Qatar Foundation Annual Research Forum Volume 2010 Issue 1

People and major projects are vitally important to the future of Qatar. The development of methodologies is important to the research community. This study brings together people, megaproject and research methodology by investigating in detail the interactions of people and project management systems at the conceptual cost estimate stage in order to identify implications and improvements. The research problem has a number of distinct dimensions; technical and human aspects operate and interact at the different levels of the individual, project team, organization and society. In addition, external factors, the nature of the project and the approach to project management also impact on the events and interactions involved. The problem situation generates the following objectives; to identify the technical and people factors and issues influencing the preparation and application of conceptual cost estimates, to understand how these factors interact, to ascertain the relative importance of different factors at different levels and to assess the implications for theory and practice of project management. The study will investigate: how conceptual cost estimates are currently produced and used in practice, including estimating techniques and software used; what factors influence their use, in particular factors related to people; how these factors interact and which exert more influence on the process; and finally, the theoretical and practical implications of this study for communities of practice, project management practitioners and academics. A wide-ranging literature review uncovered the complexity of the field. It also highlighted the need for an innovative approach to methodology, involving activity theory at the data collection stage and grounded theory and human factors error analysis as well as activity theory at the data analysis stage in order to identify the strengths and weaknesses of these different analyses in terms of the information they yield. It is argued that in management research, new insights require creative yet academically robust approaches that address multiple dimensions and perspectives of the complex and often ambiguous socio-cultural contexts situations they seek to analyse. The data analysis in this study will view the findings through a variety of theoretical lenses in a novel approach to capturing complexity.

Hereditary hearing loss is a common genetic disorder accounting for at least 60% of prelingual deafness in children. Most cases (70%) are nonsyndromic and are not associated to other signs or symptoms, while the remaining 30% are syndromic. Nonsyndromic hereditary hearing loss has different patterns of inheritance. The most common one is autosomal recessive. This accounts for 75%-85% of the cases. Another 15%-25% of cases are inherited in an autosomal dominant (DNFA) pattern, while the remaining 1%-2% is inherited as X-linked disorder. Several mitochondrial mutations are also reported of which 1555A>G in the 12S rRNA gene is a common cause of mitochondrial-associated deafness in nonsyndromic progressive sensory neural hearing loss and its aminoglycoside induced state.

The two major genes for recessive forms are GJB2 and GJB6, which belong to the connexin family. GJB2 and GJB6 code for connexin 26 and connexin 30 proteins, respectively.

Here, we report for the first time results of a study in which a series of 120 patients affected by nonsyndromic hereditary hearing loss from 100 Qatari families were screened for mutations in GJB2 and GJB6 genes and the 1555A>G mitochondrial variant. 4 patients carried 35delG mutation, 5 patients the IVS1+ 1G GJB6 mutations or the 1555A>G variant.

These findings clearly demonstrate that GJB2, GJB6 and 1555A>G account for a minor proportion of nonsyndromic hereditary hearing loss in the Qatari population and further strengthen the need to search for causative genes in our population. Results presented here in combination with other molecular epidemiology data contribute to efforts for establishing preventive strategies and developing more targeted therapies.

People of the Qatari peninsula represent a relatively recent founding by a small number of families from three tribes of the Saudi peninsula, Persia, and Oman, with some African admixture. To assess the combination of this founding effect and first-cousin marriages on Qatar's population genetic structure, in a collaborative program of Weill Cornell-Qatar and Weill Cornell-New York, Cornell University and Qatar University, we assessed DNA samples from self-reported Qatari nationals using Affymetrix SNP Array 5.0 to obtain genotype calls of nearly 500,000 single nucleotide polymorphisms (SNPs) in each individual. Principal component analysis was performed along with samples from the Human Genetic Diversity Project dataset, revealing three clusters of genotypes whose proximity to other human population samples is consistent with Arabian origin, a more eastern/Persian origin, and African admixture. The extent of linkage disequilibrium is greater than that of African populations, and runs of homozygosity reflect substantial consanguinity. Despite the fact that the SNPs have a bias toward SNPs common in Europeans, the data strongly support the notion that the Qatari population will provide a valuable resource for the mapping of genes associated with complex disorders. This approach is being tested in samples of the 3 Qatari genomic clusters of healthy vs individuals with type 2 diabetes, a disorder with a high incidence in the Qatari population. To provide a basis for these studies, we have initiated a detailed assessment of the 3 clusters of Qatari genotypes using exome capture and massive parallel sequencing. We expect that these data will provide an invaluable resource for the adaptation of “personalized medicine” for the assessment of risk and the rational use of therapies for the Qatari population.

The capillary electrophoresis (CE)-mass spectrometry (MS) interface is anticipated to have pivotal roles to play in biomarker discovery, elucidation and validation, and in diagnostics, as well as in drug discovery. We are developing a CE-MS system as the natural extension of our Label-Free Intrinsic Imaging (LFiI™) platform, allowing a large increase in analytical power.

One of the most powerful analytical tools in bio-analytical science applications is the mass spectrometer, allowing identification and extraordinary resolving power. However, this instrument too has shortcomings – it really needs a separation system ahead of it. Traditionally liquid chromatogaphy (LC) or 2D-gel separation have been coupled to MS with relative robustness. However LC techniques are not ideally suited to the analysis of biomolecules, with the use of denaturing solvents, expensive columns etc. while flat gel systems have serious shortcomings in sensitivity, reproducibility, dynamic range, quantification and throughput. These are largely overcome with capillary approaches, such as the Label Free Intrinsic Imaging system, the Peregrine, developed by deltaDOT Ltd of London.

The CE-MS interface being developed by deltaDOT QSTP (Qatar Science and Technology Park) will be based on our real-time pattern recognition known as ‘predictive trajectories’ (‘PT’) and biomolecular switching on the LFiI platform, to allow specific protein bands, selected ‘on the fly’, to be separated and quantified, before they undergo trypsin digestion, injection and full MS analysis in a Waters high-definition mass spectrometer (‘Synapt’). Such an interface considerably reduces the system noise by giving a switch opportunity to analyse selected bands of interest from the bulk of background buffer and highly concentrated proteins of low interest. Another significant advantage of such an approach would arise from a more coherent signal where peptide fragments of the same protein would elute together, as opposed to traditional liquid chromatography where any peptide fragments could come from any proteins from the sample, requiring heavy and slow analyses processing.

Based on work in our QSTP labs, we present preliminary data of analyses undertaken with partners in Qatar University on a range of proteomic targets and other analytes. We show how the unique combination of LFiI + PT + HDMS Q-Tof can provide a significant enhancement in analytical power.

Transient Receptor Potential (TRP) ion channels are formed by the juxtaposition of either homomeric or heteromeric assembly of four TRP subunits. TRP proteins have six transmembrane domains (TM) and a P-loop located between TM5 and TM6 that defines the channel pore. So far 30 different subunits, sharing as low as 20% homology, have been identified in mammals and classified in 6 families. Although heterotetramers can be formed within a family, the assembly of subunits from members of different families was thought to be unlikely. Here using biochemical and electrophysiological techniques we evaluated the interaction between xTRPV6 and xTRPC1 overexpressed in Xenopus oocytes. Western blot analysis of oocytes lysates revealed that the native cells expressed both xTRPC1 and xTRPV6. Oocytes were then injected with RNA encoding the two subunits associated or not with protein tags to allow easier immunoprecipitation. The later experiments revealed that xTRPC1 and xTRPV6 expressed in oocytes co-immunoprecipitate. The expression of solely xTRPC1 did not result in a detectable ionic current, whereas xTRPV6 injected oocytes displayed large inward rectifying cationic currents. Ion substitution experiments revealed that the xTRPV6 channel was more permeable to Mg²⁺ ions than Ca²⁺, a characteristic opposite to its mammalian counterpart. Co-expression of both subunits resulted in an ionic current mainly carried by Mg²⁺ ions. Experiments are now being performed in oocytes and in a human cell line to help us further understand Mg²⁺ and Ca²⁺ homeostasis and the contribution of different TRP subunits assemblies to it.

Genetic research raises ethical issues that differ in many ways from those that arise in other kinds of human subject research.

Aside from the generally low likelihood of injury from drawing blood, the harms that might result to subjects once the genetic data is obtained range from minor to major, from physiological to psychosocial and even economic.

Disclosure of results may cause loss or increased cost of health and/or life insurance, discrimination and stigmatization.

In this presentation, I am going to discuss the issue through the followings:

1. Privacy and confidentiality
   • Unlike other kinds of health data, genetic information applies to or is about more than one person. (parents, siblings, children, and perhaps others).
   • Research that includes follow-up studies requires that a subjects unique information be linked to the genetic information.
   • For this and other reasons, many investigators seek to unlink personal identifiers from genetic data or biological specimens.
   • Successful unlinking reduces or eliminates some threats to privacy and confidentiality.
2. Informed consent
   • The participant should be adequately informed.
   • Consent should be free from coercion or undue influence.
   • The participant should be fully competent.
3. Risks of harm
   • The idea of testing can cause pre- and post-test anxiety.
   • Disclosure of results may result in employment and social bias, discrimination and stigmatization.
   • Family members of the index subject may face similar risks of harm.

The presentation also tackles the subject of research on stored biological samples and the ethical issues, with discussion of the laws and regulations applicable.