14313 results for ""Pennsylvania+German"+ACS+study+'Socius'+open+access"

in 22.71 milliseconds.

• TRACERx pilot study, phase 2

  Multi-region Illumina whole-exome and/or whole-genome sequencing on tumor regions collected from early-stage NSCLC patients who underwent definitive surgical resection prior to receiving adjuvant therapy.Patients covered by this dataset: L012, L013, L015, L017

  Dataset EGAD00001001918

• Deep-Seq: Resistance to anti-EGFR therapy in colorectal cancer

  In this study we performed ultra deep sequencing of genes associated with anti-EGFR resistance, such as KRAS, BRAF, PIK3CA, and EGFR in 17 plasma-DNA samples from a total of 10 patients treated with anti-EGFR therapy.

  Dataset EGAD00001000688

• Metastatic breast cancer targeted gene screen (2014-09-24)

  The samples will be sequenced for a targeted panel of cancer relevant genes (n ~ 370) and analysed for somatic mutations. This dataset contains all the data available for this study on 2014-09-24

  Dataset EGAD00001001018

• multi-region sequencing of tumor samples from PDAC patients

  This study includes 542 of multi-region sampled whole exome sequencing data from 83 pancreatic cancer patients in 6 individual experiments : Kras wildtype, local recurrence, treatment-naive (MetomeV2), radiotherapy plus chemotherapy (Radome), chemotherapy-only group (Treatome) and Proj_B-100-478.

  Dataset EGAD00001011109

• Whole Exome Sequencing of healthy Spanish individuals - VCF file

  The need for a detailed catalogue of local variability for the study of rare diseases within the context of the Medical Genome Project motivated the whole exome sequencing of 267 unrelated individuals, representative of the healthy Spanish population.

  Dataset EGAD00001003101

• Metastatic breast cancer targeted gene screen (2017-05-11)

  The samples will be sequenced for a targeted panel of cancer relevant genes (n ~ 370) and analysed for somatic mutations. This dataset contains all the data available for this study on 2017-05-11.

  Dataset EGAD00001003330

• SNV vcf files for CPCG Subclonal Heterogeneity in multiple and single regions

  SNV calls generated using the MuTect-TITAN-PhyloWGS from the CPC-GENE Subclonal Heterogeneity study using single and multiple regions

  Dataset EGAD00001004433

• Expression data

  This dataset contains the RPKM and raw read counts of expression for all the individuals. This dataset was generated as part of the following study: Panousis et al (2019). Combined genetic and transcriptome analysis of patients with SLE: Distinct, targetable signatures for susceptibility and severity.

  Dataset EGAD00001005039

• Clinical phenotypes/covariates

  This dataset contains the clinical phenotypes/covariates information for all the individuals. This dataset was generated as part of the following study: Panousis et al (2019). Combined genetic and transcriptome analysis of patients with SLE: Distinct, targetable signatures for susceptibility and severity.

  Dataset EGAD00001005040

• RNASeq files for Mullighan TXVI dataset

  RNASeq files for paper titled "Prognostic and therapeutic significance of leukemia subtypes and minimal residual disease measurements in pediatric acute lymphoblastic leukemia treated with contemporary risk-directed trial: a cohort study"

  Dataset EGAD00001006609

• 16S rRNA Rectal Mucus

  16S rRNA sequencing of rectal mucus samples from patients suspected to have colorectal cancer. This is 1 of 4 sequencing experiments on the same sample type.

  Study EGAS50000001262

• WES dataset

  Associated with Molecular biomarkers in progression from refractory celiac disease to the lethal cancer variety enteropathy associated T cell lymphoma (EATL) Study. Whole Exome Sequencing (WES) of 63 samples. WES analysis done to detect mutations and copy number aberration predictive for progression from RCD to EATL.

  Dataset EGAD50000001164

• Genentech Small Cell Lung Cancer (SCLC) Screen

  Exome capture, RNA-Seq, whole genome sequencing of set of Small Cell Lung Cancer samples.

  Study EGAS00001000334

• NGS_based_viability_screening_using_haploid_cell_line

  Identification of human deubiquitylating enzymes whose knock out result in hypersensitivity to DNA damaging agents, by comparing the sequence reads of ‘barcode region’ from mixed cell culture.

  Study EGAS00001001095

• Second generation noninvasive fetal genome analysis reveals de novo mutations, single-base parental inheritance, and preferred DNA ends

  Second generation noninvasive fetal genome analysis reveals de novo mutations, single-base parental inheritance, and preferred DNA ends

  Study EGAS00001001882

• TraIT Cell Line use case

  Experimental data collected from a set of cell lines. To be used as a test for pipelines and infrastructure.

  Study EGAS00001001476

• Matched_Pair_Cancer_Cell_line_Whole_Genomes

  We propose to definitively characterise the somatic genetics of 29 matched pair cell lines through generation of comprehensive catalogues of somatic mutations by high coverage genome sequencing.

  Study EGAS00001000160

• ICGC PedBrain DNA methylation sequencing

  DNA methylation profiling of 107 medulloblastoma and 8 control samples by high-coverage whole-genome bisulfite (WBGS) sequencing and Illumina Infinium HumanMethylation450k array.

  Study EGAS00001000561

• Single cell RNA-sequencing of GSCs and GBM tumours

  Characterization of glioblastoma tumors and glioblastoma stem cell (GSCs) lines with single cell or single nuclei RNA-sequencing.

  Study EGAS00001004656

• Extramammary Paget Disease

  In order to clarify the mutational landscape of Extramammary Paget disease, we performed exome-sequencing of surgical samples and target-sequencing of formalin-fixed, paraffin-embedded tissues.

  Study EGAS00001004746

• RNA-sequencing of Non-muscle Invasive Bladder cancer (NMIBC)

  This RNA-sequencing cohort includes 78 Non-muscle Invasive Bladder cancer (NMIBC) samples and 7 Muscle Invasive Bladder cancer (MIBC) samples.

  Study EGAS00001004358

• ESGI___Whole_Genome_Sequencing_of_samples_from_the_INGI_Val_Borbera_genetic_isolate__X10_

  Whole genome sequencing of sampels from an isolated population from the Val Borbera valley in Italy. The samples are sequenced using the Illumina HiSeq X Ten system.

  Study EGAS00001001123

• Phylogenetic evolution of metastatic melanoma.

  To explore molecular factors associated with evolution and resistance in melanoma evolution, we multi-lesion sequenced primary and metastatic sites collected from autopsy in seven patients.

  Study EGAS00001003582

• ChIP Seq data of multiple myeloma and plasma cell leukaemia cell lines

  ChIP-seq data (H3K4Me1, H3K4Me3, H3K27Ac histone modifications) on multiple myeloma cell line KMS11 and plasma cell leukaemia cell lines L363 and JJN3

  Study EGAS00001002414

• Pancreatic Cancer Sequencing Initiative OICR

  Pancreatic Cancer Sequencing Initiative for the International Cancer Genome Consortium at the Ontario Institute for Cancer Research.

  Study EGAS00001000395

• RNA sequencing of AD, MCI and control OM cells

  Total RNA sequencing of cultured OM cells derived from patients with Alzheimer's disease (AD), individuals with mild cognitive impairment (MCI) and cognitively healthy controls.

  Study EGAS00001006195

• Whole genome bisulfite sequencing on 10 multiple myeloma cases

  Data quality control and adaptor-trimmed were performed with the Trimomatic tool. Paired-reads were mapped to the hg19 human reference with methylCtools aligner.

  Study EGAS00001004346

• Exploring_the_landscape_of_somatic_mutations_in_normal_tissue___GI___LYNCH___WGS

  Somatic mutations (burdens and signatures) and clonal dynamics in normal human tissues from the gastrointestinal tract of individuals with tumour predisposition syndromes and DNA damage repair defects.

  Study EGAS00001003882

• Exploring_the_landscape_of_somatic_mutations_in_normal_tissue___GI___MAP___WGS

  Somatic mutations (burdens and signatures) and clonal dynamics in normal human tissues from the gastrointestinal tract of individuals with tumour predisposition syndromes and DNA damage repair defects.

  Study EGAS00001004122

• To determine the genomic profile of Triple Negative Breast Cancer patient-derived xenografts (PDX cohort)

  Specific BRCA and immune configurations determine optimal response to platinum-based chemotherapy in triple negative breast and ovarian carcinomas (PDX_WGS)

  Study EGAS00001005995

• Res1_HT29_exp2_MC_03_03_22

  1 sample is pure plasmid DNA and 10 samples are cell pellets for genomic DNA extraction. CRISPR PCR1 and PCR2 indexing - Please use standard Kozuke primers.

  Study EGAS00001006093

• Res1_H23_exp1_MC_04_03_22

  1 sample is pure plasmid DNA and 8 samples are cell pellets for genomic DNA extraction. CRISPR PCR1 and PCR2 indexing - Please use standard Kozuke primers.

  Study EGAS00001006091

• Res1_HT29_exp1_MC_02_03_22

  1 sample is pure plasmid DNA and 10 samples are cell pellets for genomic DNA extraction. CRISPR PCR1 and PCR2 indexing - Please use standard Kozuke primers.

  Study EGAS00001006092

• Data for noninvasive lung cancer subtyping study

  This dataset included cfMethyl-Seq data of 15 plasma cfDNA samples from 15 lung cancer patients and RRBS data of 58 lung tumor tissue samples from 58 lung cancer patients. The data were generated following the standard protocols.

  Dataset EGAD00001015344

• Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers

  To identify predictive biomarkers of response and resistance to platinum agents in PDX models of triple-negative breast cancer

  Study EGAS00001006393

• Data containing genome-wide SNP data from Northwestern Amazonia

  Provide new insights about the population history of NWA and identify the impact of intense population contact on patterns of genetic variation

  Study EGAS00001006767

• Whole exome sequencing (WES) of previously untreated AML samples

  MNC were isolated from bone of 95 AML patients at initial diagnosis via Ficoll gradient. WES has been performed on all 95 samples.

  Study EGAS00001007223

• AT2 COPD Transcriptomics

  We generated transcriptomes of primary human lung AT2 cells isolated from distal parenchyma of ex-smoker controls and COPD patients, with both mild and severe disease.

  Study EGAS00001007387

• Prognostic markers of DNA methylation and NGS sequencing in progressive glioblastoma from the EORTC-26101 trial

  These dataset contains NGS data from 380 samples from the EORTC-26101 clinical trial for patients with progressive glioblastoma.

  Study EGAS00001007421

• Exome sequencing data for 40 cases of alopecia areata and vitiligo

  Sequencing of independent unrelated cases of alopecia areata (total/ universal) and vitiligo (>10%, affected family member). DNA obtained from blood

  Study EGAS00001003831

• Kids First: Genomic Studies of Orofacial Cleft Birth Defects

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. The Kids First study of nonsyndromic orofacial cleft birth defects (OFCs) is a whole genome sequencing study of 415 White parent-case trios drawn from ongoing collaborations led by Dr. Mary L. Marazita of the University of Pittsburgh Center for Craniofacial and Dental Genetics, including collaborations with Dr. George Wehby of the University of Iowa, Dr. Jacqueline Hecht of the University of Texas, and Dr. Terri Beaty of Johns Hopkins University. Sequencing was done by the Washington University McDonell Genome Institute. The case in each of the Kids First trios has cleft lip (CL, Figure A), cleft palate (CP, Figure B), or both (CL+CP, Figure C): OFCs are genetically complex structural birth defects caused by genetic factors, environmental exposures, and their interactions. OFCs are the most common craniofacial anomalies in humans, affecting approximately 1 in 700 newborns, and are one of the most common structural birth defects worldwide. On average a child with an OFC initially faces feeding difficulties, undergoes 6 surgeries, spends 30 days in hospital, receives 5 years of orthodontic treatment, and participates in ongoing speech therapy, leading to an estimated total lifetime treatment cost of about $200,000. Further, individuals born with an OFC have higher infant mortality, higher mortality rates at all other stages of life, increased incidence of mental health problems, and higher risk for other disorders (notably including breast, brain, and colon cancers). Prior genome-wide linkage and association studies have now identified at least 18 genomic regions likely to contribute to the risk for nonsyndromic OFCs. Despite this substantial progress, the functional/pathogenic variants at OFC-associated regions are mostly still unknown. Because previous OFC genomic studies (genome-wide linkage, genome-wide association studies (GWAS), and targeted sequencing) are based on relatively sparse genotyping data, they cannot distinguish between causal variants and variants in linkage disequilibrium with unobserved causal variants. Moreover, it is unknown whether the association or linkage signals are due to single common variants, haplotypes of multiple common variants, clusters of multiple rare variants, or some combination. Finally, we cannot yet attribute specific genetic risk to individual cases and case families. Therefore, the goal of the current study is to identify specific OFC risk variants in Whites by performing whole genome sequencing of parent-case trios.

  Study phs001168

• Long-Term Outcome in Offspring and Mothers of Dexamethasone-Treated Pregnancies at Risk for Classical Congenital Adrenal Hyperplasia Owing to 21-Hydroxylase Deficiency

  Summary The purpose of this study is to perform the first long-term follow up study both of adolescents and young adults with a history of prenatal treatment with dexamethasone and of their mothers and to test for adverse medical or behavioral side effects. The emphasis will be on the outcome of this prenatal treatment in those fetuses who are not affected with steroid 21-hydroxylase deficiency (21OHD) form of congenital adrenal hyperplasia (CAH) and are either heterozygotes or homozygote-unaffected. Prenatal treatment of 46,XX fetuses with 21OHD (via administration of dexamethasone to the pregnant mother) has been shown to reduce the masculinization of the genitalia and, thereby, the later need for 'corrective' feminizing genital surgery and potential impairment of sexual functioning. Along with the suppression of excess prenatal androgen production and reduction of prenatal masculinization of the genitalia in 46,XX fetuses with 21OHD, prenatal dexamethasone treatment may reduce the behavioral masculinization that is well documented in untreated 46, XX patients with 21OHD. Those fetuses who are partially treated until diagnosis of an unaffected status (heterozygous or homozygous-unaffected) will be studied as well. This latter group is of importance because these fetuses are being unnecessarily treated, but we have no way of diagnosing the unaffected status before the 8th week of gestation when treatment must begin for the female fetus who is affected. As treatment is necessary only until term in the female fetus affected with classical CAH, male fetuses and unaffected or heterozygous female fetuses do not require treatment. Thus, only one out of eight fetuses will require prenatal treatment until term. Findings of adverse effects of glucocorticoid treatment in non-human mammals [1, 2] have raised concerns among other clinicians and investigators about potential adverse side effects of such treatment on the developing human. Thus, this study will address this concern and investigate the potential adverse side effects of prenatal treatment. Detailed Description Females with classical CAH owing to 21-hydroxylase deficiency are born with ambiguous genitalia due to the production of excess androgens in utero. Prenatal treatment with dexamethasone was inaugurated in 1978 by Maguelone Forest and has been the standard of practice in the United States since 1986. Dexamethasone, which crosses the placental barrier, suppresses the fetal adrenal gland production of androgens, thus preventing ambiguous genitalia in the affected female. Children of both sexes are prenatally treated as soon as pregnancies at risk are confirmed. Treatment in females with 21OHD continues to term, but is discontinued in males and unaffected females. To date, 685 pregnancies have been diagnosed, of which 366 fetuses were treated. These investigators will study prenatally treated adolescents and adults 12 years and older with respect to medical and behavioral outcomes (see Table 5). In addition, mothers of children prenatally treated for varying periods of time for suspected 21OHD will be studied for long-term side effects of dexamethasone treatment administered during pregnancy. The long-term outcome in these children and their mothers has never before been studied.

  Study phs001317

• The Role of E2F4 in Controlling Resistance to Irinotecan (CPT-11) in Human Colon Cancer

  This study reports the results of RNA sequencing (RNA-seq) experiments performed on three isogenic clones of the human HT29 colon cancer cell line, genetically engineered to achieve the selective inactivation of the adenovirus early 2 (E2) gene transcription factor 4 (E2F4) protein, a key functional component of the multimeric transcriptional repression complex known as the dimerization partner (DP), retinoblastoma-like (RB-like), E2F and multi-vulva class B (MuvB) complex (DREAM). In previous studies, we identified E2F4 as a key regulator of colorectal cancer (CRC) resistance to irinotecan (CPT-11), a cytotoxic agent that stands at the backbone of multiple chemotherapy regimens for the treatment of metastatic CRCs. The molecular mechanisms linking E2F4 to irinotecan resistance, however, remain poorly understood. The present study was designed to identify which genes are under the transcriptional control of E2F4, either at baseline or following exposure to SN38 (i.e., the active metabolite of irinotecan, generated in vivo by biotransformation in the liver) in order to clarify the role played by E2F4 in shaping colon cancer resistance to chemotherapy. The cell line used for this study (HT29) is aneuploid and contains three copies of the E2F4 gene, because of a trisomy of chromosome 16, where the E2F4 gene is located (Kawai et al., Genes, Chromosomes & Cancer, 34:1-8, 2002; PMID: 11921276). HT29 cells were infected with lentivirus vectors encoding for CRISPR/Cas9 constructs designed to selectively inactivate the E2F4 gene, using three distinct guide-RNAs (gRNAs), each targeting a different sequence within the proximal exons of the E2F4 gene (exon 1, exon 2). Lentivirus-infected cells were sub-cloned by single-cell fluorescence-activated cell sorting (FACS), based on the differential expression of a fluorescent reporter (EGFP) expressed in tandem with the gRNAs. Isogenic clones (EGFP+) were then screened to identify those with a tri-allelic knock-out, as revealed by both genetic sequencing of the E2F4 gene (revealing the presence of three distinct frameshift mutations) and Western blot (revealing complete loss of E2F4 protein expression). The study includes twelve (n=12) RNA-seq experiments, representative of 3 experimental replicates (i.e., three distinct isogenic clones of the HT29 cell line, each displaying complete loss of E2F4 expression) and 3 negative controls (i.e., three independent preparations of the parent HT29 cell line, infected with a lentivirus vector encoding for a non-targeting gRNA) exposed to 2 distinct in vitro cell culture conditions: a) treatment with SN38 resuspended in dimethyl sulfoxide (DMSO); or b) treatment with DMSO alone (negative control). The in vitro treatment regimen used for SN38 (32 nM, 24 hours) was designed so that the exposure to SN38 experienced in vitro by HT29 cells would mirror the exposure to SN38 experienced in vivo by malignant tissues, as measured, for example, in metastatic CRC patients receiving a standard dose of irinotecan (180 mg/m2) administered by intravenous infusion over 90 minutes (Deyme et al., Cancer Chemotherapy and Pharmacology, 88:247-258, 2021; PMID: 33912999).

  Study phs003560

• Autism Post-Mortem Brain RNA-Sequencing: SRRM4 Splicing Study

  Purpose: The goal of this study was to assess the status of splicing changes in microexons in the cortex of individuals with autism. Methods: We performed RiboZero Gold (rRNA depleted) 50bp PE RNA-seq in a larger set of case and control samples to define 12 autism and 12 control samples showing the greatest global differential gene expression change. These samples, which show differential expression of the splicing regulator SRRM4, were used to evaluate global splicing changes. Results: Within these samples, 126 of 504 (30%) detected alternative microexons display, a mean ΔPSI > 10 between ASD and control subjects of which 113 (90%) also display neural-differential regulation. By contrast, only 825 of 15,405 (5.4%) longer (i.e. > 27 nt) exons show such misregulation, of which 285 (35%) correspond to neural-regulated exons. Notably, we also observe significantly higher correlations between microexon inclusion and nSR100 mRNA expression levels across the stratified ASD samples and controls, for those microexons regulated by nSR100 relative to those microexons that are not regulated by this factor (p=1.4x10-7, Wilcoxon Sum Rank test). Conclusions: These data suggest microexon regulation is a potentially important mechanism underlying ASD and likely other neurodevelopmental disorders.

  Study phs000872

• Microbiome-Host Interactions in Oral Squamous Cell Carcinoma: a Metatranscriptomic Exploratory Study

  Oral cancer (predominantly squamous cell carcinoma; OSCC) is the 14th most prevalent malignancy worldwide, accounting for more than 300,000 new cases and 145,000 deaths annually. Despite advances in cancer treatment modalities, OSCC continues to have poor prognosis with 5-year survival rates less than 50%. Although use of tobacco and alcohol consumption constitute the major risk factors, there is emerging evidence for the role of the microbiome in OSCC. However, studies on the association between the microbiome and OSCC has so far focused on compositional analysis and has been largely limited to the bacterial component of the microbiome. The aim of this study is to characterize the transcriptional activity (function) as well as composition of the multi-kingdom microbiome associated with OSCC and correlate it with the gene expression of the host using ultra-deep metatranscriptome sequencing, which will provide new insight into the role of the microbiome in OSCC and the possible mechanisms by which the tumor’s microbial community may influence on its behavior. This project comprises RNA-Seq data from twenty OSCC tumor/normal tissue pairs and twenty tongue scraping samples from healthy controls. However, due to consent constraints, the human sequences from the control data are filtered out.

  Study phs002678

• Genome-Wide Association Study of the Taste and Hedonic Ratings of the Low-Calorie Sweetener Acesulfame Potassium

  Acesulfame potassium (Ace-K) is a low-calorie sweetener (LCS) widely used as an additive in foods and beverages and an excipient in pediatric medicines. Because genetic variants play a role in individual variation in the taste of Ace-K, we sought to identify genetic contributions to its taste using a genome-wide association study (GWAS). 141 adult panelists rated the taste of an aqueous solution of Ace-K using the general labelled magnitude scale (gLMS) and its palatability using the hedonic gLMS. Genotypes were assayed on the Infinium Global Screening Array. Imputation of genotypes was performed on the Michigan Imputation Server with 1000 Genomes Project phase 3 genotype data as reference. Linear regression was performed to test genetic associations between genotyped and imputed variants with three gLMS ratings (bitterness (square-root-transformed), hedonic, sweetness) of Ace-K using PLINK2, adjusting for standardized age, sex, and the first 10 principal components of genetic ancestry. We identified that a locus spanning several TAS2R (Taste receptor 2) genes was associated with bitterness ratings of Ace-K and a locus within the gene ELMO1 (Engulfment and Cell Motility Protein 1) was associated with hedonic ratings of Ace-K (p-values 40594245).

  Study phs004031

• This project aims to study human memory capacity, including short-term memory and long-term memory, systematically via genome-wide association studies

  Development of high-throughput genotyping platforms provides an opportunity to identify new genetic elements related to complex cognitive functions. Taking advantage of multi-level genomic analysis, here we studied the genetic basis of human short-term (STM, n=1,620) and long-term (LTM, n=1,526) memory functions. Heritability estimation based on single nucleotide polymorphism showed moderate heritability of short-term memory but very low heritability of long-term memory. In a two-step genome-wide association study, the markers rs13151012 and rs1558360 passed genome-wide significance (p < 5×10-8) in digit-span STM task and for the first principal component shared by two STM tasks; however, none of them survived the replication. In turn, we selected the ten most significant single nucleotide polymorphisms (SNPs) for replication tests. Among them, a SNP near ZFAT was significantly associated with STM performance in another independent population of 2,789; a polymorphism within BCAT2 was significantly associated with LTM in another independent population of 1,865. Furthermore, we performed a pathway analysis based on the current genomic data and found six pathways significantly associated with STM capacity and one pathway associated with LTM capacity.

  Study EGAS00001002875

• Bladder Cancer Organoids as a Functional System to Model Different Disease Stages and Therapy Response

  The study 'Bladder Cancer Organoids as a Functional System to Model Different Disease Stages and Therapy Response' reports the genomic characterization at the single allele level upon Whole Exome Sequencing of Bladder Cancer (BLCa) Patient Tumor (PT) samples obtained from 18 patients and corresponding Patient Derived Organoids (PDOs), implementing the SPICE pipeline (Ciani Y et al). Our cohort included 21 PTs and 22 PDOs. In this study, we generated a unique biobank resource of BLCa organoids that encompasses a broad spectrum of disease stages. We demonstrated that PDOs retain cancer heterogeneity and mutational burden. Furthermore, we observed that BLCa PDO can have different morphologies which may reflect tumor-specific features. Indeed, a solid morphology may be associated with more advanced tumors, as supported by the high PDO genomic burden and high primary tumor stage. Moreover, with our drug screening pipeline, we demonstrated the clinical relevance and feasibility of using a BLCa PDO-based drug assay for comparing the standard of care (SOC) drugs with compounds not currently in use for BLCa. Response to SOC was highly heterogeneous with approximately 50% of non-muscle invasive bladder cancer and 33% of muscle invasive bladder cancer PDOs showing no or minimal response. The most effective targeted therapy was lapatinib. We used an integrative analysis of drug response profiles with matched PDO genomic analysis to determine enrichment thresholds for candidate markers of therapy resistance and sensitivity. Importantly, by assessing the clinical history of longitudinally sampled cases, the clonal evolution of the disease could be determined and matched with PDO drug response profiles.

  Study phs003149

• Genetic Basis of Developmental Disabilities

  Developmental disabilities are birth defects that cause lifelong problems with how a body part or system works. Developmental disabilities include nervous system insults affecting how the brain, spinal cord and nervous system function; they cause intellectual disability, including Down syndrome and fragile X syndrome; and they also cause learning and behavioral disorders, such as autism spectrum disorders. At the Kennedy Krieger Institute, approximately 450 inpatients and 13,000 outpatients are seen per year (involving 114,000 visits). For most of these disorders, the underlying molecular cause has not been identified. Some, such as chromosomal disorders, have a strongly genetic basis while others, such as traumatic brain injury, are caused by environmental insults but are nonetheless influenced by the genetic background. The purpose of the present study is to identify chromosomal abnormalities underlying a variety of developmental disabilities. The approach is to obtain blood and saliva from children, and from one or both biological parents (and in some cases from siblings and/or additional relatives). Genomic DNA is purified and assayed on single nucleotide polymorphism (SNP) microarrays and/or by sequencing, including whole genome sequencing. These technologies provide high resolution information about chromosomal changes, and the information provided by the parental (and other relatives') DNA allows an interpretation of whether changes in a child are inherited or occur de novo. The study design includes multiple data analysis procedures to interpret the biological significance of findings of chromosomal changes relative to a child's parents, relative to children with similar diagnoses, relative to children with other chromosomal anomalies, and (in some cases) relative to the chromosomal status of siblings. We will further interpret the significance of the findings relative to the general (apparently normal) population by obtaining publicly available data from apparently normal individuals.

  Study phs000337

• NHLBI TOPMed: Genetics of Cardiometabolic Health in the Amish

  The Amish Complex Disease Research Program includes a set of large community-based studies focused largely on cardiometabolic health carried out in the Old Order Amish (OOA) community of Lancaster, Pennsylvania (http://medschool.umaryland.edu/endocrinology/amish/research-program.asp). The OOA population of Lancaster County, PA immigrated to the Colonies from Western Europe in the early 1700's. There are now over 30,000 OOA individuals in the Lancaster area, nearly all of whom can trace their ancestry back 12-14 generations to approximately 700 founders. Investigators at the University of Maryland School of Medicine have been studying the genetic determinants of cardiometabolic health in this population since 1993. To date, over 7,000 Amish adults have participated in one or more of our studies. Due to their ancestral history, the OOA may be enriched for rare variants that arose in the population from a single founder (or small number of founders) and propagated through genetic drift. Many of these variants have large effect sizes and identifying them can lead to new biological insights about health and disease. The parent study for this WGS project provides one (of multiple) examples. In our parent study, we identified through a genome-wide association analysis a haplotype that was highly enriched in the OOA that is associated with very high LDL-cholesterol levels. At the present time, the identity of the causative SNP - and even the implicated gene - is not known because the associated haplotype contains numerous genes, none of which are obvious lipid candidate genes. A major goal of the WGS that will be obtained through the NHLBI TOPMed Consortium will be to identify functional variants that underlie some of the large effect associations observed in this unique population.

  Study phs000956