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PubMed2006

Blood genomic profiling: novel diagnostic and therapeutic strategies for stroke?

Findings from gene expression profiling studies are leading to new diagnostic and therapeutic strategies that can be applied in medical practice, especially in the field of oncology. Promising results of gene expression profiling of the peripheral blood in patients with ischaemic stroke have been obtained in recent pilot studies, demonstrating a partially reproducible gene signature of acute cerebral ischaemia. However, questions remain. Given that blood is at least in part a surrogate tissue for ischaemic stroke, the specificity of these signatures needs to be evaluated. Furthermore, it needs to be determined whether standardization of this methodology is required and whether clinical signatures can be identified that are improvements over the tools currently used in clinical practice. Clinically useful signatures would include those of haemorrhagic as well as ischaemic stroke, reclassification of stroke type and prognosis, and vascular disease risk. If these conditions are met, then it should be possible to develop cost-effective and rapid assays.

Blood↗
PubMed1993

[Diagnostic clue and genomic analysis of LDH-M subunit deficiency].

Lactate dehydrogenase (LDH) M(A) subunit deficiency was first discovered by urinary discoloration and a discrepancy of laboratory data. Since then, five other families with this disorder have been reported in the Japanese population. The response of pyruvate concentration after forearm ischemic work is specific for LDH-M subunit deficiency. During strenuous exercise ATP production is significantly impaired and muscle tissue is damaged. A genetic study revealed a deletion of 20 base-pairs in exon 6 of the LDH-M gene in four families that were homozygous and one family that was heterozygous for LDH-M subunit deficiency. This mutation results in a frame-shift translation and premature termination. In addition to this mutation, we found a nonsense mutation at codon 328 in exon 7 in an individual heterozygous for LDH-M subunit deficiency, and a deletion of 3 base-pairs, TGT at codon 127 in exon 3 in a proposita who was homozygous and in her parents who were heterozygous for LDH-M subunit deficiency in the fifth family. Therefore, molecular heterogeneities were revealed in genetic mutations of LDH-M subunit deficiency.

Adolescent↗
PubMed1990

Restriction endonuclease analysis of alcelaphine herpesvirus 1 DNA and molecular cloning of virus genomic DNA for potential diagnostic use.

Alcelaphine herpesvirus 1 (AHV-1) genomic DNA was analyzed using restriction enzymes having recognition sequences both low in guanine-cytosine content (BamHI, KpnI, HindIII) and high in guanine-cytosine content (SmaI, AvaI, ApaI). The results from the restriction enzyme analyses along with exonuclease treatment demonstrated that the termini of AHV-1 DNA are likely composed of polyrepetitive sequences high in guanine-cytosine content similar to those found in Herpesvirus saimiri DNA. Cleaving AHV-1 DNA with the restriction enzyme SmaI produced polyrepetitive sequences that appeared as low molecular weight supermolar bands less than 1 kilobase pairs (kb) in size. Analysis of AHV-1 DNA cleaved with HindIII indicated that the polyrepetitive sequences are approximately 29.5 kb in size. The total molecular weight for AHV-1 DNA was determined to be approximately 118 kb. Seventy-five percent of the AHV-1 genome was cloned into the plasmids pAT153 and pBR322. Cloned DNA fragments representing unique sequences of the AHV-1 genome hybridized with AHV-1 genomic DNA but showed no appreciable hybridization with AHV-2 DNA or bovine herpesvirus 1, 2, or 4 DNA.

Animals↗
PubMed1995

FISH in genome research and molecular diagnostics.

Fluorescence in situ hybridization (FISH) has profoundly altered the aspect of genome research and molecular diagnostics. Deletions of only a few kilobases can be detected by hybridizing probes to naked DNA fibers. Loss or gain of chromosomal material in tumor cells can be visualized using comparative genome hybridization. Further diversification of FISH application will result from new ultrasensitive detection techniques.

Chromosome Aberrations↗
PubMed2006

Developing and evaluating genomics- or proteomics-based diagnostic tests: statistical perspectives.

The completion of the Human Genome Project and the ongoing sequencing of mouse, rat, and other genomes have led to an explosion of genetics-related technologies that are finding their way into all areas of biological research in both basic sciences and clinical applications. High-throughput genomics and proteomics technology has been quickly adapted to develop tools for clinical and pharmacological applications. Because molecular alterations usually occur much earlier than histological, physiological, and clinical abnormality, researchers hope to extend the applications of genomics and/or proteomics technology to early diagnosis of diseases and clinical outcome prognosis. Recently, some successful attempts in molecular diagnosis or prognosis have been published. However, for such tests to be translated from the bench to the bed, they must meet some rigorous standards. To develop a clinically meaningful genomics-based diagnostic test, we must have good study design, appropriate statistical analyses, and valid assessment of its clinical efficacy. In this chapter, we discuss statistical considerations on the process of developing reliable and useful genomics- or proteomics-based tests.

Diagnostic Techniques, Cardiovascular↗
PubMed2025

Comparing the performance of exome and genome sequencing for rare disease diagnostics: A randomized implementation effectiveness trial.

PURPOSE: Exome sequencing (ES) and genome sequencing (GS) can improve rare disease diagnosis but are not routinely available in many jurisdictions. To inform implementation, we report on a randomized implementation effectiveness trial comparing ES and GS. METHODS: Eligible trios were randomized to receive ES or GS in the same clinically accredited laboratory. Patient-level data on diagnostic utility and turnaround times were collected. Outcomes were compared statistically between clinically important subgroups. RESULTS: Of 1048 patients, 68.5% had syndromic intellectual disability/developmental delay (ID/DD) and 20.5% had multisystem disorders without ID/DD. Most had prior genetic test(s) that were nondiagnostic (95.5%), and of these, 91.6% included chromosome microarray. Diagnostic yields were 33.8% and 33.6%, for ES (n = 526) and GS (n = 522), respectively. Within sequencing groups, diagnostic results were more frequent among those with ID/DD than those without (P < .005). For routine (ie, nonexpedited) patients (n = 1020), 87.0% were reported in <12 weeks, and the mean turnaround time was 55.5 days (SD: 24.0). Turnaround time for ES and GS did not differ; however, result type (P < .001) and age of onset (P < .005) significantly affected turnaround time. CONCLUSION: Findings provide robust evidence of diagnostic utility and timeliness of ES and GS and will inform policy related to the organization, delivery, and reimbursement of clinical-grade genome diagnostics for rare diseases.

Adolescent↗
PubMed1996

Conservation of low-copy gene loci in Old World leishmanias identifies mechanisms of parasite evolution and diagnostic markers.

Genome plasticity has been hypothesized to be a driving force behind parasite speciation. We have evaluated divergence in single and low-copy genes in terms of locus organization, chromosomal localization and gene expression in Leishmania infantum, L. major, L. tropica and three widely divergent geographic isolates of L. donovani. Seventeen genes of low to moderate copy number (1-4 copies/haploid genome) were analyzed to identify restriction fragment length polymorphisms (RFLPs) providing heritable markers distinguishing Old World (OW) leishmanias. These RFLP markers were conserved in parasite isolates from primary infections demonstrating their utility as diagnostic tools. The species designations established by RFLP analysis of field isolates was confirmed by use of monoclonal antibodies. All 17 genes were present in each OW leishmania analyzed except LSIP (A45), which was absent from L. infantum. The 17 genes were found to be distributed among 9 distinct chromosomes. However, in spite of variations in chromosome karyotypes among the various OW leishmanias, individual gene probes localized to a similar sized chromosome from each isolate. These observations coupled with a molecular tree derived from RFLP data suggest that the OW leishmanias comprise a monophyletic lineage, with species associated with cutaneous disease exhibiting the greatest level of divergence. Data from this study supports previous observations that species causing cutaneous and visceral disease have diverged primarily by nucleotide substitutions. Such nucleotide divergence may not only lead to changes in protein function and antigenicity, but may also alter gene regulation programs as exemplified by the finding that the LdI-9-5 and LdE-6-1 genes were expressed only in visceralizing leishmanias.

Animals↗
PubMed2006

Translating genomic biomarkers into clinically useful diagnostics.

The landmark sequencing of the human genome has ushered in a new field of large-scale research. Advances in understanding the molecular basis of disease have opened up new opportunities to develop genomics-based tools to diagnose, predict disease onset or recurrence, tailor treatment options, and assess treatment response. Although still in the early stages of research and development, genomic biomarker research has the capability of providing a comprehensive insight into pathophysiological processes as well as more precise predictors of outcome not previously attainable with traditional biomarkers. Before genomic biomarkers are incorporated into clinical practice, several issues will need to be addressed in order to generate the necessary levels of evidence to demonstrate analytical and clinical validity and utility. In addition, efforts will be needed to educate health professionals and the public about genomics-based tools, revise regulatory oversight mechanisms, and ensure privacy safeguards of the information generated from these new tests.

Biomarkers↗
PubMed1994

Advances in genome research and molecular diagnostics.

A diverse scala of refined molecular techniques, developed during early positional cloning and the Human Genome project, has caused a rapid increase of our insight into the cause of genetic diseases. Nowadays, from cytogenetic rearrangements to point mutations can be readily detected by a variety of techniques. This not only has broadened our understanding, but has also enormously assisted in providing rapid and specific diagnosis, hence reducing uncertainty and improving the choices for those concerned with genetic disease in their family. While initially restricted to the DNA-level, diagnostic technology has gradually been tailored to suit the specifics of the diseases in question, incorporating RNA and protein analysis. The latest development in the analysis of genetic disease is reviewed.

Genetic Diseases, Inborn↗
PubMed2002

The Human Genome Project and the future of diagnostics, treatment and prevention.

The Human Genome Project, the mapping of our 30,000-50,000 genes and the sequencing of all of our DNA, will have major impact on biomedical research and the whole of therapeutic and preventive health care. The tracing of genetic diseases to their molecular causes is rapidly expanding diagnostic and preventive options. The increased insights into molecular pathways, gained from high-throughput 'functional genomics', using DNA-chip and protein-chip approaches and specially designed animal model systems, will open great prospects for pharmacological and genetic therapies. Powerful bioinformatics and biostatistics will further improve our pattern recognition and accelerate progress. A rapidly expanding area of high expectations is that of 'pharmacogenomics': the design of more effective drugs with lower toxicity through tailoring of drug treatment to individual, genetically determined differences in drug metabolism. Not only will this decrease the cost of health care through reduction of adverse drug reactions, but a better stratification of populations will also provide more statistical power farther upstream in drug trials. However, the optimal benefits from the current explosion of 'data mining' will only be realized when the basic data are made and kept publicly accessible, while at the same time safeguarding the protection of intellectual property arising from downstream inventions. This is one of the goals of HUGO, the international Human Genome Organization, established 13 years ago to assist coordination of data acquisition and exchange and societal implementation of the genome project. Additional points of attention in this historic endeavour are the prevention of stigmatization and discrimination and the safeguarding of a worldwide balance in the contribution by--and benefits to--different populations, while respecting the diversity in cultures and traditions.

Ethics, Medical↗
PubMed1981

A sensitive method for the production of diagnostic fingerprints of the genome segments of field isolates of rotavirus.

The 3'-terminal labelling procedure for analyzing the genome segment profile of field isolates of rotavirus (Clarke and McCrae, 1981, J. Virol. Methods 2, 203) has been further developed to produce a rapid and sensitive method for generating diagnostic fingerprints from individual species of double-stranded RNA. The fingerprints were obtained by a one-dimensional resolution of overlapping terminally labelled oligonucleotides produced by partial nuclease digestion with a base-specific nuclease. This fingerprinting method should be of great value in characterizing the molecular details of genome segment variation and will facilitate detailed molecular epidemiological studies of this important virus group.

Animals↗
PubMed1994

Polyacrylamide gel electrophoresis of viral genomic RNA as a diagnostic method for infectious pancreatic necrosis virus detection.

A rapid and simple technique for the diagnosis of IPNV from cell culture and infected fish tissues has been developed. It is based on the observation of IPNV bisegmented double-stranded RNA genome in silver stained polyacrylamide gels after electrophoresis. The method is highly specific and can detect as little as 1 ng of viral RNA, which corresponds to 1 x 10(5) pfu, making it possible to visualize the viral genome as soon as the initial cythopatic effect appears. Furthermore, the RNA viral genome could be detected directly from fish tissues when fish showed clear clinical signs of the disease. The method has the advantage of detecting any strain of IPNV. An acrylamide concentration of 6% and bisacrylamide concentration of 0.13% give a rapid and definitive result in less than 6 h.

Animals↗
PubMed2005

System to assess genome sequencing needs for viral protein diagnostics and therapeutics.

Computational analyses of genome sequences may elucidate protein signatures unique to a target pathogen. We constructed a Protein Signature Pipeline to guide the selection of short peptide sequences to serve as targets for detection and therapeutics. In silico identification of good target peptides that are conserved among strains and unique compared to other species generates a list of peptides. These peptides may be developed in the laboratory as targets of antibody, peptide, and ligand binding for detection assays and therapeutics or as targets for vaccine development. In this paper, we assess how the amount of sequence data affects our ability to identify conserved, unique protein signature candidates. To determine the amount of sequence data required to select good protein signature candidates, we have built a computationally intensive system called the Sequencing Analysis Pipeline (SAP). The SAP performs thousands of Monte Carlo simulations, each calling the Protein Signature Pipeline, to assess how the amount of sequence data for a target organism affects the ability to predict peptide signature candidates. Viral species differ substantially in the number of genomes required to predict protein signature targets. Patterns do not appear based on genome structure. There are more protein than DNA signatures due to greater intraspecific conservation at the protein than at the nucleotide level. We conclude that it is necessary to use the SAP as a dynamic system to assess the need for continued sequencing for each species individually and to update predictions with each additional genome that is sequenced.

Base Sequence↗
PubMed2006

Antigen mining with iterative genome screens identifies novel diagnostics for the Mycobacterium tuberculosis complex.

The definition of antigens for the diagnosis of human and bovine tuberculosis is a research priority. If diagnosis is to be used alongside Mycobacterium bovis BCG-based vaccination regimens, it will be necessary to have reagents that allow the discrimination of infected and vaccinated animals. A list of 42 potential M. bovis-specific antigens was prepared by comparative analysis of the genomes of M. bovis, M. avium subsp. avium, M. avium subsp. paratuberculosis, and Streptomyces coelicolor. Potential antigens were tested by applying them in a high-throughput peptide-based screening system to M. bovis-infected and BCG-vaccinated cattle and to cattle without prior exposure to M. bovis. A response hierarchy of antigens was established by comparing responses in infected animals. Three antigens (Mb2555, Mb2890, and Mb3895) were selected for further study, as they were strongly recognized in experimentally infected animals but with low or no frequency in BCG-vaccinated and naïve cows. Interestingly, all three antigens were recognized in animals vaccinated against Johne's disease, suggesting the presences of epitopes cross-reacting with M. avium subsp. paratuberculosis antigens. Eight peptides from the three antigens studied in detail were identified as immunodominant and were characterized in terms of major histocompatibility complex class II restriction element usage and shown to be restricted through both DR and DQ molecules. Reasons for antigenic cross-reactivity with M. avium subsp. paratuberculosis and refinement of the in silico strategy to predict such cross-reactivity from the primary protein sequence will be discussed. Evaluation of the peptides identified from the three dominant antigens by use of larger field studies is now a priority.

Amino Acid Sequence↗
PubMed2001

Vertebrate serpins: construction of a conflict-free phylogeny by combining exon-intron and diagnostic site analyses.

A combination of three independent biological features, genomic organization, diagnostic amino acid sites, and rare indels, was used to elucidate the phylogeny of the vertebrate serpin (serine protease inhibitor) superfamily. A strong correlation between serpin gene families displaying (1) a conserved exon-intron pattern and (2) family-specific combinations of amino acid residues at specific sites suggests that present-day vertebrates encompass six serpin gene families which evolved from primordial genes by massive intron insertion before or during early vertebrate radiation. Introns placed at homologous positions in the gene sequences in combination with diagnostic sequence characters may also constitute a reliable kinship indicator for other protein superfamilies.

Amino Acid Sequence↗