Journal Club 17th October 2006 Koonong CMHC Dr Sebastian Theilhaber Chandler House Eastern Mental Health

Title:School Performance in Finnish Children and Later Development of Schizophrenia: A Population-Based Longitudinal StudyVolume 56, May 1999, 457-463

Authors: Cannon, Mary MD, MSc Jones, Peter MD, PhD Huttunen, Matti O. MD, PhD Tanskanen, Antti CSc Huttunen, Tiia MSc Rabe-Hesketh, Sophia PhD Murray, Robin M. MD, DSc

Institutions: Institute of Psychiatry, London, England: Department of

Psychological Medicine (Drs Cannon and Murray), Department of Biostatistics and Computing (Dr RabeHesketh), Division of Psychiatry, University of Nottingham, Nottingham,

England (Dr Jones), Department of Mental Health and Alcohol Research, National

Public Health Institute, Helsinki, Finland (Dr M. Huttunen, Mr Tanskanen, and Ms Huttunen).

Author (I) : Dr Mary Cannon Senior Lecturer in Psychiatry in RCSI (Royal College

of Surgeons in Ireland) Consultant in Beaumont Hospital, Dublin Area of special interest: The developmental

epidemiology of psychiatric illness, in particular early childhood and adolescent risk factors for adult psychotic illness more recent: Cannabis use. Medline search: Cannon M: 151, + Schizophrenia:

27 results. 16 with the above + Dr Murray, 5 with above + Dr Jones, 3 with above + Drs Murray and Jones. now in Dublin

(II.a): Dr Robin M Murray: Professor of Psychiatry, Institute of Psychiatry at the

Maudsley, Kings College, University of London; Consultant psychiatrist, Maudsley Hospital Areas of interests: epidemiology of first-onset bipolar disorder by using the Maudsley Twin Register and Family Study to examine the genetic and environmental causes of the biological abnormalities (e.g., MRI abnormalities) found in psychotic illnesses. The National Psychosis Unit at Bethlem Royal Hospital. Medline search: Murray RM: 478 resuslts, + Schizophrenia: 283 results. 16 with the above + Dr M Cannon, 19 with above + Dr Jones, 3 with above + both Drs.

Maudsley Hospital

(II.b): Dr Robin M Murray:Bio:

Awards:

1968-1972 Junior Posts in Internal Medicine at the Western Infirmary, Glasgow. 1972-1975 Senior House Officer and Registrar in Psychiatry at the Maudsley Hospital, London 1976-1977 MRC Visiting Fellow in Psychiatry at the National Institute of Mental Health, Bethesda, Maryland 1978-1989 Senior Lecturer and then Dean at the Institute of Psychiatry 1989-1999 Professor of Psychological Medicine, Institute of Psychiatry and King's College Hospital Medical School

Gaskell Gold Medal for Clinical Psychiatry of the Royal College of Psychiatrists, 1975 Research Prize of the Royal College of Psychiatrists, 1976 Leverhulme Fellowship, 1988 Royal Society Senior Research Fellowship, 1993-94 Kurt Schneider Award from "Deutsche Gesellschaft fuer Psychiatrie", 1994 President of the European Association of Psychiatrists, 1995-6 Adolf Meyer Award of the American Psychiatric Association, 1997 Paul Hoch Award of the American Psychopathological Association, 1998 Dean Award of the American College of Psychiatrists, 1999 Hilton Distinguished Investigator Award of the National Alliance for Research into Schizophrenia and Depression (NARSAD), 1999 Robert Sommer Award, 2000 Fifth Castilla del Pino Award for Achievement in Psychiatry, 2002 Honorary Member of the Association of European Psychiatry, 2002 Psykiatriyhdistys Suomen Medal of the Finnish Psychiatric Society, 2003 Lieber Award for Schizophrenia Research of NARSAD 2003 Elected Foreign Member of the US Institute of Medicine. 2003 Fellow of Kings College, London 2004 Medal of University of Helsinki 2004 William K. Warren Award of the International Congress on Schizophrenia Research 2005 Elected Member of Academia Europaea 2005

(III) Dr Peter Jones:Cambridge Nottingham

Professor of Psychiatry and Head of Department, University Cambridge Area of special interest: population-based epidemiological studies of

schizophrenia and bipolar disorder, psychotic illness, early psychosis support, lifestyle influence on adult mental health, links between migration and mental health. Medline search: Jones P: 713 results, + Schizophrenia: 46 results, 5 with the above + Dr Cannon, 19 with the above + Dr Murray and 3 with both of them.

(IV): Dr Sophia Rabe-Hesketh: Senior Lecturer in Bio-Statistics at the Institute of

Psychiatry, London Medline Search: Rabe Hesketh S: 54 results, 14 of those in relation to Schizophrenia

Whats the article about: Can apparently healthy children, diagnosed with schizophrenia in adulthood, be distinguished from their peers on performance in elementary school?

Design (I): case-control study

Epidemiologic study Individuals with disease (= cases) are identified and matched

with controls Provide odd ratios, not causalities (not to be confused with causes = aetiologies, which usually is what researchers are looking for) Used for rare conditions (= incidence low) by avoiding large and lengthy studies required to achieve adequate statistical power Common biases: Lack of precise definition of who counts as case, unsuitable controls

Design (II): Level of Evidence Systematic reviews and meta-analyses Randomised controlled trials with definitive results(confidence intervals that do not overlap the threshold clinically significant effect)

Randomised controlled trials with non-definitive

results (a point estimate that suggests a clinically significant effect but with confidence intervals overlapping the threshold for this effect) Cohort studies Case-control studies Cross sectional surveys Case reports

Design (III): Nested case-control study A case-control study drawing cases and controls from a cohort

that has been followed for a period of time.

Another example: Helicobacter pylori infection and the risk of

gastric carcinoma, Parsonnet et al (N Engl J Med. 1991 Oct 17;325 (16) : 1127-31)

Advantages over case-control studies: Can utilize the exposure and confounder data originally collected before

the onset of the disease, thus reducing potential recall bias and temporal ambiguity, Include cases and controls drawn from the same cohort, decreasing the likelihood of selection bias, Considered comparable to its parent cohort study in the likelihood of an unbiased association between an exposure and an outcome, Possible bias: remaining non-diseased persons, from whom the controls are selected, may not be fully representative of the original cohort due to death or losses to follow-up.

Methods - Overview: Population-based birth-cohort of all individuals born in Helsinki, Finland,

between 1st January 1951 and 31st December 1960. Case ascertainment from 3 national health care registers. Elementary school records of 400 children, diagnosed with Sz in adulthood, and 408 controls. Results analysed for the 4 years of schooling (ages 7-11 years) that were common to all pupils. Subjects were entered into a principal components analysis and produced 3 factors: academic, non-academic, and behavioural. These factors were compared between cases and controls after adjusting for sex and social group. Eligibility for high school and progression to high school were investigated among cases and controls.

Methods (I):Study Population and Ascertainment of cases (a):By 1950, the population of Finland, in the middle of a baby boom after WWII, in which they had been German allies, exceeded four million, 30% of whom - some 1.3 million - lived in the country's 65 towns. Todays population is just over 5.2 million and the per capita income is, with $31,208 (13th, 2005), one rank in front of Australia ($30,897).

Cohort: Individuals born in Helsinki, Finland, between 1st January 1951,

and 31st December 1960 Cases: Individuals born during this 10-year period with the diagnosis, ascertained from 3 national databases: Finnish Hospital Discharge Register (FHDR), Pension Register (PR), Free Medicine Register (FMR). Linked through unique social security number. Diagnosis made: Before 1987: by using ICD-8 After 1987: by using ICD-9 with DSM-III-R criteria All individuals with a 295 diagnosis were defined cases as the PR and the FMR only noted the first 3 digits. Therefore included was schizophrenia, schizoaffective disorder and schizophreniform disorder.

Methods (I):

Helsinki

Study Population and Ascertainment of cases (b):

Finland

FHDR: ICD-8/9 - diagnosis given by attending physician using on

discharge in all private and public hospitals. FMR / PR: Primary DSM-III-R diagnoses given by administrative staff, presumably based medical report, for individuals receiving statesubsidized outpatient medication and disability pensions, to which all Finnish citizens have free access. More than 90% of psychotic patients in Finland come into contact with the health care system in at least one of those ways. The diagnostic validity of the FHDR has been examined against DSM-IIIR criteria and has been found to have excellent (92%-100%) specificity for diagnoses of schizophrenia.

Methods (I):Study Population and Ascertainment of cases (c):

928 individuals with a "295- diagnosis were identified. For 486 (52%), health cards were located in the archives.

Old Parliament

Methods (II):Selection of Controls and Tracing of School Cards:Controls: The next Helsinki-born child with a different surname listed after each case in the Child Health Clinic archives was taken as a control. If the next card also belonged to a case, the previous card was taken instead. All with 295- diagnosis were included, other psychiatric diagnoses were not excluded. School record cards from the state elementary school system were traced for 400 cases and 408 controls in the archives. Numbers of controls, cases and repeaters in the years 1 4 were comparable When repeaters were excluded from the analysis, the results did not change

Methods (III):

The Helsinki Cathedral (Fin.: Helsingin tuomiokirkko)

Information on Correlates of Illness and Confounders:

Information derived from FHDR: 1st diagnosis (Age at this point in time was considered onset) 1st admission From School Card: Paternal occupation From City of Helsinki Social Group Classification: Four socio-economic groups, collapsed to two in the analysis: professional/clerical (1/2) and skilled/unskilled-workers (3/4) All information linked by unique social security nubmber

Methods (IV):Familial Loading Score:Calculated for each case to estimate genetic risk of schizophrenia - according to family size and age structure, based on data from health care registers, the National Population Register and the following Assumptions: Lifetime risk (of schizophrenia in a 1st deg-relative): 10% (with hx of familial Sz) Lifetime risk (of schizophrenia in a 1st deg-relative): 0.5% (with hx sporadic Sz): At risk range: 15 to 50 years, with a linear increase in risk from zero to lifetime risk. The likelihood ratio of proband's illness being familial or sporadic, given that a relative of age x is affected, is [(0.1)(x-15)/(50-15)]/[(0.005)(x-15)/(50-15)]=20 and the likelihood ratio, if a relative of age x is unaffected, is 1 minus this. Such a likelihood-ratio was calculated for each relative, and an overall likelihood ratio for whether the proband's illness was familial or sporadic was obtained by multiplying together the individual likelihood ratios. The loading score was obtained by taking the logarithm of the product. A loading score of 0 indicates equal support for the proband's illness to be familial or sporadic. A positive score indicates greater support for familiality A negative score indicates greater support for the proband's illness to be sporadic.

Methods (V):Finnish Elementary School System and School Record Cards:Children: visited the closest elementary school from age 7 years; studied the same subjects for the first 4 years of schooling; from the Swedish minority (~10%) visited separate schools, using the same curriculum; which were educationally retarded (1.3%-1.9%) or who suffered from emotional or conduct disorder (0.3%-0.8%) visited special classes within the school and were included; which were severely deaf, blind, severely brain-damaged, and some children in institutional care had separated education and were not included; Marks, Scores, Curriculum: After grade 4 (aged 11 years), a ranking score, based on the results of their summer examinations, determined whether a child went on to high school or continued elementary school. All pupils were given marks for conduct and attentiveness, a mark was deducted for transgressing school rules and a score less than full marks was an indicator of disruptive behaviour. The core curriculum subjects were mathematics, religion, reading, writing, handicrafts, physical education, and music.

Methods (VI):Statistical Analysis (a)Taking the bath Principal components analysis (PCA) to reduce the school variables to a smaller number of

underlying factors. Significance of subjects loading factors was set > 0.5 Varimax factor rotation to improve interpretability by adjusting the coordinate-system PCA resulted in three factors with eigenvalue > 1 shown in Table 1 together with loading subjects: Academic Behavioural Non-academic Results of the relevant subjects was summed to derive individual scores: Academic: high indicates better performance Behavioural: high indicates poor behaviour Non-academic: high indicates better performance

Methods (VI):Statistical Analysis (b)Taking the bath

Multilevel modeling to investigate dependence of the three factors Mean factor scores for each quintile, in which age at onset of schizophrenia,

mean annual number of days of hospitalization and familial loading score were divided, to examine the clinical correlates of the 3 factor scores among the cases;

Results (I): Significant excess of males among cases compared with controls Mean (+/- SD) age at onset of schizophrenia:

25.1 +/- 5.5 years [13.0-40.1 years] Mean annual duration of hospitalization for schizophrenia: 50.2 +/- 65.4 days [0.0-309.4 days] Mean familial loading score for schizophrenia among cases: 0.36 +/- 1.30 [-0.61 to 5.8]

Results (II):Comparison of School Performance between Cases and Controls (a):

Significant effect (SE) for case-control status for the non-academic factor:

cases performed significantly worse than controls. No SE for case-control status for the academic or the behaviour scores. No SE for sex, but there was a trend toward better performance in academic subjects by girls. SE for social group on all factors, were groups 1 and 2 (professional/clerical) performed better than groups 3 and 4 (skilled/unskilled-workers) on the academic and non-academic factor scores, but worse in the behaviour factor. There was no significant variance between schools on the academic, nonacademic, or behavioural factor scores.

Results (II):Comparison of School Performance between Cases and Controls (b):

Results (III):Correlates of Factor Scores: Age at onset, severity of illness, genetic risk of schizophrenia had no

influence on results for any of the 3 factors

Results (IV):Rank in Class and Progression to High School: No difference between cases and controls on mean rank in their class at

age 11 years, either before or after controlling for sex and social group (0.48 +/- 0.45 vs 0.52 +/- 0.29; t629 =-1.3; P=.19). No difference in the proportion of cases compared with controls who came first in their class (4.8% vs 4.4%; chi squared1 =0.03; P=.86) or last in their class (7.3% vs 8.6%; chi squared1 =0.36; P=.55). Cases were only about half as likely as controls to proceed to high school after grade 4 (adjusted odds ratio, 0.6; 95% confidence interval, 0.44-0.82).

Itae-Uusimaa

Comments (I):Advantages of the nested case-control design: the general population base minimizes selection bias; the use of standardized prospectively recorded childhood data

minimizes information and recall bias; the large number of cases gives high statistical power

Comments (II):The unexpected negative finding (a): Children, later diagnosed with Sz, performed just as well as their

peers in academic subjects throughout the school grades; Although: Previous case-control studies have found lower childhood IQ among patients; Previous cohort studies have shown an inverse linear relationship between low IQ in childhood and adolescence and risk of schizophrenia.

Comments (III):Possible Explanations (a):The Finnish school system during the 1950s and 1960s was very structured, had standardized teaching methods, rigid adherence to the curriculum, strong social pressure to conform to behavioural and social norms. The preschizophrenic child may perform well academically in such an ordered and predictable environment. An analysis of school performance as a predictor psychiatric illness in the 1966 North Finland birth cohort showed: there was no difference in examination results at age 16 years between the preschizophrenic children and a non-hospitalized general population comparison group.

Comments (III):Possible Explanations (b):

Authors found no relationship between academic ability and severity of

illness, therefore believe, it is unlikely that inclusion of schizoaffective disorder and schizophreniform disorder influenced the results. Comment: How was severity of illness defined? Preschizophrenic children might perform rather better in an in familiar

circumstances with familiar people then with more sophisticated tests, artificial testing and unfamiliar testers; Children with severe residential instability (= left Helsinki) were not included (cohort: born and educated in Helsinki)

Comments (IV):The Positive Finding:

Finland has 187,888 lakes and 179,584 islands.

Children who develop schizophrenia in adulthood perform

significantly worse than their peers on sports and handicrafts (the non-academic factor)

Comments (V):Possible Explanation (a):

Finlands highest point is 1328m, and 75% is covered by forests.

Preschizophrenic children show deficits in motor coordination in sports

and handicrafts test coordination skills. Supported through: High-risk studies: children at genetic risk for schizophrenia are distinguished by impairments of motor development and fine motor coordination, General population birth cohort studies: show delayed motor milestones, clumsiness and poor sports ability as predictors of later schizophrenia, Childhood home-movie footage of schizophrenic patients showing leftsided neuromotor abnormalities during the first 2 years of life, and the observation that 33% to 60% of schizophrenic patients, including neuroleptic-naive patients, show "soft" neurological signs in adulthood.

Comments (V):

Owing to the post-glacial rebound since the last ice age, the surface area of the country is growing by about 7 km2 / year.

Alternative Explanation (b):

Personality or motivational factors: In structured settings (such as mathematics class), individual differences may be minimized by situational pressures to conform. Sports and handicrafts represent social, unstructured aspects of the curriculum and reflect other abilities, such as artistic ability and teamwork. It may be these aspects of school life that preschizophrenic children find particularly difficult, and in which they express early schizoid tendencies.

Conclusion (I):

Swedish reign (11541809) Duchy of Russia (18091917) Civil War (19171918)

Childhood personality and motivational problems: supported by the finding that preschizophrenic children were less likely than controls to progress to high school. Supported by: of previously noted risk factors of failure to finish school and "lack of academic or vocational ambition" Although: Many of those eligible, choose not to progress to high school, for reasons unknown due to lack of data.

Conclusion (II):In favor of the motor coordination explanation: Because of the rigorous schedule of the skills and crafts to be mastered Because emphasis on acquisition of skills and athletic ability

Sources used:

Epidemiology for the Uninitiated, British Medical Journal How to read a paper, Trisha Greenhalgh, Rod Taylor Unit for EvidenceBased Practice and Policy, Department of Primary Care and Population Sciences, University College London Medical School A tutorial on Principal Components Analysis, Lindsay I Smith, February 26, 2002 Factor Rotations in Factor Analyses, Herve Abdi, The University of Texas at Dallas Clinical Investigation Online, Stanford School of Medicine http://en.Wikipedia.org Home pages of Nottingham University, Cambridge University, Institute of Psychiatry and many others

Thank you!