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 c TRIGR Trial to Reduce Type 1 Diabetes in Genetically At Risk Trial to Reduce Type 1 Diabetes in Genetically At Risk Finland - Primary Prevention c DIPP Diabetes Prediction and Prevention Trial Finland - Primary Prevention

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

4. Genetic Screening c DQB1*0302 and / or *0201 - TRIGR, DIPP c Not DQB1*0602/3 or *301 (exclusion) - DPT-1, for ICA+ individuals only c No genetic screening - ENDIT

5. Genetic Screening c Genetic counseling is not provided - Except DIPP c Psychological consequences of genetic screening and follow-up are likely to significant c Excludes >1/2 future cases c Potential benefit for reducing incidence is low

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

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

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

9. Autoantibody Screening c ICA negative individuals (excluded from clinical trials) develop type 1 diabetes c ICA negative first degree relatives with high risk DQ alleles - Pittsburgh Risk >30% after 12 years follow-up Pietropaolo, 2000

10. Intervention Trials for Type 1 Diabetes Intervention Trials for Type 1 Diabetes StudyInterventionTarget /Screen TRIGRAvoid CMFDR / genetic DIPPInsulin (N)GP / genetic DPT-1Insulin (P,0)FDR / ICA / ex ENDITNicotinamideFDR / ICA CM = cows milk, FDR = first degree realtives, ICA = islet cell antibodies, P=parenteral, O=oral, N = nasal, GP = general population

11. Avoidance of Cow’s Milk Etiologic Hypotheses c 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 c 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 Cow’s Milk Controversies c Evidence for molecular mimicry is inconsistent and lacks specificity c Natural history studies show no association between CM and BCA c Exposure to other nutrients in breast milk or later during childhood are likely important

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

14. Results From TRIGR CM HCBF Total Numbern = 58n = 61 Age enrolled1.9 mo3.0 mo * Exposure4.8 mo3.6 mo * IAA21 At 3 mo n = 14n = 9n = 17 SI to BI2.21.81.6 * IgG to BI0.210.13 * No differences after 3 mo * p < 0.05 Diabetes 49:1657-65, 2000

15. Potential Impact of TRIGR c If avoidance of cow’s 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 c Study ongoing for 4 years c Genetic screening is accepted c Adherence to follow-up ~70% c Results published relate to onset of BCA positivity / type 1 diabetes c No information on enrollment or acceptance of nasal insulin intervention Diabetologia 44:290-7, 2001

17. Results From DIPP c 22 infants developed type 1 diabetes c 12 participated in DIPP 3 refused 7 not susceptible and excluded (32%) c Revised genetic screening strategy would have missed 5 (23%) Diabetologia 44:290-7, 2001

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

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

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

21. DPT-1 c Hypothesis for high risk group (>50%): Daily insulin injections will reduce the incidence of type 1 diabetes by 35% in 5 yrs c Population: 1 & 2 o relatives > 3 yrs c Screening: ICA, IV/OGTT, IAA, DQ c Treatment: Insulin 2x/day, IV 1x/yr c Control: Placebo

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

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

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

25. Behavioral Science Research Conference c 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 c Emphasized the need to: Maximize benefits of determining risk Minimize distress of risk notification 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 c Being done in high risk families as well as in the general population - For research purposes now - For clinical purposes in the future c 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 c Molecular technology developed by Dr. Trucco is now available for screening for type 1 diabetes c 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 D Charron-Prochownik School of Nursing L SiminerioUPMC

31. Risk Status Determination c 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 c Evaluate epidemiologic associations / interactions between type 1 diabetes and: - HLA DR-DQ- TCR V  7 - BCA, other AA- Coxsackie viruses c Develop and validate risk algorithm for type 1 diabetes c Permits ‘personalized’ approach to risk estimation

33. Photo of Risk Calculator

34. Risk Notification c Develop and evaluate materials and processes for communicating information about genetic risks Programs Targeted for the Internet ‘Telegenetics’

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

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

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

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