35139, and the California Department of Health Services as part of the state-wide cancer reporting program mandated by California Health and Safety Code Section 103885, and grant 1U58DP000807-3 from the CDC. Prostate Cancer Studies at MD Anderson (MDA) was supported by grants CA68578, ES007784, DAMD W81XWH-07-1-0645, and CA140388.

  Study phs002637

• Systems Analysis of the PfSPZ Vaccine in Kenyan Infants

  The PfSPZ vaccine is a candidate vaccine targeting the Plasmodium falciparum parasite, which is the cause of the most lethal type of human malaria. This study used de-identified blood samples collected from 316 infants aged 5 to 12 months (inclusive) enrolled in a Phase 2, randomized, placebo-controlled trial (NCT02687373) of the PfSPZ malaria vaccine, conducted in a region of western Kenya where malaria transmission is high and perennial. The study began in July, 2016, after peak malaria transmission, and was completed in August, 2018. In this study, three doses of the PfSPZ Vaccine (4.5x105 PfSPZ, 9.0x105 PfSPZ, and 1.8x106 PfSPZ) were tested against a normal saline placebo comparator. In all four groups, doses were administered in 3 doses at 0, 8, and 16 weeks by direct venous inoculation. Vaccine efficacy was determined at 3, 6, and 12 months of follow-up after the third immunization. RNA was extracted from whole blood collected in PAXgene tubes before PfSPZ immunization, and two weeks after the third (final) dose, from 262 children for which sufficient material was available at both time points (82% of 316 enrolled children; 525 samples). RNA was depleted of globin and ribosome transcripts before library generation and sequencing on the Illumina NovaSeq platform. RNA-seq expression data was analyzed to determine blood transcriptional signatures, before and after PfSPZ vaccine immunization, that predicts sterile protection from naturally occurring P. falciparum infection or delayed parasitemia at 3 months post-immunization. Gene expression data will also be correlated to P. falciparum-specific IgG antibody and cellular responses to identify possible molecular correlates of vaccine-induced immunogenicity

  Study phs002196

• Study of Controlled Human Malaria Infections to Evaluate Protection After Intravenous or Intramuscular Administration of PfSPZ Vaccine in Malaria-Naive Adults

  The study was performed to evaluate whole-blood transcriptomic profiles via RNA-seq before, during, and after immunization with the PfSPZ Vaccine in malaria-na&#239;ve, health adults enrolled in VRC 314 (NCT02015091). VRC 314 was designed as an open-label evaluation of the safety, tolerability, immunogenicity, and protective efficacy of the PfSPZ Vaccine. This study was designed to substantiate the initial results with the IV vaccination route for protection against CHMI that was observed in VRC 312 (NCT01441167). Based on the potential importance of dose and schedule in optimizing sustained immunity with this vaccine, an increase in PfSPZ IV dosage on schedules of 3 to 5 vaccinations was evaluated for protection against CHMI conducted early (about 3 weeks) and late (about 24 weeks) after completion of vaccinations. To assess if a higher dose given by another route confers protection, one group received PfSPZ IM, with half of the amount administered in each arm on a schedule with 4 vaccination. The primary objectives of the study were related to the safety and tolerability of vaccinations by the IV and IM routes of administration and protection against Plasmodium falciparum (Pf) challenge performed via a well-established CHMI procedure early (2-4 weeks) after completing schedules of 3 to 5 vaccinations. The secondary objective was related to the durability of protection at 20-26 weeks after the last vaccination, and exploratory objectives were related to the immunogenicity of the PfSPZ Vaccine and identifying potential immune correlates of protection. To further determine potential molecular correlates of immunogenicity and/or protection, RNA-seq was performed on whole blood collected from subjects in all dose groups at time points before, during, and after immunization.

  Study phs002423

• Blood Transcriptome Profiling Following Seizures

  The retrospective diagnosis or confirmation of a seizure, after the event, is very challenging. Many times clinicians can only use a patient's self-reported history. To further complicate the diagnosis, it is known that 20-30% of patients reporting a seizure actually suffer from psychogenic non-epileptic seizure (PNES). The patient has the behavior of a seizure, but does not suffer from brain seizure activity. Considerable time and resources are used to monitor PNES, and many patients undergo unnecessary therapy with anti-epileptic drugs. These resources could be more effectively used if we could confirm a seizure after the event (retrospective diagnosis). Here we propose a novel approach to distinguish seizures from PNES after the seizure event has happened.We have developed an accurate blood biomarker technology to diagnose acute brain injury, and assess chronic progression following brain injury. Previous studies support the premise that seizures affect blood RNA expression; here we assess temporal RNA expression pattern changes following seizure. We present preliminary preclinical data showing the discrimination of electric-stimulation evoked animal seizures. Here, we validate this maturing technology to assist with the discrimination of epileptic seizures from psychogenic non-epileptic seizures. We will analyze blood samples from patients undergoing video EEG monitoring in an epilepsy monitoring unit (Emory University Hospital, Atlanta GA). We expect 20% of these patients will have PNES. Once a patient has an EEG verified seizure, we will collect blood at various time points and identify biomarker RNA molecules in the blood. Blood samples will be collected from patients with non-verified seizures as control. These RNA expression values will be used to develop a predictive test for the occurrence of seizures. A biomarker gene panel will be developed from this exploratory project for validation in a larger patient population.

  Study phs003460