Havaintotutkimusten meta-analyysit skitsofreniassa Jouko Miettunen, dosentti Psykiatrian klinikka Oulun yliopisto jouko.miettunen@oulu.fi

Skitsofreniatutkimus Oulun yliopistossa Pohjois-Suomen 1966 syntymäkohortti Pohjois-Suomen 1986 syntymäkohortti Adoptiolapsitutkimus Erityisesti epidemiologista tutkimusta

Katsaukset ja meta-analyysit Katsaus Systemaattinen katsaus Meta-analyysi Yhdistetty eli “pooled” analyysi

Meta-analyysit Meta-analyysissa yhdistetään aiempien tutkimuksien tulokset, erityisesti kun aiemmat tulokset ovat ristiriitaisia kun vaikutuksen suuruus on epäselvä Useimmiten käytetään kokeellisten tutkimusten (esim. lääke tai terapia) arviointiin

Havaintotutkimusten meta-analyysit Ylivoimaisesti suurin osa meta-analyyseista on kokeellisista tutkimuksista Meta-analyyseissa epäkokeellisissa eli havaintotutkimuksissa voidaan tutkia riskitekijöitä (esim. passiivisen tupakoinnin yhteyttä keuhkosyöpään), sairauden yleisyyttä, tms. Esim. Saha ym. (PLoS Medicine 2005; 2: e141) arvioivat skitsofrenian elinaikaiseksi prevalenssiksi 0.4-0.7%

Tutkimusten haku Systemaattinen artikkelien haku Tutkimuskysymys? Inkluusio/eksluusio kriteerit otoskoko, diagnostiikka, … Artikkelin kieli? Kirjallisuustietokannat Löhönen ym. Int J Circumpolar Health 2009;68:394-404 PubMed, PsycINFO, Web of Science, Scopus, Google Scholar, Elsevier, CINAHL, ERIC, EMBASE PSYNDEX, LILACS, Cochrane, … Julkaistut ja julkaisemattomat tutkimukset? otetaan yhteyttä kirjoittajiin Kaksi arvioijaa arvioi kaikki artikkelit

Vaikutuksen suuruus Pieni (small) Kohtalainen (moderate) Suuri (large) Erittäin suuri (very large) Cohenin d 0.2 0.5 0.8 1.3 Pearson r 0.1 0.3 0.7 Odds Ratio 1.5 2.5 4 10 Prosenttiero* 7 18 30 45 * Ryhmien ero psosenttiyksiköissä, kun prosentiosuudet välillä 15-85% Cohen. Psychol Bull 1992;112:155-9; Rosenthal. J Soc Serv Res 1996;21:37-59.

Tutkimusryhmän meta-analyyseja Skitsofrenia Alkoholismidiagnoosien vallitsevuus skitsofrenia-aineistoissa Kannabisdiagnoosien vallitsevuus skitsofrenia-aineistoissa Sukupuolierot skitsotypaalisissa persoonallisuuspiirteissä Isän iän yhteys skitsofreniariskiin Toipuminen skitsofreniassa (käsikirjoitus) Temperamentti Sukupuolierot temperamenttipiirteissä Temperamenttipiirteiden väliset korrelaatiot Maiden väliset erot temperamenttipiirteissä Temperamentti psykiatrisissa sairauksissa (arvioitavana)

Koskinen J, Löhönen J, Koponen H, Isohanni M, Miettunen J Thirty-five studies met our search criteria. The median current rate of CUD was 16.0% (IQR = 8.6-28.6, 10 studies) and the median lifetime rate was 27.1% (IQR = 12.2-38.5, 28 studies). The median rate of CUD was markedly higher in first episode vs. long-term patients (current 28.6%/22.0%, lifetime 44.4%/12.2%, respectively) and in studies where more than two-thirds of the participants were males than in the other studies (33.8%/13.2%). Cannabis use disorders were also more common in younger samples than in the others (current 38.5%/16.0%, lifetime 45.0%/17.9%). Approximately every fourth schizophrenia patient in our sample of studies had a diagnosis of CUD. Cannabis use disorders were especially common in younger and first-episode patient samples as well as in samples with a high proportion of males.

Objective: Advanced paternal age (APA) is a reported risk factor for schizophrenia in the offspring. We performed a meta-analysis of this association, considering effects of gender and study design. Methods: We identified articles by searching Pub Med, PsychInfo, and EMBASE, and the reference lists of identified studies. Previously unpublished data from the Northern Finland 1966 Birth Cohort (NFBC 1966) study were also included. Results: We found 9 studies (5 cohort studies and 4 case-control studies) that met the inclusion criteria. In both study designs, there was a significant increase in risk of schizophrenia in the offspring of older fathers (≥30) compared to a reference paternal age of 25-29, with no gender differences. A significant increase in risk was also found for younger fathers (<25) in both study designs. In cohort studies, the relative risk of schizophrenia in the offspring of younger fathers (<25) was significantly increased in males, but not females. There were no gender differences in the case-control studies. The population attributable risk percentage (PAR%) in all studies was 10% for paternal age ≥30, and 4% for paternal age <25. Conclusions: Both advanced paternal age (≥30) and younger paternal age (<25) increase the risk of schizophrenia; younger paternal age may be associated with an increased risk in males but not females. This risk factor increases the risk of schizophrenia as much as any single candidate gene of risk. The mechanism of these associations is not known, and may differ for older and younger fathers.

Recovery from schizophrenia – a meta-analysis Erika Jääskeläinen, Johanna Löhönen, John McGrath, Sukanta Saha, Matti Isohanni, Juha Veijola, Jouko Miettunen Recovery needed to be measured as combination of both clinical and social dimensions, with at least two-year measurement window for either of the outcome dimensions. We identified potentially relevant studies from seven electronic databases and by manual literature search. We included studies that were in English, presented primary data, were not therapy/drug trials/interventions, had at least 15 subjects and had follow up data for at least two years. All abstracts and articles were critically analysed by two of the authors. The search identified 5950 unique potentially relevant articles. After further screening, 57 studies have met our inclusion criteria. Based on these studies, between 0% to 52% of the subjects recovered (median 16.5%, 95% CI 14.5%-18.5%). Recovery percentage among males was 18.4% and females 17.3%. Compared to North-American and European studies (n=47), recovery was more common in studies from other location (n=10; mean 24.4% vs. 14.8%; meta-regression, z test –2.49, p=0.013). Recovery percentages were 8.9% in studies using DSM diagnostic systems (8 studies), 18.7% in ICD (19 studies), and 17.2% in other studies (30 studies, mainly older studies) (meta-regression, z test 0.24, p=0.81).

Combined Agra (WHO) Chandigarh (rural, WHO) Opjorsmoen 1988 Chennai (WHO) Moscow (WHO) Ogawa et al. 1987 Cali (WHO) Dixon and Innes 1966 Holmboe and Astrup 1957 Fallik and Liron 1976 Ciompi 1980 Errera 1957 Henisz 1966 Huber et al. 1980 Rajotte and Denber 1963 Vazquez-Barquero et al. 1999 Christensen 1974 Silverman 1941 Nottingham (WHO) Guttmann et al. 1939 Achte 1967a Achte 1967b Angst and Preisig 1995 Stenberg 1948 Langfeldt 1937 Robinson et al. 2004 Bland and Orn 1978 Helgason 1990 Walsh et al. 1991 Modestin et al. 2003 Prague (WHO) Beijing (WHO) Sofia (WHO) Mannheim (WHO) Obembe et al. 1995 Nyman and Jonsson 1983 Gottlieb 1940 DeLisi et al. 1998 Auslander and Jeste 2004 Rupp and Fletcher 1940 McGlashan 1984 Selten et al. 2007 Nagasaki (WHO) Dublin (WHO) Eitinger et al. 1958 Myers and Witmer 1937 Lauronen et al. 2005 Harrow et al. 1997 Hong Kong (WHO) Pillmann and Marneros 2005 17.4% (95% CI 15.0-19.9%) 51.9% 37.0% 36.6% 36.4% 32.4% 31.8% 31.1% 29.0% 27.7% 26.6% 25.9% 24.7% 24.0% 23.0% 21.0% 20.7% 20.4% 19.7% 18.8% 18.6% 18.4% 17.1% 17.0% 16.4% 16.3% 15.9% 14.0% 12.9% 12.5% 12.1% 10.0% 9.1% 9.0% 8.0% 7.7% 6.4% 6.0% 5.8% 5.0% 4.8% 4.4% 3.4% 2.8% 0.0% 5 10 15 20 25 30 35 40 45 50 55 recovery percentage

Meta-analyysien ongelmia Alkuperäiset tutkimukset eroavat huomattavasti toisistaan (heterogeenisia), joten yhdistäminen ongelmallista, esim. eroja arviointimenetelmien käytössä aineistot eri tavoin valikoituneet meta-regressiolla voi tutkia syitä heterogeenisyyteen Tutkimukset eivät ilmoita kaikkia tietoja mitä haluttaisiin käyttää Meta-analyysin inkluusiokriteerit vaikuttavat tuloksiin Julkaisuharha (publication bias, file-drawer problem) jos tutkimuksen tulokset eivät ole halutun mukaisia (esim. tilastollisesti merkitseviä), tulokset jätetään raportoimatta

Meta-analyysit - kirjallisuutta Stroup ym. Meta-analysis of observational studies in epidemiology. A proposal for reporting. JAMA 2000, 283, 2008-12. Sterne JAC (Ed.). Meta-Analysis in Stata: An Updated Collection from the Stata Journal, 2009. Egger M, Smith GD, Altman DG. Systematic reviews in health care. 2. painos. Lontoo: BMJ Publishing Group, 2001. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Introduction to Meta-Analysis. Wiley, 2009. www.joukomiettunen.net/presentations