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 Study

Volume 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 Rabe-
Hesketh),
 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. Maudsley 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.
 (II.b): Dr Robin M Murray:
Bio:
 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
Awards:
 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
What’s 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.
Today’s 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.
 Helsinki

Methods (I):
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 state-
subsidized 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-III-
R 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
 The Helsinki Cathedral

Methods (III):
(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, non-
academic, 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)
 Finland has 187,888 lakes
and 179,584 islands.
Comments (IV):
The Positive Finding:

 Children who develop schizophrenia in adulthood perform

significantly worse than their peers on sports and handicrafts
(the non-academic factor)
 Finland’s highest point is
1328m, and 75% is covered by

Comments (V): forests.

Possible Explanation (a):

 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 left-
sided 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.
 Owing to the post-glacial rebound
since the last ice age, the surface

Comments (V): 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.
 Swedish reign (1154–1809)
Duchy of Russia (1809–1917)
Civil War (1917–1918)

Conclusion (I):

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 Evidence-
Based 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”, Herv´e 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!