Qatar Foundation Annual Research Conference Proceedings Volume 2016 Issue 1

Background

Current screening for carriers of genetic diseases in oocyte donors includes the assessment of risk of transmission of inherited diseases based on personal and family history of genetic disorders. Most assisted reproduction centers also include karyotyping, mutational screening of the CFTR gene and directed the study of fragile X premutation. Next generation sequencing (NGS) technologies of have allowed to expand genetic screening to a large number of diseases at a reasonable cost.

Objective

 • Develop a new genetic test (qCarrier) based on NGS technology for extended recessive diseases in the field of reproductive medicine screening.

 • Implementation of the carrier screening test in our oocyte donation program.

Material and Methods

The test covers 200 genes (68 in full sequence analysis and targeted screening of 132 known mutations) associated with autosomal recessive diseases 185 (AR) and 11 linked to chromosome X. The test was developed by NGS technology and allows characterization of a broad spectrum of mutations (point, indels, rearrangements and CNVs). The expanded carrier screening is performed on all candidate of oocyte donors and on the male partner of the recipient of oocytes. We discard from the oocyte donor program all candidates that are carriers of X-linked disease. The heterozygous carrier status for an autosomal recessive condition is no a reason for exclusion as a donor, but it involves the selection of a recipient whose male partner is not a carrier of disease mutations in the same gene.

Results

The validation of the test showed high sensitivity (>99%). It has made the extended carrier screening a total of 445 oocyte donor candidates and a total of 587 male partners of oocyte recipients. The implementation of the test in our OD program has identified 57% of patients/donors carriers least a pathogenic mutation.

Conclusions

 • The implementation of the test in oocyte donors program has identified a 3% allocation at high risk of disease autosomal recessive. Two percent of donor candidates to enter the oocyte donors program are carriers of pathogenic mutations linked to the X chromosome.

 • The expanded carrier screening is a useful tool to reduce the rate of newborns affected of genetic diseases in children born through oocyte donors program.

 • The implementation of the test in clinical settings requires pre and post-test genetic counseling to ensure adequate information, consent of patients and safeguard the fundamental ethical issues facing patients and oocyte donors.

Malaria is a major public health concern in north east India with the preponderance of drug resistance strains. Till recently partner drug for Artemisinin Combination Therapy was Sulphadoxine Pyrimethamine. The antifolate drug resistance has been associated with the mutations at dihydropteroate synthase (dhps) and dihydrofolatereductase (dhfr) gene. The study was aimed to investigate the antifolate drug resistance at molecular level and therapeutic efficacy in 35 patients. Three novel point mutations were found in dhps gene with 10 haplotypes along with the already reported mutations. A single haplotype having quadruple mutation was found in dhfr gene. The study reports higher degree of antifolate drug resistance as evidenced by the presence of multiple point mutations in dhps and dhfr genes. The therapeutic efficacy revealed one early treatment failure and three late clinical failure. The findings of the study recommends to stop the use of SP as partner drug in malaria treatment for NE India.

Keywords

Plasmodium falciparum, North East India, Drug resistance, therapeutic efficacy

Diabetes mellitus (DM) and cardiovascular diseases (CVD) constitute a major health care challenge worldwide. We evaluated the trends and outcome of DM in patients presenting with CVD over a 22-year period in the state of Qatar.

Methods

We performed a descriptive retrospective chart review of all admitted CVD patients, including DM from the Cardiology and Cardiovascular Surgery database at the Heart Hospital (HH) of Hamad Medical Corporation (HMC) in Qatar over a 22-year period.

Results

During the study period between the year 1991 and 2012, a total of 48,803 patients (77% males; 40.3% diabetics) were admitted to the HH, resulting in an average admissions rate of 2218 CVD patients per year. Two out of five CVD patients (40%) were known diabetics. Thus, it was estimated that 14.2 per 10,000 people of the general population in Qatar have both DM and CVD. On average each year, 895 CVD patients admitted to the HH are diabetics. The overall proportion of admissions for diabetic patients with CVD increased over the study duration. Diabetic males were 6 years younger than females. DM was more prevalent in Arabs (68 vs. 32%), but its burden showed a decreasing trend over time compared with South Asians. Diabetics presented with ST-elevation myocardial infarction (47.5 vs. 22.7%), tended to be 8 years younger compared with heart failure with DM. Over the study period, beta-blocker use increased substantially (from 10 to 71%). However, angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARBs) were underutilized (from 30 to 56%). There were 4.4 deaths per 100 CVD admissions, which is equivalent to 97 deaths per year. Of this, 52% had DM (2.3 deaths per 100 CVD admissions). The overall case fatality rate (CFR) of DM was 5.6%. Diabetic Asian patients died 9 years earlier than diabetic Arabs at the HH. Age-adjusted Predictors of mortality in DM patients in the HH included lack of beta-blocker use (OR 4.35), lack of ACEI/ARBs use (OR 3.58), myocardial infarction (OR 3.20), lack of aspirin use (OR 2.56), and congestive heart failure (OR 1.75) (P = 0.001 for all).

Conclusions

In Qatar, DM is still a healthcare challenge. Although the admission rate of diabetic patients is increasing at the HH, the mortality rate is decreasing. Evidence-based medication use remains far from the guideline recommendation; however, it shows a substantial improvement. Lack of evidence-based CVD medications in diabetic patients is associated with a significant increase in the mortality in the HH. Efforts should be directed toward public awareness regarding CVD risk factors and DM through education programs and efficient primary and secondary prevention strategies.

The first task of tissue engineer trying to make a scaffold of a heart valve, is to adapt some model of a heart valve to establish target geometries and properties that should be recreated in artificial scaffold. The natural way to do so is to conduct literature research and find the current scientific consensus on the topic. Here the problems start, each researcher seems to have an individual opinion about optimal geometry of valve. What makes situation more complex is that each researcher has carefully chosen arguments to explain why that particular design is better than others. Hence, the consensus is not there yet, we chosen to contribute to this discussion. The analysis of available reports enable to “cook out” 2 distinguishable and to some extent contrary hypothesis.

1st –the optimal architecture of artificial valve is an architecture of native one.

2nd-there is not such a thing as optimal architecture of a heart valve, and never will be

The first option is very tempting due to its simplicity. Of course, in most of human beings the valves work fine for entire life so let's make the same structure for the sick patient. But which one? – Literally mine or yours? Maybe we should make an average from 1000 or million healthily examples? Hypothetically, if you would need new face, would you like to have the “median” appearance or you rather would go for the most beautiful one? Let's take it further – what is an optimal design of human face, perhaps one would wish to obtain the most beautiful face possible, while others would opt for younger variant of their old one. When it comes to faces, it is easy to distinguish beautiful from average and ugly. Using our internal standards, we are doing this every day hundreds times. But valves are usually not visible, so do we need to work out the standard of “beauty” for HV. Frequently, clinicians and researchers seem to use the same face-related-internal standards to propose geometries of scaffold. “I like this more than that, because its follows better my internal visual standards of HV beauty”. But this is not the way to go. We need hard core evidence to distinguish structure that is better than the other.

The second option is more radical – each patient needs individually chosen design of the heart valve that will reflect its specific needs and conditions. This is obviously very elegant but horribly expensive solution, since an individualized scaffold not only needs to be designed but also produced only in few copies.

The consensus of both strategies is in our opinion the establishing the most “beautiful HV” but according to objective physical parameters. What additionally supports this logic is that under physiological condition the scaffold will adjust to patient by changing the geometries.

To confirm our observation and conclusion we contacted 30 prominent clinicians (n = 11) and tissue engineers (n = 19) with question: What is an optimal design of aortic heart valve? In this report we are presenting their responses and comments.

Background

The high prevalence of obesity was observed in numerous developed and developing countries. A reduce in energy expenditure due to the low physical activity level is a factor contributed to the increase in obesity. Physical inactivity is one of the ten leading risk factors for global death, and associated with the all-cause mortality. Regular physical activity lowers the risk of various types of non-communicable diseases. The prevalence of obesity is high among women in the Gaza Strip. There is a lack of studies on the pattern of physical activity among adults in the Gaza Strip.

Objective

The aim of this study was to determine the prevalence of physical activity among mothers aged 18–50 years in the Gaza Strip and its associated factors. Additionally to explore mothers' perception and practice of physical activity.

Methodology

A mixed methods design was conducted using quantitative and qualitative methods. A total of 357 mothers were recruited from the Gaza Strip using multistage sampling method from three different geographical areas, namely, Jabalia refugee camp in the north of Gaza Strip, El Remal urban area in Gaza city, and Al Qarara rural area in the south of Gaza Strip. A structured questionnaire was used for face to face interviews with mothers to obtain information on the mothers' sociodemographic, and their nutrition knowledge. The short form of the International Physical Activity Questionnaire (IPAQ) was used to assess the physical activity pattern. In this study, sitting time is used as an independent proxy measure of sedentary behavior. For qualitative component, three focus group discussions (one group in each area) were conducted involving 24 surveyed mothers to explore mothers' perceptions and practices of physical activity. Binary logistic regression analyses were applied to identify the determinants of physical activity and were adjusted in relation to various factors.

Results

The prevalence of physical inactivity was 21.6%, about 78% of mothers were classified as moderately active, while vigorous activity was not observed. Mean sitting hours was 2.74 ± 1.32 hour/day. Results revealed that, physical activity level decreased among mothers who lived in households with low income (OR: 2.30; 95%CI: 1.20–4.45; p = 0.013), and those with high nutrition knowledge were more likely to be physically inactive (OR: 1.15; 95%CI: 1.0–1.314; p = 0.040), while mothers who had low or medium education level were more active (OR: 0.31; 95%CI: 0.15–0.62; p = 0.001), or (OR: 0.47; 95%CI: 0.23–0.96; p = 0.039). There was no significant association between physical activity levels and the geographical areas. The qualitative results showed that most of the mothers believed home chores were kind of exercises and could substitute for practicing sports. The main constraints to physical activity practice attributed to the sociocultural factors due to the limited availability of exercising facilities for Palestinian women and restrictions on their freedom.

Conclusions

Results of this study are important to monitor physical activity levels among mothers in the Gaza Strip. Despite a high level of nutrition knowledge among mothers, physical inactivity prevalence is high. More attention must be given to the policy makers to improve awareness on the importance of the physical activity practice to improve the overall health status of the community. Understanding the cultural attitudes is required as it is relevant in order to implement effective community-based intervention programs to improve physical activity levels among mothers in the Gaza Strip.

Background

Crowding in hospital Emergency Departments (EDs) is a commonly observed problem in all over the world. Although the reasons and mechanisms are different, the major factors are increasing volume of patients seeking medical care in ED services, lack of inpatient beds, and care for non-urgent conditions for patients who identify the ED as their easiest and usual site of care, notwithstanding the typical treatment of patients with serious illnesses or injuries, non availability and accessibility of other medical services in the community.

Objective

To identify the factors related to patients unscheduled revisit in ED, to find out average length of stay in different priority patients and to identify the reason for more than 6 hours stay in ED.

Methods

The alkhor hospital has 110 bed capacities in the north part of Qatar with an annual ED patient volume of 158000.

A prospective study conducted during two months periods from 15/09/2014 to 14/11/2014 in ED. The census sample of patients who had revisit within 72 hours of discharge from the ED was recruited in the Study. CERNER system utilized to collect all revisit patients data including demographic and first visit information. Two experts from ED consultants reviewed the data independently. Further data include average length of stay and reason for more than 6 hours stays in ED were collected by the research team and all the data was analyzed by the author. The factors were categorized in to four types includes: physician related: missed diagnosis, not prescribed medications, treatment error/ patient related: perception of not improved/illness related: complications of disease process, prognosis of disease process/system related: not availability of health care, not availability of health center locally.

Results

During study period 24933 patients visited in ED, 849 were revisited within 72 hours of their discharge which accounts 3.4%. 165 were excluded from the study which includes LWBS,DAMA and absconded patients. The characteristic of revisited patients, more likely young adults between 20–40 years of age (59.79%). Mostly males (78.94%) expatriate (69.73%) 30.27% patient had three visit in ED while 69.73% twice visited. The most of the patients (538) were self-reported in ED during their second visit. The vast majority of patients (542) agreed that they received discharge instructions.

Physician related Factors includes: this includes missed diagnosis (1.6%), adverse drug reaction ((1.3%) and discharged without home medication (8.4%)

Patient related: The 60.26% (331) of the patients perceived that they were not improved with initial treatment. However, among these patients only 8 were admitted in Alkhor hospital and one transferred to another health care facility for expert management. The vast majority of the patients 97.2% patients were discharge from the ED.

Illness related: This was the most common reason for revisit in ED, 52.9% (362) return with same complaints while 21.3% (146) with related complaints in which 97.6% patients were discharged and 1.3% (7) admitted in hospital 22.8% (156) patients reported in ED with new complaint.

System related: The 23.49% revisited patient's living in Alkhor or nearby area, with their primary health center facility 70 km away from their residential area. 30% patients have no health center facility for further follow up. This cause high financial burden for low income workers

During the study period 718 patients found stayed more than 6 hours in ED, which accounts 2.87% of the total ED patients, mean age of 35.43 years. Most of the patients were males (93.3%). The vast majority of patients were priority 3 and 4 which accounts 26.6% and 63.6 % respectively. The mean times for triage and physician assessment were 2.538 hours and 2.571 hrs accordingly and length of stay in ED was 8.365 hrs. The top 5 reasons for delay the patient in ED was waited for assessment by physician (26.3%), waiting for reassessment by physician (20.2%) observation (11.3%) waited for triage by nurse (8.6%) and repeat lab works (8.2%).

The revisited patients distributed unequally in the three shift duty hours. The morning (7 am–15 pm) and evening (15 pm–23 pm) shifts received the highest proportion 43.12% (295) and 38.45(263) compared to night shift (23 pm–7 am) 15.05% (103). Whereas on daily basis of revisited patients maintained almost equal distribution.

In general the average length of stay of priority 2 patients was 2 hours 14 mts, priority 3 was 2 hrs 17 mts where as priority 4 and 5 was 2 hrs 27 mts and 1 hour 54 mts respectively

Conclusion

The patients decision to revisit in ED is complex, it include several factors like poor quality of service, missed diagnosis, financial factors, disease process etc. From our study we found majority of revisit due to illness or system related factors like their perception of disease progress, lack of local health center facility for workers, financial burden etc. Effective educational program and initiation of tele nursing service for discharged patients can avoid unnecessary ED visits.

Background

ITP (Immune thrombocytopenic purpura) is the most common bleeding disorder in childhood. It is usually a self-limiting disorder, and most patients recover spontaneously without serious complication. The clinical features of ITP have remained unchanged over the past few decades but there have been many recent changes in management strategies as evidenced by the new international guidelines on the management of childhood ITP. We wanted to study our pediatric inpatient population in Qatar who were admitted with acute ITP over the last 5 years for their presenting features and the management strategies adopted by our pediatricians, most of the these decisions in our institution are in conjunction with the pediatric hematology team. This study would also serve as baseline data, which could be used to compare changes in trends of management in the future.

Methods

This was designed as a retrospective descriptive study. We included previously healthy, newly diagnosed ITP, aged 0 to 14 years, admitted to the pediatric inpatient unit, in Hamad General Hospital, Doha, Qatar from January 2008 to January 2014. Patients with a pre-existing chronic medical illness, including hematological conditions and those that were later diagnosed to have conditions other than ITP, were excluded. Data was collected from the patient's medical records using a specially designed data collection sheet that was used to gather the all the relevant patient related details including demographics, presenting signs and symptoms, investigations, treatment and outcome. The study was approved by the Medical Research Center at Hamad Medical Corporation.

Results

80 patients fulfilled the inclusion criteria with a male to female ratio of 1.1: 1. (38.3%) of the patients were in the 2–5 year age group, which reflects the peak incidence of ITP in children as per literature, (13.8%) of the patients were below the age of 12 months and (16.3 %) were above the age of 10.(34.3%) of the patients were Qatari Nationals, while the rest of them were expatriates residing in Qatar.

(40.5%) reported flu-like symptoms before the presentation of the illness. Most of the parents (>80%) denied any history of known hematological disease in their families.

The platelet counts at admission to the pediatric ward were as follows: (80%) of patients had a platelet count f 20,000 or less, (11.3%) from 21,000 to 35,000, while the rest of the patients had platelet counts between 36,000 to 100,000. The most common clinical features reported were spontaneous sub-cutaneous bruising in (77.5%) of patients, followed by oral mucosal petechial rash in (38.8%), fever in (28.8%), epistaxis in (16.3%), gum bleeding in (7.5%). 3 patients needed observation in the pediatrics intensive care unit due to life threatening bleeding, one of whom had intracranial bleeding.

The treatment modalities used in our patient population were as follows: Intravenous immunoglobulin (IVIG) alone in (86.3%), a combination of IVIG and steroids in (6.3%) and steroids alone (1.1%). Only 5 patients (6.3%) were managed by observation alone, 4 of these patients had platelet counts above 20,000 and none had any significant bleeding clinically. The most common IVIG dosing used was 1 gram/kg/day for 2 days. (28.7%) of our study population was prescribed a second dose of IVIG by their treating physician. The vast majority (74.3%) did not experience any adverse reaction after IVIG treatment. However, (10.8%) had fever, (8%) had vomiting and headache. 2 patients were clinically suspected of aseptic meningitis, post IVIG therapy, based on the treating physician's assessment. In terms of the length of stay in hospital, majority of the children (83.8%) were hospitalized for 1 to 5 days.

At follow up, (66%) children had recovered with normal platelet counts within 1 year from the date of diagnosis, while (34%) had progressed to chronic ITP, which is defined as the persistent thrombocytopenia, lasting beyond 1 year.

Conclusion

Our study showed that the clinical features of Acute ITP in Qatar were similar to those reported from various parts of the world. However, the percentage of chronic ITP was higher in our study population than that quoted in literature. Management decisions in our center, like in many centers around the world, were often based on the physician's clinical judgement, rather than the current established international guidelines.

Antibody Directed Enzyme Prodrug Therapy (ADEPT) is a technique used in cancer treatment, which convert a prodrug to a powerful cytotoxic drug only in the vicinity of the tumor. The technique relies on a bacterial enzyme, glucarpidase (former name: carboxypeptidase G2, CPG2). Also the glucarpidase is a very effective enzyme for detoxification of methotrexate, (MTX) which serves as an important component of various chemotherapeutic regimens for the treatment of cancer patients.

Repeated cycles of ADEPT and the use of wild type glucarpidase in detoxification are essential but are hampered by the human antibody response to the enzyme. Additionally, glucarpidase has a relatively slow action in detoxification.

The aim of the work is to provide solutions to overcome the pitfalls of the techniques through the application of different strategies.

In our work we successfully isolated new glucarpidase produces from soils. We cloned and overexpressed the novel gene in E.coli. The new recombinant glucarpidase has been characterized. We also produce different variants of our new gene using different strategies. These variants will be investigated to isolate glucarpidase with higher activity and glucarpidase which avoid the immune system.

Background

Electronic Medical Records (EMRs) hold diverse clinical information about large populations. When this information is coupled with genetic data, it has the potential to make unprecedented associations between genes and diseases. The incorporation of these discoveries into healthcare practice offers the hope to improve healthcare through personalized treatments. The Qatar National Genome project aims to achieve this vision by building a warehouse of genome sequencing information linked to de-identified EMR data. The warehouse should facilitate accessibility to research data, but also protect patients’ privacy and confidentiality by employing responsible data de-identification and data sharing mechanisms.

This abstract discusses the privacy and governance challenges encountered during the construction and deployment of the data warehouse. To simplify the presentation, we divide the data management lifecycle into four stages and discuss the challenges at each stage separately: 1) Initial data collection, 2) data storage, 3) data sharing (utilization) and 4) Dissemination of research findings to the community.

Data collection

The data for the Qatari genome project is sought from the community. Thus it is important to consult with the population to establish the basic principles for data collection and research oversight. To achieve that, a community engagement model should be defined. The model should establish:

1. An advocating technique for advertising the project to the community and raising the number of individuals who are aware of the project. The technique should strive to reach different elements within the society, provide clear dissemination of risks and benefits and establish methods for recurrent evaluation of the community attitudes and understanding of the Project.

2. A recruitment strategy for establishing the enrollment criteria and enrollment process:

 a. The enrollment criteria defines the basis for enrollment (should it be disease based or volunteer based) and the acceptable age for volunteers, and

 b. The enrollment process defines the scope of subjects’ consent (opt in/out or informed consent) and warrants a clear boundary between research and clinical practice.

3. The extent of institutional review board (IRB) and community oversight, given the potential impact of the project on the community, an oversight for the program by the community and the IRB should be discussed and established. The scope includes oversight on data repositories, oversight on research studies as well as oversight on any changes to the protocol (data use agreements, communications, etc.)

Data storage

Foundational documents in modern research ethics stress the importance of reducing harm to participants and maximizing benefits to the society. Re-identification of participants’ identity is one form of harm that can be involuntarily or deliberately inflicted. Personal information derived from EMR records and/or genomic data can be used against the participants to limit insurance coverage, to guide employment decisions, or to apply social stigma. To minimize the risk of harm, the research platform should store de-identified clinical and biobank data while retaining the link between both data sources (the de-identified EMR data and the biobank data). This can be achieved by applying the following two operations:

1. The first operation (known as pseudonymization) identifies a stable and unique identifier(s) (such as Qatari IDs) that is included in both data sources and replaces it with a unique random ID (or pseudonym).

2. The second removes all uniquely identifying information (such as names, record number, and emails) from the structured data and masks all unique identifiers from the unstructured data (such as doctors’ notes). To perform this step properly, we need to determine the uniquely identifying information proper to the Qatari setting. Due to the relatively small population size in Qatar, some regular attributes might prove to be very informative. For example an age of 87 or above and certain professions, such as lawyer, might uniquely identify a participant.

Multiple aspects need to be considered when designing the pseudonymization operation, these include:

1. Ensuring that each subject is assigned the same random ID (pseudonym) across the different data sources. This consistency will ensure that data belonging to a particular subject will be mapped to one record.

2. The pseudonymization process could be reversible or not. Reversible systems allow reverting back to the identity of the subjects through a process called de-pseudonymization. They are used when communication with patients is a foreseen possibility.

3. In case communication with participants is forecasted, then a secure de-pseudonymization mechanism should be specified. The mechanism should define (i) the cases for which re-identification can occur, (ii) the bodies that can initiate re-identification requests, (iii) those that rule and regulate these requests, and (iv) the actual re-identification mechanism.

Data sharing

After the removal of uniquely identifying information, the resulting data is said to be de-identified -but not anonymized. Access to (non-anonymized) biomedical data collected in Qatar is governed by the QSCH “guidelines, regulations and policies for research involving human subjects”. So a critical part in defining a data access protocol is to:

1. Identify and understand data access procedures and requirements set by QSCH, and

2. Identify and understand data access desires of the Qatari community (through surveys, meetings with community representatives, etc.)

3. And finally deploy the gathered policies and requirements along with the collected consents into the design of the data-access platform.

Note that access to the research data platform has to be provided to all research institutes within Qatar. Such as researchers from Hamad Medical Corporation, Qatar Biomedical Research Institute, Qatar Computational Research Institute, Weil Cornell Medical College in Qatar, Qatar University, Hamad bin Khalifa University, Sidra Medical and Research Center and other research institutions. Moreover, the data warehouse is viewed as a platform for worldwide collaborative research projects. With such massive mandate, a principal feature is to have the capacity to foster timely research and discoveries. Data application processes and approvals should be smooth and should not delay project initiation significantly. This cannot be realized using traditional “IRB-based” data-sharing systems. Thus, there will, eventually be a need to (fully or partially) automate the data access process. In other words, we need to design a system to automatically match data access requests with access decisions. In general, access decisions could be provided at multiple access levels. For example in some cases, the requested data could be exported to the investigator premises while in other cases, secure remote access can be imposed. In general, the granted access levels should counter the risk posed by data requests. For example, a request for highly sensitive data (such as HIV data) from an investigator affiliated with a well-established Qatari research institute is inherently less risky than a request for the same dataset by an investigator affiliated with an institution outside Qatar, thus, the second request should receive more access limitations than the first.

Dissemination of findings

Prior work demonstrated that in order to affirm the value of research participation and contribute to public education, it is important to have a mechanism for disseminating research findings to the public. This will keep the community aware of how their participation is facilitating research and improving knowledge in the biomedical field.

The mechanism should also tackle the issue of disseminating specific research findings to specific participants. One of the main challenges in that regard is to define when a finding is considered scientifically valid and when it is considered valuable information for the recipient.