A Special Calling: A Biography of The Reverend Lud Flanigan

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Once with it his acquaintance, including again joining participants and excepting the participants group. For other genes, there are no standards. For each type of data, old and new, the principles of standards, validation, quantification and transparency apply. Many of the expected gene variants have not been identified or characterized in world populations. Hence, complete re-sequencing of a gene proven or suspected to be involved in monogenic and polygenic diseases will be required to determine causal linkages between genes and phenotype.

A fundamental problem with assessing phenotypes is the diversity of the underlying molecular pathways that cause disease, and as a consequence the heterogeneity in clinical manifestations, age of onset, severity, complications, and age of death. Other groups Kaput, et al. Since the HVP seeks to collect data from laboratories and clinics, phenotype templates are needed to define ranges of i minimum sets of clinical data, ii range of subset data, and iii maximum datasets.

Such hierarchical template structures will allow scientists in all countries to participate in data and sample collection. Clinical and pathology data standards must be developed by experts in each genetic disorder for interpreting the effects of genetic variation. If a cellular function can be established that appears to correlate with the clinical syndrome, then in vitro assays could be used to classify whether a variant retains or loses function.

Standards for performing and interpreting the assays are crucial if these methods are to be accepted as a mechanism for classifying variants clinically Couch et al. In cancer genetics, the correlation of mismatch repair defects with Lynch syndrome Hereditary Non-Polyposis Colorectal Cancer is probably the most well-established example Ou et al. Multiple studies in recent years have confirmed the value of comparative sequence analysis in helping to predict whether a missense variant is pathogenic or not reviewed in Tavtigian et al.

However, the issues of standards, validation, and transparency also apply to computational methods. Most importantly, the quality of a multiple sequence alignment is critical to their accuracy Ahola et al. The choice of ortholog sequences that is used, the quality of cDNA or genomic data, and the methods used to construct the alignment are all important features.

However, several of the more commonly used algorithms have been updated. Algorithms exist for coding region variants and predictions of altered splice sites Nalla and Rogan, ; Spurdle et al. New methods, including both rule-based and machine-learning approaches, are being developed Tavtigian et al. Historically, gene variation data were first collected for specific gene s causing a Mendelian disorder or a change in the phenotype.

These listings usually were initiated and driven by the interests of an expert using the collection for research, clinical or diagnostic applications. Currently there are over such LSDBs http: Complete collection and expert curation of gene sequence variants and their coupling to phenotypic consequences if any , will be essential for proper future healthcare and research. Data Transfer and Databasing plans are outlined in Box 4. The breadth and depth of information available about human variation are rapidly expanding as new technologies e.

Uncomplicated methods of access are needed for multiple user communities with differing expertise in genetics, clinical medicine, nutrition, physiology, and probably the public. Information generated by the HVP will have many of those dimensions, ranging from how variants are identified, the type of variant, the physiological parameters associated with the variant, and where and how records are maintained and accessed.

How the data are represented will be a challenge since information will come from published literature or text-rich resources such as OMIM or GeneReviews http: The scope of the data, which includes locations of variants on reference sequences to phenotypes in humans and model organisms, increases the dimensionality. Hence, the scale of information for human genetic variation and linked phenotype can range from a single text document to petabytes of raw data derived from sequencing thousands of genomes to a high level of coverage and accuracy. Model databases capable of accessing known variants will be developed from pilot projects and provide a resource for clinicians, patient advocates, and the public i.

Given the dimensionality issues and the challenges they represent, the HVP will help develop an infrastructure to identify variants relative to a reference standard and allow facile linking of data with appropriate tools. Notification schemes would be developed to indicate missing data for each variant. The HVP is identifying a progression of doable tasks with milestones for each. The scope of information to be centralized requires further debate, but could include items described in Box 5.

Reference gene-specific standards to support LSDBs and genetic testing groups see http: With the understanding that large data sets are only as useful as their ease of access, the HVP can also foster portal sites to help direct users to tools and resources of interest, and identify areas requiring additional development. Tutorials comparing and contrasting different resources might also be commissioned.

Topics that must be addressed are how to access information in the published literature, the effect of variation on transcription, the significance of conserved non-coding regions on phenotypic variation, identification of mRNA splice sites, descriptions on the structure and maintenance of LSDBs, and strategies for interpreting the impact of single e. A major barrier to the development of comprehensive analyses of human genetic variation, and therefore LSDBs, is the reward system for clinicians and academic researchers.

Non-academic clinicians typically receive little or no credit for contributing to the scientific literature, and academic clinicians and basic researchers cannot easily persuade journals to publish the 50 th variant of a gene that has an observable effect on phenotype. Database entries could be a mandatory quality control standard for clinical laboratories and clinicians. For researchers, a publication or web-based system establishing micro-attribution and community annotation of mutations e. Similarly, database-journals would also serve this task by providing a forum for publishing gene variation data that would be eventually deposited in the PubMed literature database.

Journals, tenure and promotion committees, and funding agencies would be encouraged to cite these contributions to and citations of LSDB and international national databases Patrinos and Brookes, The HVP recommends that researchers cite these attributions and citations in their curricula vitae to foster the transition of the academic culture. The same trend and recommendations for development of coherent tools are valid for the recognition of contribution to the setting, use and sharing of any bioresource such as biobanks Cambon-Thomsen, ; Kauffmann and Cambon-Thomsen, and international efforts like P3G are being developed in the same spirit.

The recent sequencing of the Watson Wheeler, et al. Any formal attempt to identify the extent of genomic variation must include geographical regions which have not been included in haplotype mapping projects. Hence, the main focus of the HVP effort is the inclusion and analyses of clinical samples from diverse ethnic groups. The distinct advantage of some ethnic populations is the opportunity to study genetic diseases due to consanguinity, large family size, and potential founder effects e. However, biomedical research has not been the focus of resource poor countries even though such activities are likely to produce economic and health benefits for all Daar et al.

Education of healthcare providers, the public, and government officials is needed for demonstrating the universal nature of the HVP, the need to include populations in developing countries, and the benefits from cooperating in biomedical research Bhan et al. Certain populations may mistrust research involving genetic analyses or fear that results can be misused to support discrimination or worse http: Malay-Muslims, Chinese, and Indians in Singapore expressed anxiety about breach of confidentiality, the misuse of their DNA for cloning, and possibilities of being diagnosed with disease Wong et al.

Community based participatory research collaborations may provide forums for addressing cultural and ethical concerns of biomedical research McCabe-Sellers et al. Analyzing the extent of human genomic variation creates an ideal opportunity for the developed and the developing nations of the world to forge meaningful partnerships and to work together in an unprecedented way, initially to identify variation causing disease, and then to understand how general variation contributes to human phenotypic diversity.

By ensuring that all nations and ethnic groups have an equal and fair opportunity to share data and technology, we will provide evidence-based information that all populations can benefit from a global society health network. The primary objectives for including populations in emerging countries are described in Box 6. Real and tangible benefits of the HVP to improve health will be generated for participating populations; the voluntary participation of the greatest number of countries would ensure a more general applicability and it is hoped that many countries will decide to participate.

Ethical issues remain of vital concern to the Human Variome Project.

Participating researchers are committed to adhering to the highest ethical principles governing research, data sharing and ultimately enabling this new knowledge to benefit all of humanity as much as possible. LSDBs may contain a large amount of phenotypic data. Most LSDBs post a considerable amount of data on public websites and increasingly this information may be accessible through genome browsers.

While the best intention of the HVP is to ensure that participants are acknowledged as a group, without any risk of identification, a specific challenge occurs in the case of rare mutations associated with distinctive clinical features. Since epistatic and environment interactions reviewed in Kaput, alter age of onset, severity, complications and outcomes for monogenic and polygenic phenotypes, it may be necessary to analyze entire genomes for personalized healthcare. Such polygenic analyses generate data that could be used for re-identifying individual patients Craig et al. Other ethical concerns may be minimized by improving communication about the project and its goals through multiple channels such as print and broadcast media, local community outreach, and internet sources such as the HGVS website.

The HVP will develop an ethics review committee with a subcommittee focused on issues related to LSDB for i providing counsel when dilemmas arise, ii overseeing guidelines, iii identifying best practices, iv determining how best to ensure privacy in all situations, v formulating how to handle data for which explicit consent does not exist or is not possible to achieve, and vi developing a consent form that is consistent for all LSDBs but which can be adapted to the requirements of individual countries.

Such consent would contain, for example, a re-contact clause. The specific recommendation and open questions are outlined in Box 7. The HVP, through its Ethics Working Group, is committed to i soliciting, collecting and analyzing consent forms in order to develop a model consent form that can provide greater consistency across all LSDBs, ii seeking the input of relevant clinical genetic societies for comment, and iii using that input to develop ethical standards for LSDBs.

The funding possibilities are more likely if the international HVP is treated as a concerted effort. Given the limitations of existing knowledge see Introduction and Patrinos and Brookes, , this initiative will benefit research in many fields and impact prevention and clinical care of disease. Specific focus areas for developing funding streams are described in Box 8. The HVP was named and initiated to define the aims of this activity Melbourne in by an extremely high profile group of experts in all types of genetic variation analyses.

In association with world experts, Deloitte http: The HVP Planning Meeting was a designated activity of this plan and other sections of the plan will follow e. The business plan calls for a broadly defined community of interested stakeholders to develop the HVP Box 9. Open questions that must be resolved in future meetings are i the extent of data sharing between patient records and research databases, ii appropriate descriptions of data elements, and iii data ownership and confidentiality. This effort is an ongoing project but also a model or pilot for the HVP.

InSiGHT has conducted several multidisciplinary studies of Hereditary Non Polyposis Colon Cancer HNPCC patients that i require the development of a disease-specific model for integrating databases across laboratories, ii establish standards for data consistency for phenotypes which include graphic pedigrees , iii address confidentiality, and iv develop a template for consent. Clinicians from multiple countries and regions are contributing and committing to the development of these systems. Some of these issues cross disciplinary boundaries and are being addressed by other committees of the HVP.

Data transfer into a mirrored central database e. Other pilot projects are described in Box The problem of interpreting the pathogenicity of missense variants is most commonly encountered in genetic testing for cancer predisposition syndromes. InSiGHT has established committees addressing phenotype, curation, virtual histology, and funding, which provide advice and support for the Interpretation Committee comprised of experts ranging from clinicians to basic scientists.

Its two short-term goals are to i produce a paper discussing standards for data types, classification, and integration and ii convene to classify as many variants as possible from various international MMR gene mutation databases. The vision of the HVP, to catalogue and access all information related to human disease variation, is ambitious. Separate dimensions that must be linked to these variants are the main effect of gene — environment interactions e.

These data elements relate to the cells in the initial two dimensional matrix since each may affect the genetic expression of the mutation or gene variant. These dimensions are domains of knowledge that must be integrated for understanding biological processes. A predetermined bioinformatics structure to accommodate this matrix with forced fields for data entry is notionally appealing but practically impossible.

The reality is that LSDBs, which capture the core information in any one of these domains of information, are developed by experts and curated with invaluable skill and experience. To force any change on these individual efforts would risk inestimable loss of activity by the curators and threaten data of individuals in populations.

The challenge then is to integrate the existing and developing information within existing databases and public resources into a system based on this matrix of domains — the vision of the HVP.

Meaning of "lud" in the English dictionary

This challenge can be met with resources applied to software development or existing applications that allow searches to locate all information across all domains of the international data matrix. The Navigator also seeks to provide algorithms for potential interpretation of pathogenicity. The approaches presented at the HVP planning meeting contribute to this goal of integrating biological information.

The HVP efforts are also consistent with the newly emerging initiative to develop standards for scientific disciplines and research strategies: The challenge to catalogue and access this vast body of information relating to human biology and behavior is immense, but the HVP is leading this endeavor through international collaborations and harmonized protocols.

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The development of this network of LSDBs and the knowledge they generate and maintain will be beneficial not only for the genetic research community, but also for researchers in nutrition, toxicology, teratology, physiology — virtually all biological research arenas, but perhaps most importantly for the translation of basic research for improving personal and public health.

The future is indeed exciting. Mike Parker and Helen Firth are acknowledged for their contribution to the work leading up to Box 7. Members of working groups, their affiliations, institutions, and email addresses can be found at http: This work includes contributions from, and was reviewed by, the FDA. This work has been approved for publication by this agency but it does not necessarily reflect official agency policy.

Supporting Information for this preprint is available from the Human Mutation editorial office upon request moc. National Center for Biotechnology Information , U. Author manuscript; available in PMC Apr 2. Jim Kaput , 1 Richard G.

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Cotton , 2, 3 Lauren Hardman , 2 Aida I. Al Aqeel , 4 Jumana Y. Bernstein , 11 Jong Bhak , 12 Stacey L. Golubenko , 37 Marc S. Greenblatt , 38 Ada Hamosh , 39 John M. Hancock , 40 Ross Hardison , 41 Terence M. Gil-da-Silva-Lopes , 49 Finlay A. Macrae , 50 Donna Maglott , 51 Makia J. Marafie , 52 Steven G. Marsh , 53 Yoichi Matsubara , 54 Ludwine M. Netea , 57 Melissa L. Norton , 58 Peter J. Oefner , 59 William S. Oetting , 60 James C. Paalman , 63 Jillian Parboosingh , 64 George P. Patrinos , 65 Giuditta Perozzi , 66 Ian R.

Quin , 70 Rajkumar S. Ramesar , 71 C. Scheible , 74 Rodney J. Scott , 75 Daniela Seminara , 76 Elizabeth A. Shephard , 77 Rolf H. Sijmons , 78 Timothy D. Tavtigian , 81 Graham R. Weber , 89 Meredith Yeager , 90 Young I. Author information Copyright and License information Disclaimer. The publisher's final edited version of this article is available at Hum Mutat.

See other articles in PMC that cite the published article. Abstract The remarkable progress in characterizing the human genome sequence, exemplified by the Human Genome Project and the HapMap Consortium, has led to the perception that knowledge and the tools e. Introduction The completion of the consensus sequence of the human genome Lander, et al.

Will never be able to say anything bad about him or his work for the Lord.

God bless his family. He was our Pastor as we were searching the Lord for our calling into ministry and he graciously allowed us to take our first ministry steps at the church that had been our home, loving us and directing us with that HUGE heart of his. As we stepped out into the calling of the Lord Bro. Davenport was one of our biggest fans and he never failed to encourage us every time we had the pleasure of seeing him. Every homecoming was another opportunity to be poured into both for our ministry and our family that we looked forward to each time.

Our hearts are saddened by our loss of this great man but rejoicing in the gain that is Heaven's. Our prayers are with Sis. Rose, Mark, Michelle and Alora, all the while knowing there will be a great reunion day for us all. Ed is gone home but Rose, you are in our thoughts and prayers!

Pastor Davenport was an awesome Pastor. My prayers are with your family during this hour of breavement. An amazing man who served his flock well! Fisher's of men became your life's goal. Though many times it was not an easy path, you continued and the joy followed, in the way of transformed souls. Though perilous at times, you trusted Him. The gateway of Heaven is now filled with many of those souls. The journey produced and fed many, as Jesus multiplied the loaves and fishes. Our meeting, changed the path of our lives.

Thank you for being a Servant of The Lord. We know that he is walking the streets of heaven with Carolyn and talking with Jesus. Thank you Pastor Davenport for the wonderful messages and love throughout the years.

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This is not good-bye, but until we meet again. Reverend Ruel Edward Davenport was born on January 13, , and entered into his final rest on the morning of April 6,

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