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Proposed Guidelines on Genetic Screening for Type 1 Diabetes

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Screening by determining HLA type is not currently warranted outside ... Glutamic acid decarboxylase (GAD) - Islet tyrosine phosphatase (IA-2) - Insulin (IAA) ... – PowerPoint PPT presentation

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Title: Proposed Guidelines on Genetic Screening for Type 1 Diabetes


1
Proposed Guidelines on Genetic Screening for
Type 1 Diabetes
  • Screening by determining HLA type is not
    currently warranted outside the context of
    defined research studies
  • American Diabetes Association

2
Clinical Trials Genetic Screening
  • TRIGR
  • Trial to Reduce Type 1 Diabetes in Genetically
    At Risk
  • Finland - Primary Prevention
  • DIPP
  • Diabetes Prediction and Prevention Trial
  • Finland - Primary Prevention

3
Clinical Trials Antibody Screening
  • DPT-1
  • Diabetes Prevention Trial - 1
  • USA - Secondary Prevention
  • ENDIT
  • European Nicotinamide Diabetes Intervention
    Trial
  • Europe, Canada - Secondary Prevention

4
Genetic Screening
  • DQB10302 and / or 0201
  • - TRIGR, DIPP
  • Not DQB10602/3 or 301 (exclusion)
  • - DPT-1, for ICA individuals only
  • No genetic screening
  • - ENDIT

5
Genetic Screening
  • Genetic counseling is not provided
  • - Except DIPP
  • Psychological consequences of genetic screening
    and follow-up are likely to significant
  • Excludes gt1/2 future cases
  • Potential benefit for reducing incidence is low

6
Autoantibody Screening
  • Beta cell autoantibodies (BCA)
  • - Islet cell antigens (ICA)
  • - Glutamic acid decarboxylase (GAD)
  • - Islet tyrosine phosphatase (IA-2)
  • - Insulin (IAA)
  • Utilized as pre-clinical markers

7
Beta Cell Autoantibodies
  • Most type 1 cases (90) are positive at onset
    for 1 BCA
  • Prevalence decreases with duration
  • General population prevalence 1
  • Risk of type 1 diabetes increases with number of
    BCA
  • 2 BCA - Risk 65
  • 3 BCA - Risk gt 90

8
Autoantibody Screening
  • Considered as endpoints
  • - TRIGR, DIPP
  • ICA positives are further tested
  • - DPT-1, for ICA individuals only
  • ICA only
  • - ENDIT

9
Autoantibody Screening
  • ICA negative individuals (excluded from clinical
    trials) develop type 1 diabetes
  • ICA negative first degree relatives with high
    risk DQ alleles - Pittsburgh
  • Risk gt30 after 12 years follow-up
  • Pietropaolo, 2000

10
Intervention Trials for Type 1 Diabetes
  • Study Intervention Target /Screen
  • TRIGR Avoid CM FDR / genetic
  • DIPP Insulin (N) GP / genetic
  • DPT-1 Insulin (P,0) FDR / ICA / ex
  • ENDIT Nicotinamide FDR / ICA
  • CM cows milk, FDR first degree realtives,
  • ICA islet cell antibodies, Pparenteral,
  • Ooral, N nasal, GP general population

11
Avoidance of Cows Milk Etiologic Hypotheses
  • Molecular mimicry
  • Exposure to CM proteins very early in life, when
    the infant gut is extremely permeability, may
    trigger humoral and cellular responses that later
    become autoreactive
  • Disturbance in oral tolerance
  • Exposure to bovine insulin in CM disturbs oral
    tolerance to insulin and leads to the development
    of IAA

12
Avoidance of Cows Milk Controversies
  • Evidence for molecular mimicry is inconsistent
    and lacks specificity
  • Natural history studies show no association
    between CM and BCA
  • Exposure to other nutrients in breast milk or
    later during childhood are likely important

13
Results From TRIGR
  • N 173 high risk infants from Finland were
    randomized
  • Treatment was for 6-8 months
  • with ICA in treatment vs. control group 3.6
    vs. 11.2 , p 0.06
  • Abstract 1.9 vs. 12.5, p lt 0.04
  • American Diabetes Association, 1999

14
Results From TRIGR
  • CM HC BF
  • Total Number n 58 n 61
  • Age enrolled 1.9 mo 3.0 mo
  • Exposure 4.8 mo 3.6 mo
  • IAA 2 1
  • At 3 mo n 14 n 9 n 17
  • SI to BI 2.2 1.8 1.6
  • IgG to BI 0.21 0.13
  • No differences after 3 mo
  • p lt 0.05 Diabetes 491657-65, 2000

15
Potential Impact of TRIGR
  • If avoidance of cows milk was the only potential
    diabetogenic exposure AND prevented ALL
    susceptible cases, AT MOST
  • 30 of cases prevented
  • 70 of cases NOT prevented

16
Results From DIPP
  • Study ongoing for 4 years
  • Genetic screening is accepted
  • Adherence to follow-up 70
  • Results published relate to onset of BCA
    positivity / type 1 diabetes
  • No information on enrollment or acceptance of
    nasal insulin intervention
  • Diabetologia 44290-7, 2001

17
Results From DIPP
  • 22 infants developed type 1 diabetes
  • 12 participated in DIPP
  • 3 refused
  • 7 not susceptible and excluded (32)
  • Revised genetic screening strategy would have
    missed 5 (23)
  • Diabetologia 44290-7, 2001

18
Insulin Intervention Etiologic Hypotheses
  • Animal studies show that prophylactic insulin
    therapy can delay the onset of type 1 diabetes
  • Possible mechanisms involve
  • - Beta cell rest
  • - Immune modulation
  • - Tolerance

19
Insulin Intervention Controversies
  • Mechanisms of action via any route of
    administration are unclear
  • Animal studies show that insulin therapy can
    induce type 1 diabetes
  • Initial results of human pilot studies are based
    on very small samples and short-term follow-up

20
Insulin Intervention Controversies
  • Concerns about the potential for severe
    hypoglycemia in the treatment group
  • Long-term physiological and psychological
    consequences of daily insulin therapy are unknown

21
DPT-1
  • Hypothesis for high risk group (gt50) Daily
    insulin injections will reduce the incidence of
    type 1 diabetes by 35 in 5 yrs
  • Population 1 2o relatives gt 3 yrs
  • Screening ICA, IV/OGTT, IAA, DQ
  • Treatment Insulin 2x/day, IV 1x/yr
  • Control Placebo

22
DPT-1
  • Hypothesis for moderate risk group (25-50) Oral
    insulin will reduce the incidence of type 1
    diabetes by 35 in 5 years
  • Population 1 2o relatives gt 3 yrs
  • Screening ICA, IV/OGTT, IAA, DQ
  • Treatment Daily oral insulin
  • Control Placebo

23
Results of Insulin Injection Arm
  • Screened gt 89,000 relatives
  • 3.5 had ICA
  • Enrolled 339 high risk individuals
  • Age range 4 - 45 mean age 11 yrs
  • After 5 years
  • 60 of the intervention and control groups
    developed type 1 diabetes
  • American Diabetes Association, 2001

24
Results of InsulinInjection Arm
  • No adverse events reported
  • Enrolled subjects are still followed
  • Questions remaining
  • - Disease had progressed to far
  • - Incorrect dose
  • - Could be effective in adults
  • Oral insulin arm is still recruiting
  • American Diabetes Association, 2001

25
Behavioral Science Research Conference
  • Regarding type 1 diabetes intervention trials
    identified
  • Sub-adequate methods of risk notification
  • Barriers to efficient utilization of screening
    information

26
Behavioral Science Research Conference
  • Emphasized the need to
  • Maximize benefits of determining risk
  • Minimize distress of risk notification
  • Provide accurate risk information
  • Educate children, families and health
    professionals regarding genetic testing

27
Genetic / Autoantibody Testing for Type 1 Diabetes
  • Being done in high risk families as well as in
    the general population
  • - For research purposes now
  • - For clinical purposes in the future
  • Critical need to
  • - Consider risks and benefits
  • - Develop appropriate strategies for risk
    identification, notification and evaluation

28
Plan for Pittsburgh
  • New Advanced Technology to Improve Prediction
    and Prevention of Type 1 Diabetes
  • M. Trucco, PI
  • Previous funding from the DOD to develop
    suspension microarrays for HLA molecular typing

29
Current DOD Proposal
  • Molecular technology developed by Dr. Trucco is
    now available for screening for type 1 diabetes
  • Suspension microarrays
  • Genetic HLA DR-DQ
  • Immunologic BCA, TCR V?7
  • Environmental Coxsackie viruses

30
Proposed Sub-Project
  • Genetic Testing for Type 1 Diabetes in Families
    of Military Dependents Translating the Results
    from the Laboratory to the Community
  • J Dorman GSPH
  • D Charron-Prochownik School of Nursing
  • L Siminerio UPMC

31
Risk Status Determination
  • Risk algorithm based on population-based
    molecular epidemiologic data
  • Genetic / Environment-Specific Risk
  • Available from the WHO DiaMond Molecular
    Epidemiology Project, including China

32
Risk Status Determination
  • Evaluate epidemiologic associations /
    interactions between type 1 diabetes and
  • - HLA DR-DQ - TCR V?7
  • - BCA, other AA - Coxsackie viruses
  • Develop and validate risk algorithm for type 1
    diabetes
  • Permits personalized approach to risk estimation

33
Photo of Risk Calculator
34
Risk Notification
  • Develop and evaluate materials and processes for
    communicating information about genetic risks
  • Programs Targeted for the Internet
  • Telegenetics

35
Risk Notification
  • Consider ethical issues associated with genetic
    testing
  • Develop, implement and evaluate highly
    interactive, culturally sensitive, internet-based
    education programs for
  • Military and their dependents
  • Health-care professionals

36
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37
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38
Risk Evaluation
  • Evaluate psychosocial / behavioral effects of
    receiving type 1 diabetes risk information and
    being followed
  • Develop Strategies to Reduce Distress

39
Risk Evaluation
  • Explore possible medical, behavioral and
    psychological factors that may be important in
    risk perception
  • Develop and disseminate information on
    interventions for informed decision making

40
Proposed Sub-Project
  • Opportunity to develop standards for genetic
    translation based on molecular epidemiology
    research
  • As per guidelines from the Task Force on Genetic
    Testing at NHGRI
  • Essential as Human Genome Project comes to
    completion

41
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