The Genetics of Schizophrenic and Schizoid Disease1IIiiiiil..1IiiiII@
Leonard L. Heston
Science, New Series, Vol. 167, No. 3916. (Jan. 16, 1970), pp. 249-256.
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The Genetics of Schizophrenicand Schizoid Disease
Summary
Photochenlical reactions in the troposphere, stratosphere, ,and mesosphereare, to a large extent, reactions anl0ngluinor constituents of the atmosphere.The chemistry is markedly limited bythe minimum w'avelength of the solarradiation which penetrates to, a .givenatnl0spheric level. It is useful to differentiate between the chelnistry of citysmog and' that of the anlbient atmosphere, but the entire atmosphere isbeing polluted and the difference is oneof degree.
Both laboratory ,and :Held studies arecontributing to our knowledge of atmospheric photochemistry, and the mostconvincing conclusions have been obtain~d by combining the results of thetwo methods of investigation.
References and Notes
1. T. M. Donahue, Science 159, 489 (1968).2. R. D. Cadle, W. H. Fischer, E. R. Frank,
J. P. Lodge, Jr., J. Atmos. Sci. 25, 100(1968); R. W. Fenn, H. E. Gcrbcr, D. Wasshausen, ibid. 20, 466 (1963).
3. C. E. Junge, Air Chemistry and Radiowactivity (Academic Press, New York, 1963).
4. R. D. Cadle and M. Ledford, Int. J. AirWater Pollute 10, 25 (1966); J. M. Hales,thesis, University of Michigan (1968).
5. G. Liuti, S. Dondes, P. Harteck, J. Amer.Chem. Soc. 88, 3212 (1966).
6. Many rate constants are temperature dependent. l-Iowever, for purposes of compari-
The contribution of genetic factorsto the etiology of schizophrenia hasbeen confirmed decisively. Because theinvestigations that have led to thisresult have uncovered questions cuttingacross several fields of inquiry, a freshlook at some central aspects of theschizophrenia probleln is warranted.These questions and the factual background underlying, them are the mainconcerns of this article. Because emphasis is placed on formulating testablehypotheses, the evidence is organizedin support of a particular genetictheory.
16 JANUARY 1970
son, only values for _ 300 0 K are given inthis article. The rate constants presentedwere in nlany cases selected from among several given" in the literature. Although considerable judgment was used in the selection,there was often little basis for choice amongseveral values. If we use the product of therate constant and reactant concentrations,the rate of disappearance of reactants orformation of products may be estimated asabove. The rates obtained in this way areused as a guide to the relative importanceof shnultaneous reactions occurring in theatmosphere.
7. R. D. Cadle, in Air Pollution, Handbook, P.L. Magill, F. R. Holden, C. Ackley, Eds.(McGraw-Hill, New York, 1956), pP. 3-1 to3-27.
8. E. R. Gerhard and H. F. Johnstone, Ind.Eng. Chem. 47, 972 (1955); T. C. Hall, Jr.,thesis, University of California, Los Angeles(1963); N. A. Renzetti and G. T. Doyle, l.Air Pollute Control Ass. 8" 293 (1959); Int.J. Air Pollute 2, 327 (1960).
9. P. Drone, H. Lutsep, C. M. Noyes, J. F.Parcher, Environ. Sci. Technol. 2, 611 (1968).
10. H. F. Johnstone and D. R. CoughanoWf,Ind. Eng. Cheln. 50, 1169(1958).
11. R. D. Cadle and J. W. Powers, Tellus 18,176 (1966).
12. R. D. Cadle and R. C. Robbins, Discuss.Faraday Soc. 30, 155(1960).
13. E. L. Wong and A. E. Potter, Jr., J. Chem.Phys. 39, 2211 (1963).
14. R.D. Cadle, Discuss. Faraday Soc. 37, 66(1964). '
15. H. W. Ford, G. J. Doyle, N. Endow, J.Chem. Phys. 26, 1337 (1957).
16. J. P. Lodge, Jr., and J. B. Patc, Science 153,408 (1966).
17. }-L W. Ford and N. Endow, J. Chem. Phys.27, 1156 (1957).
18. F. Kaufman and J. R. Kelso, ibid. 40, 1162(1964).
19. J-L W. Ford, G. J. Doyle, N. Endow, ibid.26, 1336 (1957).
20. L. R. J. McHaney, thesis, University ofIllinois (1953).
21. L. A. Cavanagh, C. F. Schadt, E. Robinson, Environ. Sci. Technol. 3, 251 (1969).
Leonard L. Heston
l~be Basic Evidence
During the first half of this century,systen1atic family studies demonstratedth'at the distribution of schizophrenia isthat of a genetic disease. Relatives ofschizophrenics were found to be affticted with the illness much morefrequently than members of the generalpopulation. The child of a schizophrenicparent, for example, was found to havea risk of schizophrenia about 15 timesthat of a member of the population atlarge. It was found that, among allc] asses of relatives, the closer the ge-
22. Of course, CO2 is involved ill plant photosYllthesis.
23. P. A .. Leighton, Photochemistry of Air Pollution (Academic Press, New York, 1961).
24. R. D. Cadle and H. S. Johnston, in Proceedings oj the Second National Ail' PollutionSymposium (Stanford Research Institute,Menlo Park, California, 1952), 1'1'. 28-34.
25. R. D. Cadle and J. W. Powers, J. Phys.Chent. 71, 1702' (1967).
26. W. E. Wilson, Jr., and J. T. O'Dollovan,J. Chenl. Phys. 47, 5455 (1967).
27. M. A. A. Clyne and B. A. Thrush, Proc.Roy. Soc. London Sere A Math. Phys. Sci.275, 559 (1963).
28. .J. N. Pitts, Jr., A. U. Khan, E. B. Smith,R. P. Wayne, Envil'oll. Sci. Technol. 3, 241(1969).
29. 1. M. Campbell and B. A. Thrush, Proc.Roy. Soc. London, Sere A Math. Phys. Sci.296, 222 (1967); F. Kaufman and J. R. Kelso,Discuss. Faraday. Soc. 37, 26 (1964); O. R.Lundell, R. D. Ketcheson, H. I. Schiff, paperpresented at the 12th International Symposiumon Combustion, Poitiers, France, 1968.
30. L. F. Phillips and H. 1. Schiff, J. Chem.Phys. 37, 1233 (1962).
31. F. Kauflllan, Ann. Geophys. 20, 106 (1964).32. R. l~. Cadle, R. Bleck, J~ P. Shedlovsky, I.
H. BUfford, J. Rosinski, A. L. Lazrus, J.Appl. Meteorol. 8, 348 (1969).
33. T. G. Scholz, L. E. I-Ieidt, E. A. Martell, D.II. Ehalt, Trans. Amer. Geophys. Union 50,176 (1969).
34. A. E. Bainbridge and L. E. Heidt, Tellus18, 221 (1966).
35. T. G. Kyle, D. G. Murcray, F. H. Murcray,W. J. Williams, J. Geophys. Res. 74, 3421(1969).
36. Based 011 U.S. Standard Atmosphere 1962(U.S. Government Printing Office, Washington, D.C., 1962).
37. P. M. Furukawa, P. L. Haagenson, M. J.Scharberg, Nat. Center Atmos. Res. Tech.Note 26 (1967), pp. 0-55.
38. B. G. Hunt, J. Geophys. Res. 71, 1385 (1966).39. J. B. Pearce, ibid. 74, 853 (1969).40. The National Center for Atmospheric Re
search is sponsored by the National ScienceFoundation.
netic relationship to a schizophrenicproband (or index case) is, the greateris the likelihood of schizophrenia inthe relative. Finally, and most tellingof all, 1110nozygotic twins were foundto be concordant with respect to schizophrenia about four tinles as often asdizygotic twins. Several authorities havecritically reviewed these basic data (1,2) . But, despite the supporting evidence,a genetic etiology for schizophreniawas not widely accepted, especially inthis country. It was pointed out thatthe investigators did not pay enoughattention to important procedural matters, such as providing sanlpling safeguards and insuring against bias 011 thepart of the investigator. But the paranl0unt objection to a genetic interpretation of the evidence was the objectionthat the whole research strategy wasfaulty. The results of these studies, itwas held, were just as compatible withtransn1ission of schizophrenia throughthe social environment as with ttansnlission through genes. T'he closer the
The author is assistant professor of psychiatryat the University of Iowa ~1edical School, IowaCity.
249
genetic relationship, the closer the social relationship. Were genes or wasnoxious social learning responsible forthe familial clustering of schizophrenia?
Recently, several studies have beenaimed at closing those methodologicaland conceptual gaps. In these newerstudies diagnoses either were made byraters who did not know the geneticbackground of the subjects or weretaken unchanged from medical records.Care was taken to remove samplingbiases, and, most importantly, controlgroups were used. The strategy permitted separation of the effects of genesfrom the effects of social environmentthrough the use, as subjects, of childrenreared in adoptive or foster hOlnes.
The results of one such study areshown in Table 1 (3). The experimental subjects were individuals bornto schizophrenic mothers, and the controls were individuals born to parentswho had no record of psychiatric disturbance. The nlelnbers of both groupshad been permanently separated fromtheir biological mothers in the firstmonth of life and reared mainly infoster or adoptive homes. The subjects,as adults, were assessed through psychiatric interviews and review of everyavailable record-for example, school,police, Veterans Administration, andmedical-and then evaluated by ateam of clinicians. The significant excess of schizophrenia found amongthose subjects whose biological motherswere schizophrenic seelns impossible toexplain except on a genetic basis. Moreover, among those sanle experimentalsubjects, and thus also linked to schizophrenia by the evidence, was an evengreater excess of various apparentlynonschizophrenic disorders. The latterfinding, which is reflected in nearlyevery entry in Table 1, is a central concern throughout this article.
The preliminary results from a verysinlilar study which stressed exenlplaryinvestigative safeguards were much thesame. Rosenthal et al. (4) reported thatbiological children of schizophrenicsreared in adoptive honles exhibited"schizophrenic spectrum" disorders insignificant excess over sinli1arly rearedcontrols. The "schizophrenic spectrum"-an expression coined in a quite reasonable attempt to find a term thatwould encompass the various disorders'seen anl0ng biological relatives of schizophrenics-included schizophrenia, pos~sible schizophrenia, borderline states,certain paranoid disorders, schizoid disorders, and the condition ,known asinadequate personality.
250
Karlsson (5), as one result of hisstudy of schizophrenia in Icel andicfamilies, found that 6 of 29 persons,sonle of them siblings, born to a schizophrenic parent but reared in fosterhomes developed schizophrenia. Noneof their 28 foster sibs who were rearedin the same homes developed schizophrenia. This difference, too, is significant. Karlsson did not ascertain anydisorders other than typical schizophrenia alnong his subjects.
In two ingeniously designed researchprojects, adopted individuals served asthe starting point. Wender et al. (6)studied the biological and adoptive parents of ten adopted schizophrenics andthe adoptive parents of ten normalpersons. The biological parents of theschizophrenics were found to exhibitsignificantly more psychopathology thaneither group of adoptive parents. Ina similar but wider-ranging study conducted by Kety et al. (7), psychopathology, again reported as "schizophrenicspectrunl" disorders, was found to beconcentrated in significant excess amongthe biological relatives of adopted schizophrenics. The adoptive families ofschizophrenics were indistinguishablefrom the adoptive and biological families of adopted controls. Since thepsychopathology found in these studieswas significantly greater alnong thegroup of biological relatives of theschizophrenic probands than anl0ng theadoptive relatives who actually livedwith thenl, this evidence too stronglyfavors genetic over social transmissionof schizophrenia.
The results of the studies of adoptedand foster children-results which arestrikingly consisterit from study tostudy, considering the vagaries of research in this area-present seeminglyinsurm"ountable difficulties for adherentsof environmental theories of schizophrenia. The evidence must surely conlpel acknowledgnlent of a genetic contribution to schizophrenia, and probably to related disorders as well. To gofurther, however, requires infornlationon other types of genetic relationshipsand larger nunlbers of subjects. Happily, the older family studies can nowmeet these needs. For perhaps the mostimportant .contribution of the recentstudies of adopted and foster childrenis the fact that they have confirmed theresults of the older studies in all material respects. The familial clusteringof psychopathology that had been documented in such detail has been linkedto one critical variable, a genetic relationship to schizophrenia.
The Schizoid
The presence of so much psychopathology other than typical schizophrenia among relatives of schizophrenics was first noticed by physicianson visiting days in the earliest asylulns.Isaac Ray, writing in 1863,'gave a gooddescription (8). Because the relatives'disabilities resenlbled schizophrenia, investigators associated with the Munichschool called these disabilities "schizoid"(schizophrenic-like) . Describing theschizoid individual, delimiting schizoidfrom psychiatric and general populations, and placing the schizoid in relationto the schizophrenic were central concerns of the psychiatry of that day.After perhaps the longest detour inthe modern history of science, we havecome full circle in returning to thesame concerns. Meanwhile, problenls ofnomenclature have developed.
To me, "schizoid" and "schizophrenicspectrum" seem to denote precisely thesame disabilities, except that the latterterm also includes schizophrenia. Oneconsideration that may have led Kety(7), Rosenthal (4), Wender (6), andtheir co-workers to coin the new ternlis the obvious danger of confusing"schizoid" with "schizoid personality."The latter term, a diagnosis in theAmerican Psychiatric Association andWorld Health Organization nomenclature, although descended from descriptions of the abnornlal relatives of schizophrenics, has evolved and changedin nleaning so that it is no 10ngeI: applicable to most of those relatives. Forexample, it was not often applied torelatives of schizophrenics by the ratingclinicians in the studies of adopted andfoster children. But other diagnosescurrently considered applicable to suchindividuals also fit these relatives inlperfectly, so no forlnal categorizationis now available. Because of a centraltrait of the schizoid-his. clinical resemblance to the schizophrenic-andbecause of the desirability of nlaintaining continuity with older studies, Iuse the tern1 "schizoid" as a nanle forthe schizophrenic-like disabilities seenin relatives of schizophrenics, or forthe individual manifesting such disabilities.
Nearly all observers of the schizoidhave noted his clinical resemblance tothe schizophrenic, but clinical criteriaadequate to reliably distinguish theschizoid from members of a generalor a psychiatric population or evenfron1 other kinds of abnormal personswith a coincidental genealogical con-
SCIENCE, VOL. 167
Table 1. Results of a study of individuals born to schizophrenic mothers and reared inadoptive or foster homes, and of controls born to normal parents and similarly reared.
Table 2. Explicatives used by relatives of schizophrenics in describing their schizoid relatives. [After Slater (13)].
* The MHSRS is a global rating of psychopathology moving froln 0 to 100 with decreasing psychopathology. Total group mean, 72.8; S.D., 18.4. t One mental defective was also schizophrenic;another had antisocial personality. :1: Considerable duplication occurs in the entries under"neurotic personality disorder"; this designation includes subjects diagnosed as having varioustypes of personality disorder' and neurosis whose psychiatric <liability was judged to he a significanthandicap. § Group 1, highest social class; group 7, lowest.
Paranoid eccentricities: suspicious, sensitive, sullen, touchy, grouchy, morose, resentful,unforgiving, difficult, quarrelsome, self-conscious, jealous, litigious, critical, and others.
Eccentricities: giggly, opinionated, pedantic, narrow-minded, meticulous, obstinate, humorless, rigid, little-minded, spiritualists, and many others.
Lack oj feeling: passive, cruel, calculating, placid, hard and stingy, unsympathetic, cold,withdrawn, little-feeling, and others.
Reserve: shy, serious,haughty, snobbish, studious, unforthcoming, taciturn, unsociable,seeks solitude, and so on.
Anergic: dependent, tired, slack, unreliable, subservient, and so on.
.054
.006
.021
0.0006.024.052.017.052
Exact probability(Fisher's test)
84.55.4
94.011.671
69
473035.82265.2
549
13
11112
721
Experiluental
COJnpared with 3 percent of the generalpopulation. l:'he expected reciprocalrelationship, an excess of schizophrenicsal1long Inental defectives or their relatives, was found by Penrose (15) andBook (16) alllong nlental defectives butnot by Reed and Reed (17) in theirInonumental survey of the relatives of11lental defectives. Also, Kallmann founda nluch higher rate of Inental deficiency(10.8 percent) anlong relatives of sinlpIe schizophrenics, where there is aclinical conlmonality of sorts, thanalTIOng relatives of other subtypes inthe Kraepelinian classification. The evidence for or against an association bet.ween schizophrenia and mental deficiency is inconclusive, land nloredata are needed before the nlatter canbe decided.
Obviously there is 111uch yet to belearned before we can describe anddelinl it schizoidia. H:owever, the samething can be said of schizophrenia itself, and in this regard study of theschizoid Blay lighten sonle dark corners.
215
2.17
503336.31980.loo27
14.24.7
103.712.484
74
Control
llladc, his concept of the schizoid is ofcritical inlportance (11). From his description (11, p. 102) it is clear thathe relied heavily on the schizoid's clinical reselnblance to the schizophrenic.Kalhl1ann regarded the distinguishingfeatures of the schizoid to be the "fun~
dall1ental sylnptonls of schizophrenia inthe nlilder fornl of characterologicalabnonnalities . . . dOlninating the personality of the individual in question."Kallnlann also looked analytically attraits other than those obviously associated with schizophrenia or schizoidiathat seenled to occur in excess anlongrelatives of schizophrenics, with theainl of including or excluding then1fron1 the group of schizoid traits. Onvarious grounds he excluded all thetraits that he considered.
One of the traits which Kallnlannconsidered and rejected, nlental deficiency, perhaps deserves another look.About 6 to 10 percent of schizophrenics(see 14) and their first-degree relatives(see 3, 11) are ll1cntally subnormal, as
N ulnber of subjectsN unlbcr of malesAge, nlcan (years)N'umber adoptedMHSRS, means*N'umber with schizophreniaNUlllber with mental deficiency (LQ. < 70) tN'unlber with antisocial personalitiesNUlnber with neurotic personality disorder~(
Persons spending more than 1 year inpenal or psychiatric institutionNUlnber'rotal years incarcerated
NUlubcr of felonsN Ulllber serving in armed forcesNU111ber discharged from armed forces on
psychiatric or behavioral groundsSocial group, first home, nlean ~
Social group, present, mean ~
I.Q., 111eanYears in school, 111eanN'uluber of children, totalN'umber of divorces, totalNU111ber never married, > 30 years of age
nection to a schizophrenic are nlostinlperfect (9). Though unsatisfactory,the only means of identifying manyperhaps most-schizoids remains genealogical, and a clinical understandingof the schizoid can best be gained byreading descriptions of abnornlal relatives of schizophrenics (see 10-13 forgood examples). The circularity thusintroduced is regrettable but inescapable. The schizoid exists, and he sonlCtinlCS shows as much itnpairnlcnt psychiatrically as a typical schizophrenic.
Several problenlatical behaviors havebeen associated with the schizoid.Aillong nlales, antisocial behavior hasbeen found cOlnlnonly enough to warrant the older subdesignation "schi'zoidpsychopath." Entries in the· police records of the schizoid psychopaths in D1Y
study reflectcd impulsive, seelningly illogical crime such as arson, unreasoningassault, and poorly planned theft (3).Social isolation, heavy intake of alcohol,and sexual deviance have been notedfrequently. Other schizoids, both nlaleand female, have been described as eccentric, suspicion-ridden recluses. T'he111ai n disability of still other schizoids,lTIOStly feln,ales, has been found to heincapacitating attacks of panic or unreasoning fear in response to ordinarysocial challenges.
On a more technical level the reselnblance to schizophrenia is, more apparent. Rigidity of thinking, bluntingof affect, anhedonia, exquisite sensitivity, suspiciousness, and a relativepoverty of ideas-in variable conlbinations and intensities-characterize boththe schizoid and the schizophrenic,through such characteristics ,are lesspro111inent in the former. Though schizoids do not show a well-Inarked thoughtdisorder, delusions, and hallucinations~
descriptions of sonle of the behaviorallapses of schizoids, especially the schizoid psychopath, are bizarre enough tosuggest micropsychotic episodes.
SI ater took a different approach. He1isted a series of explicatives, partiallyreproduced in Table 2, used by relatives of schizophrenics when describingtheir abnormal but nonschizophrenicrelatives (13). Slater went on to say( 13, p. 83) that "the same or similarwords or phrases occur in descriptionsof abnormal personalities from otherkinds of families, but much less frequently, not in such concentrated fornl,and they are usually submerged bydescriptions of a very different tone."
Because K'alhnann's investigations ofthe families of schizophrenics were byfar the most extensive that have been
16 JANUARY 1970 251
Table 3. Data on monozygotic twins of schizophrenics.
::: Investigators' diagnoses: ? schizophrenia, schizophreniform, transient schizophrenia, reactive psychosis,borderline state, schizoid, suicide, psychopathic, neurosis, and variations of these diagnoses. -;- FromShields, Gotteslnan, and Slater (44).
Other Nonnal,
Investigator Pairs Schizophrenia significant or mild(No.) (No.) abnonnality* abnornlality
(No.) (No.)
Essen-Moller (19) 9 0 8 1Slater (13) 37 18 11 8Tienari (41) 16 1 12 3Kringlen (12) 45 14 17 14Inouye (42) 53 20 29 4GottesnUln and Shields (23) 24 10 8 6Kalhnann -;- (43) 174 103 62 9
Totals 358 166 (46.4% ) 147 (41.1%) 45 (12.6% )
Schizophrenia is defined operationally,not etiologically. It is the clinician whodeternlines whether schizophrenia ispresent. But of course the limits ofthe clinical entity lnay not correspondto those of the ,etiological entity. Infact the linking of schizoidia to schizophrenia by genetic evidence raisesserious questions about the etiologicalreality of the clinical definition of schizophrenia. There has always been a fuzzy border about schizophrenia alongwhich several nanled entities, includingabortive, ambulatory, borderline, latent,pseudoneurotic, pseudopsychopathic,and reactive schizophrenia and the"schizotype" of Meehl (18) haveseemed to lie. These terms nlay bestbe viewed as attelnpts to cope withan operationally defined border be-
. tween schizoidia and schizophrenia thatis clinically imprecise because it is biologically unreal.
Quantitative Aspects
Given a schizophrenic who has amonozygotic twin, the enlpirical probability that his twin will also be schizophrenic has been found to be about0.46 (Table 3). Most of the remaining54 percent of monozygotic twins ofschizophrenics have also been foundto be abnornlal. From clinical descriptions included in five studies (12, 13,19-21 ) it appears that nearly all ofthe abnormal though nonschizophrenicco-twins were schizoid. Overall, onlyabout 13 percent of the monozygotictwins of schizophrenics have been regarded as normal or nearly norlnal, and,because most of the errors inherent inthis sort of research tend to increasethe proportion of apparent norlnals,this is surely an overestimate. But,while a critic could easily quibble aboutany of the proportions in l"'able 3, acrude but critical conclusion is inescapable: monozygotic twins of schiz-
252
ophrenics are about as likely to beschizoid as schizophrenic. What then isinherited? These considerations ledEssen-Moller (19) to regard schizoidiaas the basic inherited trait, and I(ringlen, in a careful and sensitive analysis of twin research, including hisown nlajor study, seelns to have reacheda similar conclusion, although he regarded the predisposition as less specific (12). At the very least a primafacie case has been lnade for considering the whole group of schizoidand schizophrenic disorders as alternative expressions of a single genotype.Moreover, because monozygotic twinsare identical genetically, there is presUlnptive evidence that the range ofvariability within pairs can in principlebe accounted for by environmentalfactors. The genes allow a range ofoutcolnes.
A critical point to be established isthe proportion of schizoids or schizophrenics anlong the first-degree relatives(parents, sibs, children) of schizophrenics. Table 4 gives Kallnlann's results. No one else has investigated sonlany relatives of schizophrenics, andfew others have' conducted field studiesintensive enough to identify schizoids.l"'he more intensive lnodern studieshave tended to show sOlnewhat largerproportions of afflicted relatives (3, 10,22). So did Slater among dizygotictwins of schizophrenics (13). The proportions found by Gottesman andShields (23) and by Odegard (24) weresonlewhat snlaller. Kallmann's valuesmay be taken as fair average estimatesof the proportion of schizoids or schizophrenics anl0ng first-degree relativesof schizophrenics.
Table 4 also shows the results offour studies of the children of twoschizophrenics. An estiInated 66 percent of the children of these matingswere schizoid or schizophrenic, again,this is surely an underestimate becausethe subjects were still quite young. The
results of one such study, that ofLewis (25), was not included. Lewisdid not give ages, and he stated thathis follow-up was incomplete. Rosenthalhas recently reviewed these studies (26).
An inlportant uilknown lnust nowbe considered. There is no adequateestinlate of the proportion of schizoidsin the general population. Then, isthe clusteriIig of schizoids anlong relatives of schizophrenics greater thannlight occur by chance? Although theproportion of schizoids. found in fanlilies of schizophrenics is surely greaterthan that expected by even the mostpessimistic observer of the general population, a better answer is that neitherthe relatives of other kinds of psychiatric patients nor the controls used inpsychiatric studies have been found tobe afflicted in' significant numbers withdisorders of a schizoid character orwith any kind of behavioral disorderto the extent seen in relatives of schizophrenics. Furth~r evidence-the smallproportion of schizoids found amongdescendants of normal relatives ofschizophrenics-is discussed below.
While the lack of data for the general population and the related lack ofdata for the families of schizoid probands preclude estimates of gene frequency, it should be noted that schizoiddisorders surely afflict a large proportion of the population. With only isolated exceptions, schizophrenia afflictsabout 1 percent of any population. /Ifeach schizophrenic has five living firstdegree relatives (about the number inKallmann's study), a simple extrapolation yields an estimate of 4 percentfor the proportion of schizoids plusschizophrenics in the general population. This crude estimate can onlymake the point that any population, and
-especially any psychiatric population(persons identified because they came topsychiatric clinics or hospitals), is likely to contain large numbers of schizoids. One of the most neutral iInplications of this conclusion has an obvious application to the choosing ofcontrol groups for research in schizophrenia. '
Genetic Hypothesis
The nlost parsinlonious explanationof the data is given by the hypothesisthat a defect in a single autosonlalgene accounts for the genetic contribution to both schizoid and schizophrenic disease (the "donlinance hypothesisH
). By including schizoid dis-
SCIENCE, VOL. 167
Table 4. Percentages of first-degree relatives found to be schizophrenic or schizoid.
I~OI
MZtwins
49.045.844.0
66.1
Total: schizoidplus schizophrenic
(%)
32.631.534.8
32.2
Schizoid(%)
§ From Kallmann (11), Kahn (45),
0.61
in schizoidia-schizophrenia. First of all,there remain small deviations fromthe theoretical expectations under thedominance hypothesis, deviations whichhave been cited by Shields (2). Thesemainly take the forn1 of a greater resemblance between relatives than canbe explained by sim.ple dominance. Forexample, the monozygotic twin of aseverely afflicted individual is morelikely to be schizophrenic than thetwin of a mildly affected individual.If only a single gene \vere involvedone would expect the risk of schizophrenia for a monozygotic twin of anyschizophrenic to be equal to that ofany other. Likewise, the larger theproportion of schizophrenic relatives is,
16.414.3
9.2
33.9
jo.a1st degree Children of tworelatives schizophrenics
Schizophrenia:::(%)
:(: From (43),
0.4
100011912741
171
NORMAL
Numberof individuals
0.2
Degree of genetic relationship
1.0---------------------~
Fig. 1. Observed and expected proportion of schizoids and schizophrenics.
253
0.4
0.2
0.6
0.8-0Q)+-'UQ.)
'+'+-menC1>>....,COQ)'-
"'tO
enc::o
........'-oC-O'--a..
But research 111ust proceed fronl hypotheses based on present understand~
ing. From that viewpoint, and forpractical purposes, it is not at all unreasonable to proceed on the workingassumption that IUOSt schizoidia-schizophrenia is associated with defects in asingle basic biochemical or physiological pathway, translnitted by a singlemode of inheritance. It matters littlethat new research will no doubt turnup complexities that cannot even beimagined today.
Apart from insights gained frolnanal~gies to other genetic diseases, thereare factual reasons for expecting thatmany elements in addition to a singleDlain gene go into the mix that results
Relationship
* Age-corrected rates. t From (11).Schulz (46), and Elsasser (47).
Childreni'Siblings~
Parents~:
Children of twoschizophrenics§
ease (schizoidia), this hypothesis extends that of Slater (27). The view thatschizoidia and schizophrenia are asingle disease genetically is supportedby their clinical similarity and is virtually required by the finding that the disorders occur with equal probability inlTIonozygotic twins of schizophrenics.Further 8upport for the hypothesis ispresented in Fig. 1. The proportions ofaffected first-degree relatives fit reasonably well with the theoretical proportions expected under the donlinancehypothesis.
Kallmann presented SOUle data 011second-degree relatives (11). Among822 grandchildren of his schizophrenicprobands he found 4.3 percent to beschizophrenic and 22.8 percent to beschizoid. The corresponding rates fornephews and nieces were considerablylower (3.9 and 6.2 percent). However,Kallmann pointed out that the normalsibs of his schizophrenia probands contributed many more nephews and niecesthan the schizoid or schizophrenic sibsdid. While the total of 27.1 percent foraffected grandchildren is certainly closeto the 25 percent expected under thedOlTIinance hypothesis, the proportionsof affected nephews and nieces nlay ornlay not be compatible \vith that hypothesis.
The segregation of schizophrenia andschizoidia within families fits well withthe dominance hypothesis. In I(allnlann's study, which included threegenerations, the normal children of hisschizophrenic proballds, produced fewschizophrenic or schizoid children (1.8and 2.6 percent, respectively), no nlorethan might be expected in a generalpopulation. This is in contrast to thecorresponding values of 13.7 and 33.4percent for the ,children of the schizoidor schizophrenic children of Kallnlann'sschizophrenic probands (11).
The matter cannot be so sinlple, ofcourse. The mechanisms involved ina disease like schizoidia-schizophreniawill surely be found to be extrenlelyconlplex. Even phenylketonuria, whichonly a few years ago provided a prototype of rigorous simplicity for behavioral genetics, has. turned out tobe enormously complicated by secondary biochemical effects and by other,1110Stly unknown, factors (28). Heterogenity is also likely. Probably the mostcOll1pletely known genetic disease inhU111ans, glucose-6-phosphate dehydrogenase deficiency, occurs in at least 18variants, each one presumably due toan amino acid substitution at a different place in the sanle enzyme (29).
16 JANUARY 1970
the greater is the risk of schizophreniafor any given individual. Another sortof problem is that of accounting for thevariability seen among schizophrenics;this becomes more difficult when schizoids are included. Although there areno grounds for expecting 'any particular degree of resemblance between affected persons, it has often been arguedthat, if only one gene were involved,the range of obs~rvable phenotypesshould be slnaller than is the case. Andthe persistance of schizophrenia presents 'a problem. Before the introduction of antipsychotic drugs, schizophrenics reproduced at a rate 30 percent lower (16), and slchizoids at arate 22 percent lower (11), than therate for the general population. Suchreproductive deficits should have lowered the rates of occurrence of a disorder due to a main gene of largeeffect far below the presently observedrates for schizophrenia.
Attempts to account for such findingshave led to widespread espousal ofpolygenic theories of schizophrenia (12,24, 30). As Gottesman 'and Shieldshave pointed out (31), the facts areexplained adequately by polygenic theory. Most polygenic theorists have regarded schizophrenia as a thresholdtrait. But clinically schizoidia and schizophrenia seem to form a continuumof psychopathology, much as first described by Kretschmer (32). If thereis a threshold it probably falls betweenthe schizoid and the normal condition,but it seenlS that any such "threshold"is as likely to be a function of lacko.f diagnostic precision as a function ofthe disease. It is not necessary to consider other aspects of the polygenicargument here. Known modifiers of thephenotypic expression of the diseasepoint toward plausible solutions of theproblems encountered by the dominancehypothesis and toward resolution of theapparent differences between main-geneand polygenic theories.
Modifying Factors
One class of modifiers must be environmental events in the broadest sense-events occurring from conception onward that produce some change in theorganism. The nature-nurture dilemmais unreal. It is change in the environment of the cell that induces changein the genetically mediated .metabolicsystems of the cell. The functional stateof the cell is a result of the interplay
254
of these deternlinants. But realizationthat phenotypic traits depend on interaction between gene and environmentimposes conditions on research aimedat assessing the environment contribution. Genes function within cells. Theyinteract with chemical, thermal, or otherphysical events and not with the abstractions ("stress," for example) thattoo often have passed for environmentaldata. The ultimate questions implicitin the concept of ge~e-environmentinteraction are, for example: How doesa noxious learning experience alter theenvironment of the ,cell? What responseis elicited from the genetic program ofthe cell? How is the later operation ofthe cell modified? Of course, such questions cannot be approached directlytoday. But unless the environmentalcontribution is too variable from caseto case to allow generalization, it shouldbe possible to build up a series of associations between environment and behavior that would point toward theenvironmental events that enter intothe gene-environment interaction. Thecritical requirement is that such associations be potentially translatable intoevents that occur at the level of thegene. Despite all the research that hasbeen done on the effects of environmenton the development of schizophrenia,and despite the scope for environmentalfiactors demonstrated by the differencesbetween members of monozygotic twinpairs, practically no associations thatmeet this requirement have been established. Clinicians have learned to predict the effects of environmental features on their patients, but it is difficulttp see any etiological clues in this bodyof experience. On general clinicalgrounds it makes sense to continue tostudy the effects of environmentallystinlulated autonomic and endocrineresponses. An association between lowerbirth weight and the development ofschizophrenia in one member of amonozygotic twin pair has been reported (21), but it must be quite imperfect in view of the failure of otherinvestigators to confirm it (12, 23).Perhaps differences in autonomic responses among children of schizophrenics that were described in a preliminary report from a wide-rangingprospective study (33) are the mostpromising associations so far defined.Alnlost everything remains to· be done.
A second class of modifiers consistsof complex traits that have been linkedto schizophrenia by decades of empirical research. Somatotype has been
found by several investigators to beassociated with major modification ofschizophrenia. Mesomorphs are underrepresented among schizophrenics,and especially underrepresented amongschizophrenics younger than 25. Ectomorphs are correspondingly overrepresented. Schizophrenic mesomorphs arepredominantly paranoid and have ashorter mean period of hospitalizationthat other schizophrenics. Parnell (34),who has reviewed the subject and contributed his own data, found all theseassociations to be statistically significant.A relation between intelligence and theprognosis in schizophrenia is wellknown: the higher the intelligence thebetter the prognosis. But higher intelligence may also affect the expression ofschizophrenia. Lane and Albee (35)found that the I.Q. of children who laterbecame schizophrenic was seven pointslower than that of their si~lings whoremained nonschizophrenic. There area host of other established associationsbetween complex traits and schizophrenia-for example, patterns of autonomic nervous system reactivity, immunological phenomena, resistance tocertain chronic diseases, and toleranceof wound shock. Some such traits appear to be only oddities, given our present knowledge; others are known to belinked to favorable or unfavorable prognosis in schizophrenia, and still othersare known only to be more frequent orinfrequent among schizophrenics. Several reviews of thes,e findings are available (36).
The large number of such complextraits and the magnitude of the modification of schizophrenia associated withsome of them nlust mean that they havea significant role in the ecology of thedisease. F or one thing, they suggesta plausible solution to the puzzle posedby the persistence of high rates of schizophrenia. Sir Julian Huxley et ale (37)postulated that the gene responsible forschizophrenia conferred sufficient physiological or reproductive advantages tonlaintain a balanced polymorphism.They listed several physiological tr~its
found in schizophrenics that could bedue to pleiotropism. Although the number of traits listed seems large, widespread pleiotropism might result fronla mutation at a regulatory locus (38).But many modifying traits are clearlynot due to pleiotropism, and some ofthose-particularly differences in somatotype and intelligence-which demonstrably affect the outcome in schizophrenia must have conferred general
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biological advantages through nluch ofman's history as well. In either event,schizophrenics possessing advantageoustraits would be expected to reproduceat relatively higher rates than those notpossessing such traits. Over tinle, theevolutionary process would, theoretically, act to establish sets of favorabletraits that, on the average, would tendto accompany schizophrenia. Theoryaside, the popular association betweengenius and insanity, thought to be erroneous by Kallmann, was given SOOle
substance by Karlsson's finding thatcreative achievements and schizophreniaoccurred in the same faolily lines (39).I reported a similar impression; however, the evidence was not gatheredsystematically (40). Althoughthe problenl posed by the persistence of schizophrenia relnains theoretical and unsolved, further exploration of modifyingtraits provides as likely a path as anyother now in view toward solution ofthe puzzle.
Modifying traits also suggest an approach to the problenl of deviationsfrom strict expectations under the dOIninance hypothesis. As pointed out above,polygenic theory can account for suchdeviations. But traits like S0111atotypeand intelligence are themselves alnlostcertainly polygenic. Polygenic n10difiersof a single n1ain gene explain the samefacts, and indeed would yield the sanlC111athematical results as sin1ple ·additivepolygenic theory per see A n1ultitude ofgenes summating to produce schizophrenia directly or a single main geneplus groups of genes summating toproduce n10difying traits account equally well for findings such as the tendencyof nlonozygotic twins to be concordantwith respect to severity of illness.
Conclusion
A main gene of large effect nlodifiedby multiple factors, including polygenictraits, suggests a number _of testablehypotheses. Biochemical or other effectsof a main gene should be present inschizoids as well as in schizophrenics.In family studies, the critical test of theplace of the schizoid would be his reproductive performance in matings withnorn1al individuals; 50 percent of theoffspring of such matings should beschizoid or schizophrenic. However,po'ygenic modifiers should, on the average, maintain lesser degrees of disability in particular families. Thus,'schizoid parents should have fewer
16 JANUARY 1970
schizophrenic but n10re schizoid children than-schizophrenic parents. Thereis' incomplete support for this contention in Kallmann's study (11) of thegrandchildren of his schizophrenic subjects: the schizoid children of his schizophrenic probands had nlore schizoidand fewer schizophrenic children thantheir schizophrenic siblings, but nlen1bers of the third generation, the grandchildren of the probands, \vere tooyoung to yield decisive evidence. Alongthe sanle Jines, it would be expectedthat nearly all schizophrenics shouldhave at least one schizoid or schizophrenic parent. -Although the work ofKalln1ann and the intensive familystudies of Alanen (10) and IJdz (22)support this expectation, luore rigorousevidence is needed. The traits, that favorably nl0dify schizophrenia shouldbe nlore apparent alnong schizoid thanamong schizophrenic relatives of schizophrenics. One would hypothesize, forexalnplc, that the nlore mesomorphicor m.ore intelligent an10ng the childrenof schizophrenics would tend to haveless severe illnesses and to have morechildren than the less mesomorphic orless intelligent. These hypotheses, andmany n10re that are ilnplicit in the preceding discussion, constitute a significant refinement of the genetic hypotheses so far explored in schizophrenia.
l'he inlportance of genetic factorsin the development of schizophreniahas by now been established beyondreasonable dispute, although it is clearthat environment too plays its etiologicrole. The results of recent researchhave refocused attention on schizoiddisorders, a term applied to psychiatricdisorders reselnbling schizophreniawhich afflict relatives of schizophrenics.The many conceptual and researchproblems presented by the schizoid areconsidered.
Schizoids and schizophrenics" occurwith about the saIne frequency amongmonozygotic twins of schizophrenics.About 45 percent of the _sibs, parents,and children of a schizophrenic areschizoid or schizophrenics, as are about66 percent of the children of two schizophrenics. Fron1 the known risk ofschizophrenia for the population as awhole, it is estimated that at least 4percent of the general population willbe afflicted with schizoid-schizophrenicdisease.
Since lnonozygotic twins are identicalgenetically, it appears that the samegenotype is compatible with either schizophrenic or schizoid disease. The proportions of affected first-degree relatives and the segregation of affectedindividuals -within falnilies closely approximate theoretical expectations basedon the hypothesis of a defect in asingle autosomal dominant gene. However, modifying traits play a significantrole; this is 'discussed and integratedinto the main genetic hYP9thesis. Emphasis is placed on hypotheses testableby future research.
References and Notes
L E. Slater, in The Transmission of Schizophrenia, D. Rosenthal and S. Kety. Eds. (Pergamon, Oxford, 1968); D. Rosenthal, in TheOrigins 0/ Schizophrenia. J. Romano, Ed.(Excerpta Medica Foundation, New York,1967).
·2. J. Shields, in The TranS1'11ission of Schizophrenia, D. Rosenthal and S. Kety, Eds. (Pergamon, Oxford, 1968).
3. L. L. Heston t Brit. J. Psychiat. 112, 819(1966).
4. D. Rosenthal, P. Wender, S. Kety, F. Schul-singer, L. Ostergard, J. 'VeIner, in The Transmission of Schizophrenia, D. Rosenthal andS. Kety, Eds. (Pergamon,' Oxford, 1968).
5. J. Karlsson, The Biological Basis of Schizophrenia (Thomas, Springfield, Ill.. 1966).
6. P. Wender, D. Rosenthal, S. Kety, in TheTransmission of Schizophrenia, D. Rosenthaland S. Kety, Eds. (Pergamon, Oxford, 1968).
7. S. Kety, ·n.Rosenthal, F. Schulsinger, P.Wender, ibid.
8. I. Ray, Mental llygiene (Hafner, New York,new ed., 1968).
9.K. Planansky, J•.Nerv. Ment. Dis. 142, 318(1966); E. Essen-l\.1011er, Alschl'. Psychiat.Neuro1. 112, 258 (1946).
10. Y. 0.· Alanen, Acta Psychiat. Scand., SuppleNo. 189 (1966).
1L F. J. Kallmann, The Genetics of Schizophrenia (Augustin, New York, 1938).
12. Kringlen, "IIeredity and Environment inFunctional Psychoses," Norwegian
Monogr. Med. Sci. Univ. Oslo (1967).13. E. Slater, with the assistance of J. Shields,
"Psychotic and Neurotic Illness in· Twins,"Med. Res. COU1lC~ (Great Brit.) Spec. Rep.Sere No. 278 (1953).
14. B. Jlallgren and T. Sjogren, Acta Psychiat.Neurol. Scand., Suppl. No. 140 (1959).
15. L. S. Penrose, A Clinical and Genetic Studyof 1280 Cases o/Mental Defect (Her Majesty's Stationery Office, London, 1938).
16. J. A. Book, Acta Genet. 4, 1 (1953).17. E. W. Reed and S. C. Reed, Mental Retarda
tion: A F amity Study (Saunders, Philadelphia,1965).
18. P. E. Meehl, Amer. Psychol. 17, 827 (1962).19. E. Essen-Moller, Acta Psychiat., Supple No.
23 (1941.).20. ·P. Tienari, ActaPsychiat., Supple No. 171
(1963).21. W. Pollin, J. R. Stabenau, J. Tupin, Psychia
try 28, 60 (1965).22. T. Lidz, S. Fleck, A. Cornelison, Schizo
phrenia and the Family (International Universities Press, New York, 1966).
23. I. I. Gotteslnan and J. Shields, Brit. J.Psychiat. 112, 809 (1966).
24. O. Odegard, Acta Psychiat., Supple No. 169(1963), p. 94.
25. A. Lewis, Acta Genet. 7, 349 (1957).26. D. Rosenthal, J. Psychiat. Res. 4, 169 (1966).27. E. Slater, Acta Genet. 8, 50 (1958).28. C. Johnson, J. Iowa Med. Soc. 59, 27 (1968).29. H. Harris, Brit. Med. J. 2, 135 (1968).30. D. Rosenthal, The Genain Quadruplets (Basic
Books, New York, 1963).31. 1. Gottesman and J. Shields, Proc. Nat. Acad.
Sci. U.S. 58, 199 (1967).32. E. Kretschmer, Physique and Character (W.
Sprott, Trans.) (Paul, Trench and Trubner,London, 1925).
255
Casualties of OUf Time
Social and technological changes produce new sources
of death and disability which raise public issues.
33. S. Mednick and F. Schulsinger,· in TheTransmission of Schizophrenia, D. Rosenthaland S. Kety, Eds. (Pergamon, Oxford, 1968).
34. R. Parnell, Behavior and Physique (Arnold,London, 1958).
35. E. A. Lane and G. W. Albee, Amer. J.Orthopsychiat. 35, 747 (1965).
36. E. Gellhom and G. Loofbourrow, Emotionsand Emotional Disorders: A Neurophysiological Study (Harper & Row, New York,1963); W. Ross, J. Hay,M. McDowal,Psychosom. Med. 12, 170 (1950); P. Hustonand M. Pepemik, in Schizophrenia, A Review0/ the SJ'ndrome, L. Bellak, Ed. (Logos, NewYork t 1958); C. Rosenbaum t J. N'erv. Ment.
"It is changes that are chiefly responsible for diseases, especially the greatestchanges, the violent alterations both inthe seasons and in other things."
-HIP:POCRATES
Violent alterations in the humanenvironment have occurred at an increasing rate since the beginning ofthe Industrial Revolution. From thelate 18th century, dislocation fromthe land, turbulent crowding in growing cities, and the econonlic deprivations of factory life aff.ected thehealth of the people. Old diseases liketuberculosis flared up, and newsources of death and disability developed, such as the industrial injurieswhich were incurred 'by inexperienced hands attempting to masternew machinery. Great changes, visible in a man's lifetime, gave motivesfor new laws and institutions. Socialhygiene, with tardy assistance fromtherapeutic medicine, broughteffective lneasures to bear on the newhealth problems, while hospitals, asylunls, and other institutions were established to take the place of the nowobsolete welfare systems of farm andvillage. Economic and technologicalchanges thus produced specific newkinds of casualties, along with newr.esources for coping with them.
In the present century, the rate of
256
Dis. 146, 103 (1968); H. Freeman, in Schizophrenia, A Review of the Syndrome, L. Bellak, Ed. (Logos, New York, 1958); L. Rees,in Schizophrenia: Somatic. Aspects, D. Richter, Ed. (Macmillan, New York, 1957).
37. J. Huxley, E. Mayr, H. Osmond, A. Hoffer,Nature 204, 220 (1964).
38. R. J. Britten and E. H. Davidson, Science165, 349 (1969).
39. J. Karlsson, in The Transmission 0/ Schizophrenia, D. Rosenthal and S. Kety, Eds.(Pergamon, Oxford, 1968).
40. L. Heston and D. Denney, ibid.41. P. Tienari, ibid.42. E. Inouye, in Proceedings, Third World Con..
Amasa B. Ford
change has accelerated. Many oldproblems have been mastered, butnew ones have arisen. "Poor l'aws"and workhouses have gone the way ofphthisis and chlorosis. Now we mustask whether general hospitals cancope with increasing drug addictionamong alienated youth or how healthdepartments can protect the publicagainst ,cigarettes and overeating. Butbefore we can restructure our healthservices we must assess what we knowabout the particular health needs oftoday. Because established social institutions have great inertia, change isslow and· tends to lag behind need.New problems, therefore, call for special attention, since they foreshadowfuture needs.
The purpose of this report is toidentify sources of death and majordisability which are new or are ofnew inlportance in. developed countries in the two decades since WorldWar II. Using examples from GreatBritain and the United States, wem1ake some estimates of how peopleare being affected.
Certain casualties result from immediate causes, such as the toxic effects of a new drug or the increaseduse of nlotor vehicles. Many, possiblymore, take the fornl of nlajor disability resulting fronl conditions that have
gress of Psychiatry (Univ. of Toronto Press,Montreal, 1961), vol. 1, p. 524.
43. F. J. Kallmann, Amer. 1. Psychiat. 103, 309(1946).
44. J. Shields, I. Gottesman, E. Slater, ActaPsychiat. Scand. 43, 385 (1967).
45. E. Kahn, Monogr. Gesamtgeb. Neural.Psychiat. 36, 1 (1923).
46. B. Schulz,Z. Gesamte N eurol. Psychiar. 168,322 (1940).
47. G. Elsasser, Die N achkommen geisteskrankerElternpaare (Thieme, Stuttgart, 1952).
48. I thank James Shields, John Price, IrvingGottesman', and Russell Noyes, who commented on various phases of this manuscript.
complex origins. Examples are theextended survival of old people ·withchronic disease and the social alienation of young people. A rough classification by cause will serv.e as an outline, since an understanding of howdisease originates is the most reasonable basis for control and prevention.Effects on health may be produced bychanges in population, by technological develqplnents, by new factors inmedicine, or by shifting social andcultural patterns. These categories,however, should not obscure the factthat specific casualties may resultfrom multiple causes.
Signs of Change
,Prosperity and life expectancy havereached unprecedented levels in developed countries during the past 20years, but there are indications thatwe may be approaching the limit ofeffectiveness of current methods ofdis.ease control and prevention.
In the early 1950's infant mortalityrates ceased to improve at the ratewhich had prevailed for many. years.
lIn the decade 1946-56, rates had decreased 46 percent in the UnitedStates and 45 percent in England andWales. In the subsequent 10 years,they decreased' only 16 and 22 p.ercent, respectively. The estimated average length of life, which in effect isinversely related to infant mortality,has increased to 70.1 years in theUnited States and 68.4 years in England and Wales, but the rates of increase since 1956 have been less thana fifth of what they wer.e in the previous 10.years. The progressive reduction of deaths in the first year of life,which has been one of the finest fruitsof social and medical development
Dr. Ford is assistant professor of medicine andpreventive medicine at. Case Western ReserveSchool of Medicine, Cleveland, Ohio 44106.
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