Portal de Periódicos da CAPES

Response to Visscher

2002; Elsevier BV; Volume: 71; Issue: 4 Linguagem: Inglês

10.1086/342992

1537-6605

Susan E. Hodge, David A. Greenberg, Catalina Betancur, Christopher Gillberg,

Virology and Viral Diseases

To the Editor: We must admit that Dr. Visscher (Visscher, 2002Visscher P Increased rate of twins among affected sib pairs.Am J Hum Genet. 2002; 71 (in this issue): 995-996Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar [in this issue]) is quite correct and that in our two reports of twins in autism (Greenberg et al. Greenberg et al., 2001Greenberg DA Hodge SE Sowinski J Nicoll D Excess of twins among affected sibling pairs with autism: implications for the etiology of autism.Am J Hum Genet. 2001; 69: 1062-1067Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar; Betancur et al. Betancur et al., 2002Betancur C Leboyer M Gillberg C Increased rate of twins among affected sibling pairs with autism.Am J Hum Genet. 2002; 70: 1381-1383Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar) we overlooked the elementary application of Bayes’s rule in this situation, namely: If MZ twin pairs are more likely to be concordant than nontwin pairs, then sampling concordant pairs will produce an excess of MZ twin pairs relative to nontwin pairs. This excess says nothing about the relative strengths of genetic or nongenetic effects in autism, contrary to what we concluded in our papers. However, the points made by Dr. Visscher explain only part of our observations, and they also highlight the sensitivity of the conclusions to the accuracy of the population data. Because twin concordance rates vary from study to study, the issue of increased autism risk to twins is not yet settled. In particular, interpreting the findings from the DZ twins remains problematic. We begin with some calculation issues. First, Visscher’s formulas contain an error, although the error does not affect his conclusions and may even strengthen them. The probability of both members of a sib pair being affected, his P(2 affected), does not equal rp, as he states. (We use his notation of r for the “pairwise concordance rate,” but note that p should represent disease population prevalence, not incidence.) Rather, P(2 affected) is given by Kp, where K is the “recurrence risk” for that particular kind of sib pair (James James, 1971James JJ Frequency in relatives for an all-or-none trait.Ann Hum Genet. 1971; 35: 47-49Crossref PubMed Scopus (122) Google Scholar; Risch Risch, 1990Risch N Linkage strategies for genetically complex traits. I. Multilocus models.Am J Hum Genet. 1990; 46: 222-228PubMed Google Scholar). To see why, let us use πi for Visscher’s P(i affected)—that is, the probability that a sib pair has i affected sibs. The standard definition (also used by Visscher) says that the pairwise concordance rate r gives the probability that both sibs are affected, given that at least one is affected—that is, r≡π2/(π2+π1). In contrast, the recurrence risk K is defined as the recurrence risk to the sib of an affected individual—that is, P(sib #2 is affected|sib #1 is affected), which can be written as π2/P(random individual is affected)=π2/p. Since K=π2/p, π2=P(2 sibs affected)=Kp.(1) (The recurrence risk K is the same as the “probandwise concordance rate” for twins [Smith Smith, 1974Smith C Concordance in twins: methods and interpretations.Am J Hum Genet. 1974; 26: 454-566PubMed Google Scholar]; also see Wickramaratne and Hodge Wickramaratne and Hodge, 2001Wickramaratne P Hodge SE Estimation of sibling recurrence-risk ratio under single ascertainment in two-child families.Am J Hum Genet. 2001; 68: 807-810Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). K is always ⩾r, approaching twice r when both are small: K=2r/(1+r).(2) We now recalculate Visscher’s f*MZ, defined as P(MZ|2 affected). We incorporate the above correction from equation (1) (i.e., replace r with K), and we use the values for f (the population probability of each type of sib pair, among all sib pairs) from Greenberg et al. (Greenberg et al., 2001Greenberg DA Hodge SE Sowinski J Nicoll D Excess of twins among affected sibling pairs with autism: implications for the etiology of autism.Am J Hum Genet. 2001; 69: 1062-1067Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar): fMZ=.008, fDZ=.016, fS=1−.008−.016=.976. The formula becomes fMZ*≡P(MZ|2 affected)=(.008)KMZ(.008)KMZ+(.016)KDZ+(.976)KS.(3) Visscher approximates this quantity by (.008)KMZ/[(.976)KS] and examines the effect on the ratio fMZ/fS, but we prefer to work directly with f*MZ. Combining data from the three epidemiologically based twin studies of autism cited by Folstein and Rosen-Sheidley (Folstein and Rosen-Sheidley, 2001Folstein SE Rosen-Sheidley B Genetics of autism: complex aetiology for a heterogeneous disorder.Nat Rev Genet. 2001; 2: 943-955Crossref PubMed Scopus (623) Google Scholar) (Folstein and Rutter Folstein and Rutter, 1977Folstein S Rutter M Infantile autism: a genetic study of 21 twin pairs.J Child Psychol Psychiatry. 1977; 18: 297-321Crossref PubMed Scopus (891) Google Scholar; Steffenburg et al. Steffenburg et al., 1989Steffenburg S Gillberg C Hellgren L Andersson L Gillberg IC Jakobsson G Bohman M A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden.J Child Psychol Psychiatry. 1989; 30: 405-416Crossref PubMed Scopus (624) Google Scholar; Bailey et al. Bailey et al., 1995Bailey A Le Couteur A Gottesman I Bolton P Simonoff E Yuzda E Rutter M Autism as a strongly genetic disorder: evidence from a British twin study.Psychol Med. 1995; 25: 63-77Crossref PubMed Scopus (1780) Google Scholar), we note that 25 of 36 MZ twin pairs are concordant. (This figure comes from rMZ=15/25=0.60 in the work by Bailey et al., which includes the Folstein and Rutter data, as well as 10 of 11 concordant MZ pairs in the work by Steffenburg et al.) This yields rMZ=25/36=0.69, which we convert to KMZ=0.82, using equation (2). As for nontwin sib pairs, several studies (August et al. August et al., 1981August GJ Stewart MA Tsai L The incidence of cognitive disabilities in the siblings of autistic children.Br J Psychiatry. 1981; 138: 416-422Crossref PubMed Scopus (165) Google Scholar; Piven et al. Piven et al., 1990Piven J Gayle J Chase GA Fink B Landa R Wzorek MM Folstein S A family history study of neuropsychiatric disorders in the adult siblings of autistic individuals.J Am Acad Child Adolesc Psychiatry. 1990; 29: 177-183Abstract Full Text PDF PubMed Scopus (153) Google Scholar; Bolton et al. Bolton et al., 1994Bolton P Macdonald H Pickles A Rios P Goode S Crowson M Bailey A Rutter M A case-control family history study of autism.J Child Psychol Psychiatry. 1994; 35: 877-900Crossref PubMed Scopus (803) Google Scholar, cited in Lauritsen and Ewald Lauritsen and Ewald, 2001Lauritsen MB Ewald H The genetics of autism.Acta Psychiatr Scand. 2001; 103: 411-427Crossref PubMed Scopus (97) Google Scholar) agree on a sib recurrence risk of ∼3%. Note that this is a recurrence value, so we use it unchanged. Ritvo et al. (Ritvo et al., 1989Ritvo ER Jorde LB Mason-Brothers A Freeman BJ Pingree C Jones MB McMahon WM Petersen PB Jenson WR Mo A The UCLA-University of Utah epidemiologic survey of autism: recurrence risk estimates and genetic counseling.Am J Psychiatry. 1989; 146: 1032-1036PubMed Google Scholar), in the largest published study of sibs, reported a slightly higher figure of 4.5% among all sibs of the firstborn subject. We will also assume KDZ equals KS for the purposes of these calculations. Using equation (3), we calculate f*MZ as 18% or 13%, for KS=3% or 4.5%, respectively. These predictions agree reasonably closely with the rates of MZ twin pairs observed by us: 10%–14% (Greenberg et al. Greenberg et al., 2001Greenberg DA Hodge SE Sowinski J Nicoll D Excess of twins among affected sibling pairs with autism: implications for the etiology of autism.Am J Hum Genet. 2001; 69: 1062-1067Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar) and 10%–13% (Betancur et al. Betancur et al., 2002Betancur C Leboyer M Gillberg C Increased rate of twins among affected sibling pairs with autism.Am J Hum Genet. 2002; 70: 1381-1383Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Thus, we agree with Visscher that our observed rates fit right within what would be predicted by the respective MZ twin and sibling recurrence rates. (We have used somewhat different input figures than Visscher, because we went back to the original studies, but the point remains the same.) However, additional questions remain: (1)Although the sib recurrence rates seem to be fairly consistent among studies, that is not true of the published MZ twin concordance rates, which vary widely and depend highly on issues of ascertainment, diagnosis, etc. (Smith Smith, 1974Smith C Concordance in twins: methods and interpretations.Am J Hum Genet. 1974; 26: 454-566PubMed Google Scholar). It appears to be more difficult to collect unbiased, clearly diagnosed samples of twin pairs than of nontwin sib pairs. Thus, the KMZ rates are “soft”; if they turned out to be lower than those used here, then the conclusions could be quite different.(2)If the reasoning outlined by Visscher and discussed above completely “explains away” the striking increase in twin pairs among affected sib pairs observed by both our groups, then why has that increase not been observed in other autism data sets as well? Is this phenomenon wholly due to most investigators rejecting MZ twin pairs for their studies, which our two groups did not do? And/or is it due to investigators simply not examining their data sets for excess twins? We do not know the answer, but this situation illustrates the usefulness of tracking how and what kind of families enter a study.(3)Similarly, if the above reasoning explains the increase in twin pairs, why is a similar increase not observed in data from other diseases? In one of our original articles (Greenberg et al. 2001), for example, we had looked at affected sib pairs (ASPs) with insulin-dependent diabetes mellitus (IDDM) for just this reason, to provide a control. A relatively recent study (Kyvik et al. Kyvik et al., 1995Kyvik KO Green A Henning B-N Concordance rates of insulin dependent diabetes mellitus: a population based study of young Danish twins.Brit Med J. 1995; 311: 913-917Crossref PubMed Scopus (267) Google Scholar) of IDDM concordance in Danish twins found recurrence risks (probandwise concordances) of KMZ=0.70 and KDZ=0.13 (cumulative age-adjusted). This study was based on 20,888 twin pairs from a population-based nationwide register and was probably more free of ascertainment problems than earlier studies. Sib recurrence risks for IDDM are usually estimated at ∼0.06 (Thomson et al. Thomson et al., 1988Thomson G Robinson WP Kuhner MK Joe S MacDonald MJ Gottschall JL Barbosa J Rich SS Bertrams J Baur MP Partanen J Tait BD Schober E Mayr WR Ludvigsson J Lindblom B Farid NR Thompson C Deschamps I Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus.Am J Hum Genet. 1988; 43: 799-816PubMed Google Scholar; Dorman et al. Dorman et al., 1995Dorman JS McCarthy BJ O’Leary LA Koehler AN Risk factors for insulin-dependent diabetes.in: Harris MI Bennett PH Boyko EJ Cowie CC Dorman JS Everhart JE Herman WH Martin DB Palumbo PJ Reiber GE Stern MP Diabetes in America. 2nd ed. National Institutes of Health, Washington DC1995: 165-177Google Scholar). Inserting these values into equation (3) yields f*MZ=.085, yet, in our control sample of ASPs with IDDM, collected in the same manner as the ASPs with autism, we observed only 13/649=0.02 MZ twin pairs—nothing like the kind of excess predicted by equation (3). In fact, our observed proportion would represent a highly significant deficit relative to what was expected. Moreover, one can also calculate f*DZ—that is, P(DZ|2 affected)—by replacing (.008)KMZ with (.016)KDZ in the numerator of equation (3), yielding f*DZ=0.03. So we should have observed a proportion of 0.03 DZ twins among the IDDM sib pairs, higher than the population rate of .016; yet, we observed again a statistically significant deficit of DZ twin pairs (1/649=0.002). This remains puzzling.On the other hand, a 1992 Finnish study of IDDM twin concordance (Kaprio et al. Kaprio et al., 1992Kaprio J Tuomilehto J Koskenvuo M Romanov K Reunanan A Eriksson J Stengard J Kesaniemi YA Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland.Diabetologia. 1992; 35: 1060-1067Crossref PubMed Scopus (487) Google Scholar) found much lower recurrence rates: KMZ=0.23 and KDZ=0.05. Using those values, one would predict observing f*MZ≈0.04 and f*DZ≈0.016 (we set both KDZ and KS to 0.05 for that calculation), which is much closer to what we did observe in the IDDM data. This discrepancy between the two studies, only 3 years apart, highlights again the “softness” of twin concordance rates and the difficulty of drawing firm conclusions from them. An older study by Cahill (Cahill, 1979Cahill Jr, GF Current concepts of diabetic complications with emphasis on hereditary factors: a brief review.in: Sing CF Skolnick M Genetic analysis of common disease: applications to predictive factors in coronary disease. Alan R Liss, New York1979: 113-123Google Scholar) had also reported a low KMZ of only 5/28=18%.(4)The DZ twin pairs in the autism data sets are puzzling as well. We did observe increased numbers of these pairs—a striking and significant increase under both narrow and broad diagnostic criteria by Greenberg et al. (Greenberg et al., 2001Greenberg DA Hodge SE Sowinski J Nicoll D Excess of twins among affected sibling pairs with autism: implications for the etiology of autism.Am J Hum Genet. 2001; 69: 1062-1067Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar) and a slight (not significant) increase by Betancur et al. (Betancur et al., 2002Betancur C Leboyer M Gillberg C Increased rate of twins among affected sibling pairs with autism.Am J Hum Genet. 2002; 70: 1381-1383Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Yet the literature reports KDZ no higher than KS for autism, so there should have been no increase over population proportions. Visscher mentions the “stoppage” phenomenon as possibly explaining the excess in DZ twins, but we did account for stoppage in the original Greenberg et al. (2001) article. We agree with Dr. Visscher that to provide a definitive answer to these questions will require a population-based twin study examining the prevalence of autism among MZ and DZ twins. One of us (C.G.) is currently undertaking such a study in Sweden, and we hope this will help answer these questions. Moreover, a just-published epidemiological study examined >3.5 million live births in California between 1989 and 1994, of whom 4,381 were diagnosed with what those authors call “full-syndrome” autism (Croen et al. Croen et al., 2002Croen LA Grether JK Selvin S Descriptive epidemiology of autism in a California population: who is at risk?.J Aut Dev Disord. 2002; 32: 217-224Crossref PubMed Scopus (251) Google Scholar). This study found an increased autism risk associated with multiple births: relative risk was 1.7 (95% CI 1.4–2.0), when adjusted for all other factors considered by the authors. Thus, we feel that whether twinness represents a risk factor for autism is still an open question. However, for the time being, we must agree with Dr. Visscher that the observed proportions of twins in both our autism data sets argue neither for nor against the hypothesis that being a twin is itself a risk factor for autism.