Detecting Undiagnosed Type 2 Diabetes: Family History as a Risk Factor and Screening Tool. Rodolfo Valdez, Ph.D.

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1 Journl of Dietes Science nd Technology Volume 3, Issue 4, July 2009 Dietes Technology Society SYMPOSIUM Detecting Undignosed Type 2 Dietes: Fmily History s Risk Fctor nd Screening Tool Rodolfo, Ph.D. Astrct A fmily history of dietes is mjor risk fctor for the disese. As such, it is often included in vriety of tools designed to detect either people t risk of dietes or people with undignosed dietes. One of the resons to screen for dietes is tht it hs prolonged symptomtic phse, which includes impired fsting glucose, impired glucose tolernce, nd the erly stges of dietes. In terms of prevlence, dietes is mjor pulic helth prolem. Evidence shows tht the detection of impired glucose metolism in its erly stges (predietes) could led to the dely or prevention of the disese nd its complictions. However, the issue of using fmily history to screen for dietes must e discussed within the context of screening for dietes in generl. Screening for disese mong symptomtic people must meet series of stringent requirements to ensure the est possile outcomes. Screening for dietes meets most of these requirements ut the ones it does not meet re still importnt. Therefore, sed on systemticlly collected evidence or simply y consensus mong scientists, influentil orgniztions recommend screening only mong high-risk individuls. As result, reserchers hve developed vriety of simple tools to identify high-risk individuls for dietes in popultions. Fmily history is included s key vrile in the vst mjority of them. This rticle is rief overview of the resons to screen for dietes in generl, the tools ville for conducting this screening, nd the role of fmily history in these tools. J Dietes Sci Technol 2009;3(4): Bckground Overt type 2 dietes mellitus (T2DM) is preceded y two mjor symptomtic indictors of imlnce in the metolism of glucose: impired glucose tolernce (IGT) nd impired fsting glucose (IFG). 1 These two indictors, collectively leled s predietes, re correlted ut they my lso pper seprtely. (Tle 1 contins the different ctegories used for determining norml nd impired glucose metolism.) Similr to IFG nd IGT, the erly stges of T2DM re symptomtic; consequently, people with the disese my go undignosed for prolonged periods. In the continuum of plsm glucose distriutions (fsting or 2 hour), the escltion from predietes to T2DM is mrked y shrp increse in the risk of complictions, which, in the long run, cn Author Affilition: Office of Pulic Helth Genomics, Coordinting Center for Helth Promotion, Ntionl Center for Chronic Disese Prevention nd Helth Promotion, Centers for Disese Control nd Prevention, Atlnt, Georgi Arevitions: (ADA) Americn Dietes Assocition, (AUC ROC) re under the receiver operting chrcteristic curve, (BMI) ody mss index, (IFG) impired fsting glucose, (IGT) impired glucose tolernce, (T2DM) type 2 dietes mellitus, (WHO) World Helth Orgniztion, (USPSTF) U.S. Preventive Services Tsk Force Keywords: fmily history, glucose intolernce, predietes, screening, type 2 dietes Corresponding Author: Rodolfo, Ph.D., CDC\Office of Pulic Helth Genomics, 1600 Clifton Rd, NE, Milstop E61, Atlnt, GA 30333; emil ddress rvldez@cdc.gov 722

2 seriously ffect vriety of orgns nd tissues, such s eyes, kidneys, nerves, nd lood vessels (lrge nd smll). 1 Therefore, predietes nd undignosed T2DM re conditions for which screening cn e helpful in preventing mjor helth prolems in sizle portion of the popultion. This rticle exmines the conditions under which such screening cn tke plce nd emphsizes the use of fmily history of dietes s screening tool. Tle 1. Current Ctegories for Norml nd Impired Glucose Metolism Ctegory Fsting glucose (mg/dl) 2-hour glucose c (mg/dl) Norml <100 <140 Impired glucose tolernce 140 nd <200 Tle 2. Estimted Numer of U.S. Adults (Age 20 yers) in Severl Ctegories of Impired Glucose Metolism for 2007 Non-Hispnic White Non-Hispnic Blck Mexicn Americn Totl popultion Predietes (IFG/IGT) Dietes Undignosed (FG/OGTT) Dignosed (self-report) 151,789,928 44,474,449 8,500,236 10,018,135 26,051,718 6,538,981 1,068,120 3,334,620 18,338,148 5,813,193 1,155,303 1,540,404 Totl 196,179,794 56,826,623 10,723,659 14,893,159 Portions tken from Cowie nd collegues 2 nd pplied to census dt from the 2007 U.S. popultion ( According to fsting glucose or the orl glucose tolernce test. Impired fsting glucose 100 nd <126 Dietes From Americn Dietes Assocition. 1 After n overnight fsting of t lest 8 hours. c After ingesting stndrd solution with 75 grms of glucose. The Popultion Recent estimtes mong U.S. dults ged 20 yers or older indicte tht pproximtely 13% hve T2DM (dignosed or undignosed) nd n dditionl 30% hve predietes. 2 Results vry y rce or ethnicity. The numer of people ffected y these conditions in the United Sttes ws clculted y pplying recent prevlence estimtes to popultion estimtes from the 2007 U.S. census. Tle 2 shows results of this clcultion for the three mjor U.S. rcil or ethnic groups, ccording to their glycemic sttus. In totl, out 56.8 million people hve predietes, out 25.6 million hve dietes, nd 10.7 million of them remin undignosed. Is Screening for Dietes Justifile? The vriety nd severity of the helth consequences of dietes nd the lrge numer of people tht re or cn e ffected y the disese leve no dout tht dietes is mjor pulic helth prolem. 3 A criticl step towrd the solution of this prolem is to screen the popultion in serch of individuls t high risk, prticulrly those t the erly stges of impired glucose metolism. The World Helth Orgniztion (WHO) hs set stringent conditions for ny screening progrm tht would ssign helth risk to potentilly lrge numer of symptomtic individuls. 4,5 First, the condition should e n importnt helth prolem, menle to primry prevention, nd its epidemiology nd nturl history should e dequtely understood. Second, the screening test should e simple, sfe, precise, nd vlidted; the distriution of the vlues generted y the test nd its risk thresholds should e known in the trget popultion; the test should e cceptle to the popultion; nd there should e cler policy on the mngement of individuls with positive test result. Third, there should e n effective intervention with etter outcomes for those treted erly rther thn lte s well s cler policy to deliver such intervention; the clinicl mngement of the condition nd the helth outcomes should e optimized y the helth cre providers efore they join the screening progrm. Fourth, there should e strong evidence tht the screening progrm is effective in reducing mortlity or moridity nd tht the entire progrm is cliniclly, socilly, nd ethiclly cceptle to helth professionls nd the pulic; the enefits of the progrm should clerly outweigh the hrms; the cost of the screening progrm should e resonle in reltion to expenditure on medicl cre s whole; the screening progrm should e dequtely stffed nd mnged from the strt; potentil prticipnts should e well informed of the consequences of testing nd ville tretment; nd there must e flexiility for widening the eligiility criteri, reducing the screening intervl, nd improving the test if such chnges re supported y scientific evidence. Does screening for dietes meet the conditions just stted? Dietes nd its ssocited conditions meet most of the requirements for screening progrm, 5 ut no mjor ntionl orgniztion recommends universl J Dietes Sci Technol Vol 3, Issue 4, July

3 screening for dietes. The reson is tht screening for dietes does not meet some importnt requirements set y the WHO; 5 nmely, there is no evidence tht screening progrm would eventully reduce mortlity nd moridity, no country hs the infrstructure in plce to hndle lrge-scle screening nd tretment progrms for dietes, nd the clinicl mngement of the disese my not e optiml throughout entire helth cre systems. 5 The WHO, then, considers tht the est pproches to screen for undignosed dietes or predietes re (1) selective (mong groups known to hve risk fctors for dietes) nd (2) opportunistic (mong potentilly high-risk individuls t the time they visit their helth cre providers). 6 It is importnt to note here tht recent evidence-sed screening recommendtions, issued y the U.S. Preventive Services Tsk Force (USPSTF), do not fvor universl screening for dietes either. 7,8 The min reson is tht the USPSTF found, with moderte certinty, tht even though screening for dietes in dults with hypertension would led to sustntil enefit, the evidence ws insufficient to determine the enefit of screening in other popultions. 7 On the positive side, dignosis of hypertension offers the opportunity for helth cre providers to offer dietes test to their ptients. Who Is t Risk of Dietes? The current recommendtions on who should e screened for dietes rnge from considering just one risk fctor to complete list of common risk fctors. For exmple, s result of systemtic review of the evidence, the USPSTF recommends screening for type 2 dietes only in symptomtic dults with sustined lood pressure (treted or untreted) greter thn 135/80 mm Hg. 7,8 However, sed on long-stnding consensus mong its ntionl nd interntionl memers nd prtners, the Americn Dietes Assocition (ADA) recommends screening for type 2 dietes in ll overweight dults [ody mss index (BMI) 25 kg/m 2 ] who hve one or more of the following risk fctors: physicl inctivity; first-degree reltive with dietes; memers of high-risk ethnic popultion; women who developed gesttionl dietes or hd y weighing 9 pounds or more; hypertension; low concentrtions of highdensity lipoprotein cholesterol or high concentrtions of triglyceride in lood; polycystic ovrin syndrome; IGT or IFG on previous test; other clinicl conditions ssocited with insulin resistnce; nd medicl history of crdiovsculr disese. In the sence of these risk fctors, the ADA recommends tht testing for dietes should egin t ge 45 yers. If results re norml, the test should e repeted fter 3 yers or sooner, depending on risk sttus. 1 Given the pulic helth importnce of dietes nd the extensive knowledge of its mny risk fctors, reserchers hve developed numer of lgorithms (risk tools) tht, short of mesuring glucose in lood, cn e used to detect people with either predietes or undignosed dietes in the generl popultion. These risk tools hve een the suject of recent review. 9 Tle 3 provides few exmples extrcted from this review of some of these risk tools long with the vriles they include nd the percentge re under the receiver operting chrcteristic curve (AUC ROC, stndrd mesure of the ility of screening test to distinguish cses from no cses). Percentge res under the curve in these exmples, which rnge from lmost 70 to 80%, show resonle ility of these simple tools to discriminte etween people with nd without undignosed dietes. 9 Of the risk fctors commonly ssocited with incresing the risk of T2DM, the ones consistently displying the strongest ssocitions re old ge, high BMI, high lood pressure, dyslipidemi, one or more first-degree reltives with the disese, nd elonging to some rcil or ethnic groups. In the U.S. popultion, these risk fctors hve een found to increse the risk of hving T2DM independently of ech other. 10 Tle 3. Exmples of Simple Tools Used to Screen for Type 2 Dietes Mellitus (DM) in Popultions, Vriles Included, nd Performnce According to Receiving Operting Chrcteristic Curve Nme Vriles included %AUC Cmridge risk score Age, ntihypertensive mediction, BMI, fmily history of DM, sex, smoking, steroid use 80.0 Dnish dietes risk score Age, BMI, fmily history of DM, hypertension, physicl ctivity, sex 80.3 Indin dietes risk score Adominl oesity, fmily history of DM, physicl ctivity 69.8 Extrcted from Schwrz nd collegues. 9 Percentge re under the receiving operting chrcteristic curve. J Dietes Sci Technol Vol 3, Issue 4, July

4 Genetic nd Environmentl Risk Fctors for Dietes Evidence of the influence of genes on the development of T2DM hs emerged from multiple sources: high recurrence mong reltives (fmily history), twin concordnce studies, doption studies, the existence of monogenic nd mitochondril cses of dietes, nd the growing numer of genetic mrkers found ssocited with the disese. 11 However, there is lso cler influence of environmentl risk fctors on the development of T2DM, prticulrly risk fctors conducive to oesity. 12 Much hs een rgued out the reltive contriution of genes nd environment to the development of chronic diseses, mostly ecuse determining the predominnce of one fctor over the other hs mjor implictions for prevention. In the cse of dietes, where oth influences hve een clerly estlished, the rgument of interest should e less out the predominnce of one fctor over the other nd more out how oth fctors, genes nd environment, come together to produce the disese. Fmily History s Risk Fctor for Dietes Proilisticlly, disese such s dietes with demonstrted genetic component is expected to cluster mong reltives. Fmily history is reflection of this fct with the dded vlue tht it lso reflects the environment, culturl prctices, nd ehviors shred to some extent y close reltives. It hs een mply documented tht hving one or more first-degree reltives with T2DM increses the odds of hving the disese compred with someone without such reltives. The estimtions vry, ut the odds usully rnge from two to six times more likely. 13 Also, long-term study reported tht the cumultive prevlence of T2DM t ge 80 yers is out 3.5 times higher (38% vs 11%) for people with first-degree reltive with T2DM compred to people without ny ffected reltive. 14 The strength, independence, nd consistency of the ssocition etween fmily history of dietes nd presence of the disese justify the inclusion of fmily history in ny simple tool designed to identify potentil cses of predietes nd undignosed dietes in popultion. Indeed, most dietes screening tools include fmily history of dietes mong their key vriles, nd these tools disply n cceptle degree of discrimintion judging from their AUC ROC vlues (exmples given in Tle 3). 9 The only cvet is tht these tools include fmily history s dichotomous (positive/ negtive) vrile. A more useful pproch used to ssess fmilil risk of dietes hs een proposed nd corroorted in severl studies: this risk cn e divided into severl strt nd sizle group of individuls t reltively higher fmilil risk cn e identified The strtifiction hs een detiled elsewhere. Essentilly, high fmilil risk is hving t lest two first-degree reltives or one first-degree nd two second-degree reltives with dietes; moderte fmilil risk is hving just one first-degree reltive or t lest two second-degree reltives with dietes; nd others re t verge risk. Tle 4 shows results of this strtifiction in three rcil/ethnic groups of the U.S. popultion. Dt for Tle 4 re from previous puliction. 18 Overll, out 1 in every 4 dults hs moderte fmilil risk nd 1 in every 13 dults hs high fmilil risk of dietes. Compred with individuls of verge fmilil risk, nd independently of other importnt vriles, individuls t moderte nd high fmilil risk re out 2.3 nd 5.5 times more likely to hve dietes, respectively. Tle 4. Percentge Distriution of Fmilil Risk of Dietes in Adults (Age 18 Yers) from Three Rcil/Ethnic Groups of U.S. Popultion nd Overll Odds of Hving Dietes According to Risk Strtum (Ntionl Helth nd Nutrition Exmintion Survey ) Fmilil risk of dietes Averge Moderte High Non-Hispnic White Non-Hispnic Blck Mexicn Americn Totl Odds of hving dietes (95% CI ) Referent 2.3 c ( ) 5.5 c ( ) Dt otined from nd collegues. 18 Confidence intervl. c Controlling for sex, rce or ethnicity, ge, BMI, hypertension, nd household income. Conclusion The USPSTF, the WHO, nd the ADA do not recommend universl screening for dietes. Bsed on systemtic review of the literture, the USPSTF recommends screening for dietes only mong individuls with high lood pressure. Bsed on list of consistent risk fctors developed y consensus, the WHO nd the ADA recommend screening only mong high-risk, symptomtic individuls. Given these recommendtions, mny reserchers hve J Dietes Sci Technol Vol 3, Issue 4, July

5 proposed nd tested risk tools composed of simple vriles to detect individuls t high risk for dietes. A review of the literture found mny of them cple of such detection. 9 Consistently, fmily history of dietes is one of the vriles included in these tools s n independent contriutor to risk. Recent studies hve shown tht people t moderte or high fmilil risk of dietes re reltively common in the U.S. popultion. 16,17,18 Therefore, since genetic tests re not currently ville for the most common forms of dietes, the use of tools tht include fmily history of dietes is potentilly pplicle to the U.S. generl popultion. The use of such tools in widespred screening progrms, however, must not e evluted less rigorously thn the wy other genetic tests re evluted. 19 Disclosure: The findings nd conclusions in this rticle re those of the uthor nd do not necessrily represent the officil position of the Centers for Disese Control nd Prevention Vn Dm RM. The epidemiology of lifestyle nd risk for type 2 dietes. Eur J Epidemiol. 2003;18(12): Hrrison TA, Hindorff LA, Kim H, Wines RC, Bowen DJ, McGrth BB, Edwrds KL. Fmily history of dietes s potentil pulic helth tool. Am J Prev Med. 2003;24(2): Köerling J, Tillil H. Empiricl risk figures for first degree reltives of non-insulin dependent dietics. In: Koerling J, Tttersll RB, editors. The genetics of dietes mellitus. London: Acdemic Press; p Scheuner MT, Wng SJ, Rffel LJ, Lrell SK, Rotter JI. Fmily history: comprehensive genetic risk ssessment method for the chronic conditions of dulthood. Am J Med Genet. 1997;71(3): Hriri S, Yoon PW, Qureshi N, R, Scheuner MT, Khoury MJ. Fmily history of dietes: popultion-sed screening tool for prevention. Gene Med. 2006; 8(2): Annis AM, Culder MS, Cook ML, Duquette D. Fmily history, dietes, nd other demogrphic nd risk fctors mong prticipnts of the Ntionl Helth nd Nutrition Exmintion Survey Prev Chronic Dis. 2005;2(2):A19. R, Yoon PW, Liu T, Khoury M. Fmily history nd prevlence of dietes in the U.S. popultion: the 6-yer results from the Ntionl Helth nd Nutrition Exmintion Survey ( ). Dietes Cre. 2007;30(10): Yoon PW, Scheuner MT, Peterson-Oehlke KL, Gwinn M, Fucett A, Khoury MJ. Cn fmily history e used s tool for pulic helth nd preventive medicine? Gene Med. 2002;4(4): References: Americn Dietes Assocition. Stndrds of medicl cre in dietes Dietes Cre. 2009; 32 Suppl 1:S Cowie CC, Rust KF, Ford ES, Eerhrdt MS, Byrd-Holt DD, Li C, Willims DE, Gregg EW, Binridge KE, Sydh SH, Geiss LS. Full ccounting of dietes nd pre-dietes in the U.S. popultion in nd Dietes Cre. 2009;32(2): Vinicor F. Is dietes pulic-helth disorder? Dietes Cre. 1994; 17 Suppl 1:s22-7. Ntionl Screening Committee. UK NSC criteri for evluting screening progrmmes. Aville from: criteri.pdf. Wugh N, Scotlnd G, McNmee P, Gillett M, Brennn A, Goyder E, Willims R, John A. Screening for type 2 dietes: literture review nd economic modelling. Helth Technol Assess. 2007;11(17):iii-iv, ix-xi, World Helth Orgniztion. Guidelines for the prevention, mngement nd cre of dietes mellitus. Khti OM, editor. EMRO Technicl Pulictions Series 2006; 32. U.S. Preventive Services Tsk Force. Screening for type 2 dietes in dults: U.S. Preventive Services Tsk Force recommendtion sttement. Ann Intern Med. 2008;148(11): Norris SL, Knsgr D, Bougtsos C, Fu R; U.S. Preventive Services Tsk Force. Screening dults for type 2 dietes: review of the evidence for the U.S. Preventive Services Tsk Force. Ann Intern Med. 148(11): Schwrz PE, Li J, Lindstrom J, Tuomilehto J. Tools for predicting the risk of type 2 dietes in dily prctice. Horm Met Res. 2009;41(2): Dllo FJ, Weller SC. Effectiveness of dietes mellitus screening recommendtions. Proc Ntl Acd Sci U S A. 2003;100(18): Florez JC, Hirschhorn J, Altshuler D. The inherited sis of dietes mellitus: implictions for the genetic nlysis of complex trits. Ann Rev Genomics Hum Genet. 2003;4: J Dietes Sci Technol Vol 3, Issue 4, July