Statistical analysis of the associations of hereditary factors with the risk of Type 1 diabetes and Diabetic Nephropathy based on the familial data collected through ascertaiment from population-based registers

In genetic epidemiology, population-based disease registries are commonly used to collect genotype or other risk factor information concerning affected subjects and their relatives. This work presents two new approaches for the statistical inference of ascertained data: a conditional and full likelihood approaches for the disease with variable age at onset phenotype using familial data obtained from population-based registry of incident cases. The aim is to obtain statistically reliable estimates of the general population parameters. The statistical analysis of familial data with variable age at onset becomes more complicated when some of the study subjects are non-susceptible, that is to say these subjects never get the disease. A statistical model for a variable age at onset with long-term survivors is proposed for studies of familial aggregation, using latent variable approach, as well as for prospective studies of genetic association studies with candidate genes. In addition, we explore the possibility of a genetic explanation of the observed increase in the incidence of Type 1 diabetes (T1D) in Finland in recent decades and the hypothesis of non-Mendelian transmission of T1D associated genes. Both classical and Bayesian statistical inference were used in the modelling and estimation. Despite the fact that this work contains five studies with different statistical models, they all concern data obtained from nationwide registries of T1D and genetics of T1D. In the analyses of T1D data, non-Mendelian transmission of T1D susceptibility alleles was not observed. In addition, non-Mendelian transmission of T1D susceptibility genes did not make a plausible explanation for the increase in T1D incidence in Finland. Instead, the Human Leucocyte Antigen associations with T1D were confirmed in the population-based analysis, which combines T1D registry information, reference sample of healthy subjects and birth cohort information of the Finnish population. Finally, a substantial familial variation in the susceptibility of T1D nephropathy was observed. The presented studies show the benefits of sophisticated statistical modelling to explore risk factors for complex diseases.

Oral Health among Iranian Preadolescents : A School-Based Health Education Intervention

The present study assessed oral health and its determinants among Iranian preadolescents, and evaluated a school-based health education programme aimed to promote their oral health. The target population of this study comprised a random sample of the third-grade school children (n = 459) of all public primary schools in 19 areas of Tehran city. The data came from a clinical examination of the children and two self-administered questionnaires: one for children, and one for mothers. The clinical dental examination was performed for recording children's oral health. The mothers' questionnaires covered background factors, oral self-care (OSC) behaviours and oral health-related knowledge and attitude statements. After baseline data collection, a community trial was designed as a 3-month school-based intervention study. For the intervention trial, the third-grade classes as the clusters were randomly assigned to the intervention and control groups. Three kinds of intervention were implemented, one in class, one via the parents, and one as a combination of these. One group served as controls with no intervention. The outcome measures of the study were changes in plaque and bleeding scores recorded. The results showed that mean dmft was 3.75 (SD = 2.8) for the primary teeth and mean DMFT was 0.4 (SD = 0.9) for the permanent teeth. All children had plaque on at least one index tooth and bleeding on probing in at least one index tooth occurred in 81%. About one-third (34%) of the children reported favourable OSC and less than half (46%) of the children reported brushing their teeth at least twice daily. Girls reported favourable OSC (OR = 2.0), had decay-free teeth (OR = 1.8) and treated permanent teeth (OR = 3.3) more than did boys. Mother's oral health-related aspects, i.e., mother's favourable OSC, high knowledge levels of and positive attitudes towards oral health, and active supervision of the child's tooth brushing had a positive effect on all aspects of children's oral health status and behaviours (ORs from 1.3 to 1.9). After the intervention, the results showed a strong intervention effect on healthy gingiva in both groups where parents were involved: the parental-aid group (OR = 7.7, 95% CI 2.2-27.7) and combined group (OR = 6.6, 95% CI 2.0-22.1). To improve children's oral health, community school-based oral health educational programmes should be established to include all primary schools. These programmes should benefit from the common risk factor approach and a multi-sectored approach to employ for communication between the community, the school, and the family. Oral health interventions should empower the parents' ability to improve their own oral health behaviour and then to transfer that healthy behaviour to their children.

The effects of the 2004 reduction in the price of alcohol on alcohol-related harm in Finland : A natural experiment based on register data

Changes in alcohol pricing have been documented as inversely associated with changes in consumption and alcohol-related problems. Evidence of the association between price changes and health problems is nevertheless patchy and is based to a large extent on cross-sectional state-level data, or time series of such cross-sectional analyses. Natural experimental studies have been called for. There was a substantial reduction in the price of alcohol in Finland in 2004 due to a reduction in alcohol taxes of one third, on average, and the abolition of duty-free allowances for travellers from the EU. These changes in the Finnish alcohol policy could be considered a natural experiment, which offered a good opportunity to study what happens with regard to alcohol-related problems when prices go down. The present study investigated the effects of this reduction in alcohol prices on (1) alcohol-related and all-cause mortality, and mortality due to cardiovascular diseases, (2) alcohol-related morbidity in terms of hospitalisation, (3) socioeconomic differentials in alcohol-related mortality, and (4) small-area differences in interpersonal violence in the Helsinki Metropolitan area. Differential trends in alcohol-related mortality prior to the price reduction were also analysed. A variety of population-based register data was used in the study. Time-series intervention analysis modelling was applied to monthly aggregations of deaths and hospitalisation for the period 1996-2006. These and other mortality analyses were carried out for men and women aged 15 years and over. Socioeconomic differentials in alcohol-related mortality were assessed on a before/after basis, mortality being followed up in 2001-2003 (before the price reduction) and 2004-2005 (after). Alcohol-related mortality was defined in all the studies on mortality on the basis of information on both underlying and contributory causes of death. Hospitalisation related to alcohol meant that there was a reference to alcohol in the primary diagnosis. Data on interpersonal violence was gathered from 86 administrative small-areas in the Helsinki Metropolitan area and was also assessed on a before/after basis followed up in 2002-2003 and 2004-2005. The statistical methods employed to analyse these data sets included time-series analysis, and Poisson and linear regression. The results of the study indicate that alcohol-related deaths increased substantially among men aged 40-69 years and among women aged 50-69 after the price reduction when trends and seasonal variation were taken into account. The increase was mainly attributable to chronic causes, particularly liver diseases. Mortality due to cardiovascular diseases and all-cause mortality, on the other hand, decreased considerably among the-over-69-year-olds. The increase in alcohol-related mortality in absolute terms among the 30-59-year-olds was largest among the unemployed and early-age pensioners, and those with a low level of education, social class or income. The relative differences in change between the education and social class subgroups were small. The employed and those under the age of 35 did not suffer from increased alcohol-related mortality in the two years following the price reduction. The gap between the age and education groups, which was substantial in the 1980s, thus further broadened. With regard to alcohol-related hospitalisation, there was an increase in both chronic and acute causes among men under the age of 70, and among women in the 50-69-year age group when trends and seasonal variation were taken into account. Alcohol dependence and other alcohol-related mental and behavioural disorders were the largest category in both the total number of chronic hospitalisation and in the increase. There was no increase in the rate of interpersonal violence in the Helsinki Metropolitan area, and even a decrease in domestic violence. There was a significant relationship between the measures of social disadvantage on the area level and interpersonal violence, although the differences in the effects of the price reduction between the different areas were small. The findings of the present study suggest that that a reduction in alcohol prices may lead to a substantial increase in alcohol-related mortality and morbidity. However, large population group differences were observed regarding responsiveness to the price changes. In particular, the less privileged, such as the unemployed, were most sensitive. In contrast, at least in the Finnish context, the younger generations and the employed do not appear to be adversely affected, and those in the older age groups may even benefit from cheaper alcohol in terms of decreased rates of CVD mortality. The results also suggest that reductions in alcohol prices do not necessarily affect interpersonal violence. The population group differences in the effects of the price changes on alcohol-related harm should be acknowledged, and therefore the policy actions should focus on the population subgroups that are primarily responsive to the price reduction.

Cognitive Functioning in Young Adults with Depression, Anxiety Disorders, or Burnout Symptoms : Findings from a Population-based Sample

Background. Evidence of cognitive dysfunction in depressive and anxiety disorders is growing. However, the neuropsychological profile of young adults has received only little systematic investigation, although depressive and anxiety disorders are major public health problems for this age group. Available studies have typically failed to account for psychiatric comorbidity, and samples derived from population-based settings have also seldom been investigated. Burnout-related cognitive functioning has previously been investigated in only few studies, again all using clinical samples and wide age groups. Aims. Based on the information gained by conducting a comprehensive review, studies on cognitive impairment in depressive and anxiety disorders among young adults are rare. The present study examined cognitive functioning in young adults with a history of unipolar depressive or anxiety disorders in comparison to healthy peers, and associations of current burnout symptoms with cognitive functioning, in a population-based setting. The aim was also to determine whether cognitive deficits vary as a function of different disorder characteristics, such as severity, psychiatric comorbidity, age at onset, or the treatments received. Methods. Verbal and visual short-term memory, verbal long-term memory and learning, attention, psychomotor processing speed, verbal intelligence, and executive functioning were measured in a population-based sample of 21-35 year olds. Performance was compared firstly between participants with pure non-psychotic depression (n=68) and healthy peers (n=70), secondly between pure (n=69) and comorbid depression (n=57), and thirdly between participants with anxiety disorders (n=76) and healthy peers (n=71). The diagnostic procedure was based on the SCID interview. Fourthly, the associations of current burnout symptoms, measured with the Maslach Burnout Inventory General Survey, and neuropsychological test performance were investigated among working young adults (n=225). Results. Young adults with depressive or anxiety disorders, with or without psychiatric comorbidity, were not found to have major cognitive impairments when compared to healthy peers. Only mildly compromised verbal learning was found among depressed participants. Pure and comorbid depression groups did not differ in cognitive functioning, either. Among depressed participants, those who had received treatment showed more impaired verbal memory and executive functioning, and earlier onset corresponded with more impaired executive functioning. In anxiety disorders, psychotropic medication and low psychosocial functioning were associated with deficits in executive functioning, psychomotor processing speed, and visual short-term memory. Current burnout symptoms were associated with better performance in verbal working memory and verbal intelligence. However, lower examiner-rated social and occupational functioning was associated with problems in verbal attention, memory, and learning. Conclusions. Depression, anxiety disorders, or burnout symptoms may not be associated with major cognitive deficits among young adults derived from the general population. Even psychiatric comorbidity may not aggravate cognitive functioning in depressive or anxiety disorders among these young adults. However, treatment-seeking in depression was found to be associated with cognitive deficits, suggesting that these deficits relate to increased distress. Additionally, early-onset depression, found to be associated with executive dysfunction, may represent a more severe form of the disorder. In anxiety disorders, those with low symptom-related psychosocial functioning may have cognitive impairment. An association with self-reported burnout symptoms and cognitive deficits was not detected, but individuals with low social and occupational functioning may have impaired cognition.

Dental health and school-based health education among 15-year-olds in Tehran, Iran

The aim of the present study was to assess dental health and its determinants among 15-year-olds in Tehran, Iran and to evaluate the impact of a school-based educational intervention on their oral cleanliness and gingival health. The total sample comprised 506 students. Data collection was performed through a clinical dental examination and a self-administered structured questionnaire. This questionnaire covered the student s background information, socio-economic status, self-perceived dental health, tooth-brushing, and smoking. The clinical dental examination covered caries experience, gingival status, dental plaque status, and orthodontic treatment needs. Participation was voluntary, and all students responded to the questionnaire. Only three students refused the clinical dental examination. The intervention was based on exposing students to dental health education through a leaflet and a videotape designed for the present study. The outcome examinations took place 12 weeks after the baseline among the three groups of the intervention trial (leaflet, videotape, and control). High participation rates at the baseline and scanty drop-outs (7%) in the intervention speak for reliability of the results. Mean value of the DMFT (D=decayed, M=missing, and F=filled teeth) index of the 15-year-olds was 2.1, which comprised DT=0.9, MT=0.2, and FT=1.0 with no gender differences. Dental plaque existed on at least one index tooth of all students, and healthy periodontium (Community Periodontal Index=0) was found in less than 10% of students. Need for caries treatment existed in 40% of students, for scaling in 24%, for oral hygiene instructions in all, and for orthodontic treatment in 26%. Students with the highest level of parents education had fewer dental caries (36% vs. 48%) and less dental plaque (77% vs. 88%). Of all students, 78% assessed their dental health as good or better. Even more of those with their DMFT=0 (73% vs. 27%) and DT=0 (68% vs. 32%) assessed their dental health as good or better. Smokers comprised 5% of the boys and 2% of the girls. Smoking was common among students of less-educated parents (6% vs. 3%). Of all students, 26% reported twice-daily tooth-brushing; girls (38% vs. 15%) and those of higher socio-economic background (33% vs. 17%) did so more frequently. The best predictors for a good level of oral cleanliness were female gender or twice-daily tooth-brushing. The present study demonstrated that a school-based educational intervention can be effective in the short term in improving the oral cleanliness and gingival health of adolescents. At least 50% reduction in numbers of teeth with dental plaque compared to baseline was achieved by 58% of the students in the leaflet group, by 37% in the videotape group, and by 10% of the controls. Corresponding figures for gingival bleeding were 72%, 64%, and 30%. For improving the oral cleanliness and gingival health of adolescents in countries such as Iran with a developing oral health system, school-based educational intervention should be established with focus on oral self-care and oral health education messages. Emphasizing the immediate gains from good oral hygiene, such as fresh breath, clean teeth, and attractive appearance should be key aspects for motivating these adolescents to learn and maintain good dental health, whilst in planning school-based dental health intervention, special attention should be given to boys and those with lower socio-economic status. Author s address: Reza Yazdani, Department of Oral Public Health, Institute of Dentistry, University of Helsinki, P.O. Box 41, FI-00014 Helsinki, Finland. E-mail: reza.yazdani@helsinki.fi

Helicobacter pylori in Vammala, Finland: seroepidemiological studies and a population-based ‘screen-and-treat’ programme

Helicobacter pylorin (helikobakteeri) tartunta saadaan yleensä lapsena ja tauti jää tavallisesti pysyväksi ilman täsmähoitoa. Onnistunut hoito parantaa pysyvästi helikobakteerista aiheutuvan mahan haavataudin ja näyttää ehkäisevän mahalaukun pahanlaatuisten muutosten kehittymistä. Aloitimme Vammalassa terveyskeskuksessa toteutetun kansainvälisesti ainutlaatuisen väestöpohjaisen helikobakteeritulehduksen seulonta- ja hoito-ohjelman pilottitutkimuksella 1994. 1996 kaikki 15-40-vuotiaat ja 1997-2000 15- ja 45-vuotiaat vammalalaiset kutsuttiin verinäyteseulontaan. Yhteensä 4626 henkilöä (75% kutsutuista) osallistui seulontaan. Vasta-ainepositiivisille tarjottiin helikobakteeritulehduksen lopettava lääkekuuri. Toiminnan seurauksena helikobakteeritulehduksen esiintyvyyden laskettiin vähentyneen 12%:sta 4%:iin 15-40-vuotiaiden ikäryhmässä. Tutkimme myös helikobakteerivasta-ainepositiivisten ja -negatiivisten eroja sekä helikobakteeritulehduksen riskitekijöitä kyselytutkimuksella. Lapsuudenkodin asumisahtauden, äidin matalan koulutusasteen, tupakoinnin, alkoholinkäytön, huonojen asunto-olojen ja ylävatsavaivoista johtuvien sairauslomien todettiin liittyvän helikobakteeritulehdukseen monimuuttuja-analyysissa. Tutkimme seulontaohjelmassa käyttämiemme IgG- ja IgA-luokan helikobakteeri-vasta-ainetestien luotettavuutta eri ikäryhmissä ottaen huomioon atrofisen gastriitin esiintyvyyden. 561 kliinisin perustein gastroskopoidun potilaan aineistossa IgG-testi osoittautui erittäin herkäksi kaikissa ikäryhmissä (99%). Tarkkuus oli myös vanhemmissa ikäryhmissä hyvä (97-93%), kun atrofista gastriittia sairastavat suljettiin pois. IgA- ja CagA-helikobakteerivasta-aineiden on todettu liittyvän lisääntyneeseen mahahaava- ja mahasyöpäriskiin. Analysoimme 560 henkilön pariseeruminäytteet, jotka oli otettu kahden vuosikymmenen välein, ja totesimme, että IgA-vasta-aineiden esiintyvyyden lisääntyyminen iän myötä johtuu paitsi syntymäajankohdasta ja uusista infektioista myös IgA-vasta-ainetasojen kohoamisesta helikobakteeritulehduksen aikana. Selvitimme myös CagA-vasta-ainetasojen muuttumista analysoimalla seeruminäytteet, jotka oli otettu kahden vuosikymmenen välein. Totesimme, että samanaikaisesti kun helikobakteerin esiintyvyys väestössä on alentunut, erityisesti CagA-positiiviset infektiot ovat vähentyneet. Tutkimuksemme osoittaa, että Suomessa terveyskeskuksen yhteydessä voidaan toteuttaa näin laajamittainen seulonta- ja hoito-ohjelma, johon suomalaiset osallistuvat aktiivisesti. Nähtäväksi jää, kuinka paljon ohjelma kykeni vähentämään helikobakteeritulehdukseen liittyviä myöhäisseuraamuksia.

Conjunctival Melanoma in Finland 1967-2000: a population-based study

Eighty-five new cases of conjunctival melanoma (CM) were diagnosed in Finland between 1967 and 2000. The annual crude incidence of CM was 0.51 per million inhabitants. The average age-adjusted incidence of 0.54 doubled during the study period, analogous to the increase in the incidence of cutaneous malignant melanoma during this period, suggesting a possible role for ultraviolet radiation in its pathogenesis. Nonlimbal tumors were more likely than limbal ones to recur and they were associated with decreased survival. Increasing tumor thickness and recurrence of the primary tumor were other clinical factors related to death from CM. The histopathologic specimens of 85 patients with CM melanoma were studied for cell type, mitotic count, tumor-infiltrating lymphocytes and macrophages, mean vascular density, extravascular matrix loops and networks, and mean diameter of the ten largest nucleoli (MLN). The absence of epithelioid cells, increasing mitotic count and small MLN were associated with shorter time to recurrence according to the Cox univariate regression. None of the histopathologic variables was associated with mortality from CM. Four (5%) patients had a CM limited to the cornea without evidence of a tumor other than primary acquired melanosis of the conjunctiva. Because there are no melanocytes in the cornea, the origin of these melanomas most likely is the limbal conjunctiva. All four corneally displaced CM were limited to the epithelium, and none of the patients developed metastases. An anatomic sub-classification based on my patients and world literature was developed for corneally displaced CM. In 20 patients the metastatic pattern could be determined. Ten patients had initial systemic metastases detected, nine had initial regional metastases, and in one case the two types were detected simultaneously. The patients most likely to develop either type of initial metastases were those with nonlimbal conjunctival melanoma, those with a primary tumor more than 2 mm thick, and those with a recurrent conjunctival melanoma. Approximately two thirds of the patients had limbal CM, a location associated with good prognosis. One third, however, had a primary CM originating outside the limbus. In these patients the chance of developing local recurrences as well as systemic metastases was significantly higher than in patients with limbal CM. Each recurrence accompanies an increased risk of developing metastases, and recurrences contribute to death along with increasing tumor thickness and nonlimbal tumor location. In my data, an equal number of patients with initial locoregional and systemic metastasis existed. Patients with limbal primary tumors less than 2 mm in thickness rarely experienced metastases, unless the tumor recurred. Consequently, the patients most likely to benefit from sentinel lymph node biopsy are those who have nonlimbal tumors, CM that are over 2 mm thick, or recurrent CM. The histopathology of CM differs from that of uveal melanoma. Microvascular factors did not prove to be of prognostic importance, possibly due to the fact that CM at least as often disseminates first to the regional lymph nodes, unlike uveal melanoma that almost always disseminates hematogenously.

Methodological perspectives for register-based health system performance assessment : Developing a hip fracture monitoring system in Finland

The resources of health systems are limited. There is a need for information concerning the performance of the health system for the purposes of decision-making. This study is about utilization of administrative registers in the context of health system performance evaluation. In order to address this issue, a multidisciplinary methodological framework for register-based data analysis is defined. Because the fixed structure of register-based data indirectly determines constraints on the theoretical constructs, it is essential to elaborate the whole analytic process with respect to the data. The fundamental methodological concepts and theories are synthesized into a data sensitive approach which helps to understand and overcome the problems that are likely to be encountered during a register-based data analyzing process. A pragmatically useful health system performance monitoring should produce valid information about the volume of the problems, about the use of services and about the effectiveness of provided services. A conceptual model for hip fracture performance assessment is constructed and the validity of Finnish registers as a data source for the purposes of performance assessment of hip fracture treatment is confirmed. Solutions to several pragmatic problems related to the development of a register-based hip fracture incidence surveillance system are proposed. The monitoring of effectiveness of treatment is shown to be possible in terms of care episodes. Finally, an example on the justification of a more detailed performance indicator to be used in the profiling of providers is given. In conclusion, it is possible to produce useful and valid information on health system performance by using Finnish register-based data. However, that seems to be far more complicated than is typically assumed. The perspectives given in this study introduce a necessary basis for further work and help in the routine implementation of a hip fracture monitoring system in Finland.

α-Synuclein pathology in very elderly Finns : A population-based clinico-neuropathologic and molecular genetic study of Dementia with Lewy bodies

Populations in developed countries are ageing fast. The elderly have the greatest incidence of de-mentia, and thus the increase in the number of demented individuals, increases the immediate costs for the governments concerning healthcare and hospital treatment. Attention is being paid to disorders behind cognitive impairment with behavioural and psychological symptoms, which are enormous contributors to the hospital care required for the elderly. The highest dreams are in prevention; however, before discovering the tools for preventing dementia, the pathogenesis behind dementia disorders needs to be understood. Dementia with Lewy bodies (DLB), a relatively recently discovered dementia disorder compared to Alzheimer’s disease (AD), is estimated to account for up to one third of primary degenerative dementia, thus being the second most common cause of dementia in the elderly. Nevertheless, the impact of neuropathological and genetic findings on the clinical syndrome of DLB is not fully established. In this present series of studies, the frequency of neuropathological findings of DLB and its relation to the clinical findings was evaluated in a cohort of subjects with primary degenerative dementia and in a population-based prospective cohort study of individuals aged 85 years or older. α-synuclein (αS) immunoreactive pathology classifiable according to the DLB consensus criteria was found in one fourth of the primary degenerative dementia subjects. In the population-based study, the corresponding figure was one third of the population, 38% of the demented and one fifth of the non-demented very elderly Finns. However, in spite of the frequent discovery of αS pathology, its association with the clinical symptoms was quite poor. Indeed, the common clinical features of DLB, hypokinesia and visual hallucinations, associated better with the severe neurofibrillary AD-type pathology than with the extensive (diffuse neocortical) αS pathology when both types of pathology were taken into account. The severity of the neurofibrillary AD-type pathology (Braak stage) associated with the extent of αS pathology in the brain. In addition, the genetic study showed an interaction between tau and αS; common variation in the αS gene (SNCA) associated significantly with the severity of the neurofibrillary AD-type pathology and nominally significantly with the extensive αS pathology. Further, the relevance and temporal course of the substantia nigra (SN) degeneration and of the spinal cord αS pathology were studied in relation to αS pathology in the brain. The linear association between the extent of αS pathology in the brain and the neuron loss in SN suggests that in DLB the degeneration of SN proceeds as the αS pathology extends from SN to the neocortex instead of early destruction of SN seen in Parkinson’s disease (PD). Furthermore, the extent of αS pathology in the brain associated with the severity of αS pathology in the thoracic and sacral autonomic nuclei of the spinal cord. The thoracic αS pathology was more common and more severe compared to sacral cord, suggesting that the progress of αS pathology proceeds downwards from the brainstem towards the sacral spinal cord.

Insights into the molecular genetics of celiac disease : Applying family- and population-based strategies

Celiac disease, or gluten intolerance, is triggered by dietary glutens in genetically susceptible individuals and it affects approximately 1% of the Caucasian population. The best known genetic risk factors for celiac disease are HLA DQ2 and DQ8 heterodimers, which are necessary for the development of the disease. However, they alone are not sufficient for disease induction, other risk factors are required. This thesis investigated genetic factors for celiac disease, concentrating on susceptibility loci on chromosomes 5q31-q33, 19p13 and 2q12 previously reported in genome-wide linkage and association studies. In addition, a novel genotyping method for the detection of HLA DQ2 and DQ8 coding haplotypes was validated. This study was conducted using Finnish and Hungarian family materials, and Finnish, Hungarian and Italian case-control materials. Genetic linkage and association were analysed in these materials using candidate gene and fine-mapping approaches. The results confirmed linkage to celiac disease on the chromosomal regions 5q31-q33 and 19p13. Fine-mapping on chromosome 5q31-q33 revealed several modest associations in the region, and highlighted the need for further investigations to locate the causal risk variants. The MYO9B gene on chromosome 19p13 showed evidence for linkage and association particularly with dermatitis herpetiformis, the skin manifestation of celiac disease. This implies a potential difference in the genetic background of the intestinal and skin forms of the disease, although studies on larger samplesets are required. The IL18RAP locus on chromosome 2q12, shown to be associated with celiac disease in a previous genome-wide association study and a subsequent follow-up, showed association in the Hungarian population in this study. The expression of IL18RAP was further investigated in small intestinal tissue and in peripheral blood mononuclear cells. The results showed that IL18RAP is expressed in the relevant tissues. Two putative isoforms of IL18RAP were detected by Western blot analysis, and the results suggested that the ratios and total levels of these isoforms may contribute to the aetiology of celiac disease. A novel genotyping method for celiac disease-associated HLA haplotypes was also validated in this thesis. The method utilises single-nucleotide polymorphisms tagging these HLA haplotypes with high sensitivity and specificity. Our results suggest that this method is transferable between populations, and it is suitable for large-scale analysis. In conclusion, this doctorate study provides an insight into the roles of the 5q31-q33, MYO9B, IL18RAP and HLA loci in the susceptibility to celiac disease in the Finnish, Hungarian and Italian populations, highlighting the need for further studies at these genetic loci and examination of the function of the candidate genes.

Randomised Evaluation of New Technologies within the Population‐Based Cervical Cancer Screening Programme in Finland: Cross‐Sectional Performance and Validity

A randomised and population-based screening design with new technologies has been applied to the organised cervical cancer screening programme in Finland. In this experiment the women invited to routine five-yearly screening are individually randomised to be screened with automation-assisted cytology, human papillomavirus (HPV) test or conventional cytology. By using the randomised design, the ultimate aim is to assess and compare the long-term outcomes of the different screening regimens. The primary aim of the current study was to evaluate, based on the material collected during the implementation phase of the Finnish randomised screening experiment, the cross-sectional performance and validity of automation-assisted cytology (Papnet system) and primary HPV DNA testing (Hybrid Capture II assay for 13 oncogenic HPV types) within service screening, in comparison to conventional cytology. The parameters of interest were test positivity rate, histological detection rate, relative sensitivity, relative specificity and positive predictive value. Also, the effect of variation in performance by screening laboratory on age-adjusted cervical cancer incidence was assessed. Based on the cross-sectional results, almost no differences were observed in the performance of conventional and automation-assisted screening. Instead, primary HPV screening found 58% (95% confidence interval 19-109%) more cervical lesions than conventional screening. However, this was mainly due to overrepresentation of mild- and moderate-grade lesions and, thus, is likely to result in overtreatment since a great deal of these lesions would never progress to invasive cancer. Primary screening with an HPV DNA test alone caused substantial loss in specificity in comparison to cytological screening. With the use of cytology triage test, the specificity of HPV screening improved close to the level of conventional cytology. The specificity of primary HPV screening was also increased by increasing the test positivity cutoff from the level recommended for clinical use, but the increase was more modest than the one gained with the use of cytology triage. The performance of the cervical cancer screening programme varied widely between the screening laboratories, but the variation in overall programme effectiveness between respective populations was more marginal from the very beginning of the organised screening activity. Thus, conclusive interpretations on the quality or success of screening should not be based on performance parameters only. In the evaluation of cervical cancer screening the outcome should be selected as closely as possible to the true measure of programme effectiveness, which is the number of invasive cervical cancers and subsequent deaths prevented in the target population. The evaluation of benefits and adverse effects of each new suggested screening technology should be performed before the technology becomes an accepted routine in the existing screening programme. At best, the evaluation is performed randomised, within the population and screening programme in question, which makes the results directly applicable to routine use.

Determinants of institutional care at older ages in Finland

Väitöskirjassa selvitettiin ikäihmisten laitoshoitoon siirtymisen todennäköisyyttä ja sen taustoja kansainvälisesti ainutlaatuisen rekisteriaineiston avulla. Selvitettäviä asioita olivat eri sairauksien, sosioekonomisten tekijöiden, puolison olemassaolon ja leskeksi jäämisen yhteys laitoshoitoon siirtymiseen yli 65-vuotiailla suomalaisilla. Tutkimuksessa havaittiin, että dementia, Parkinsonin tauti, aivohalvaus, masennusoireet ja muut mielenterveysongelmat, lonkkamurtuma sekä diabetes lisäsivät ikäihmisten todennäköisyyttä siirtyä laitoshoitoon yli 50 prosentilla, kun muut sairaudet ja sosiodemografiset tekijät oli otettu huomioon. Korkeat tulot vähensivät laitoshoidon todennäköisyyttä, kun taas puutteellinen asuminen (ilman peseytymistiloja tai keskus- tai sähkölämmitystä) sekä erittäin puutteellinen asuminen (ilman lämmintä vettä, vesijohtoa, viemäriä tai vesivessaa) lisäsivät todennäkösyyttä, kun muut sosiodemografiset tekijät, sairaudet ja asuinalue oli huomioitu. Kerrostalon hissittömyys ei ollut yhteydessä laitoshoidon todennäköisyyteen. Todennäköisyys siirtyä laitoshoitoon oli jostain syystä korkeampaa niillä ikäihmisillä, jotka asuivat vuokralla ja matalampaa omakotitalossa asuvilla ja niillä, joilla oli auto. Puolison olemassaolo vähensi ja leskeksi jääminen lisäsi laitoshoidon todennäköisyyttä huomattavasti. Todennäköisyys oli erityisen suuri, yli kolminkertainen, kun puolison kuolemasta oli kulunut enintään kuukausi verrattuna niihin, joiden puoliso oli elossa. Todennäköisyys laski, kun puolison kuolemasta kului aikaa. Miesten ja naisten tulokset olivat samansuuntaisia. Korkeat tulot tai koulutus eivät suojanneet riskiltä joutua laitoshoitoon puolison kuoltua. Puolison kuolema näyttää lisäävän hoidon tarvetta, kun kotona ei ole enää puolisoa tukemassa ja huolehtimassa kodin askareista. Laitoshoidon tarve vähenee, jos ja kun lesket ajan kuluessa oppivat elämään yksin. Toisaalta tutkimustulokset saattavat viitata myös siihen, että kaikkein huonokuntoisimmat lesket, jotka eivät pärjää yksin asuessaan, siirtyvät laitoshoitoon hyvin nopeasti puolison kuoltua. Tutkimuksessa oli mukana yhteensä yli 280 000 yli 65-vuotiasta henkilöä, joiden pitkäaikaiseen laitoshoitoon siirtymistä seurattiin tammikuusta 1998 syyskuuhun 2003. Laitoshoidoksi määriteltiin terveyskeskuksissa, sairaaloissa ja vanhainkodeissa tai vastaavissa yksiköissä tapahtuva pitkäaikainen hoito, joka kesti yli 90 vuorokautta tai oli vahvistettu pitkäaikaishoidon päätöksellä. Tutkimuksessa käytetty aineisto koottiin väestörekistereistä, sosiaali- ja terveydenhuollon rekistereistä ja lääkerekistereistä.

Invasive pneumococcal infections in Finland before routine use of conjugate vaccines : opportunities for prevention

Streptococcus pneumoniae is a leading cause of pneumonia, meningitis and bacteremia worldwide. The 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended for adults less than 65 years old with certain chronic medical conditions and for all elderly persons because of high rates of invasive pneumococcal infections (IPI) and increased risk of death. This study provides a comprehensive picture of the epidemiology of pneumococcal infections in Finland before the introduction of childhood pneumococcal conjugate vaccines, focusing on disease rates, risk factors, clinical outcome, and healthcare associated infections. This study was based on national, population-based laboratory surveillance for IPI. Information on all episodes of IPI was collected from the primary diagnostic laboratory. A case with IPI was defined as the isolation of S. pneumoniae from blood or cerebrospinal fluid during 1995-2002. Information on comorbidities and underlying conditions for IPI patients was obtained by linking the IPI surveillance database to other national, population-based health registries using each patient’s unique national identity code. In total, 4357 cases of IPI were identified. The overall annualized IPI incidence increased by 35% during the study period and was 10.6 per 100 000 population. The temporal increase in disease rates was associated with higher blood culturing rates over time. In working age adults, two-thirds of severe infections and one half of fatal cases occurred in persons with no recognized PPV23 indication. Persons with asthma were at increased risk for IPI and this new risk factor accounted for 5% of the overall disease burden. One tenth of pneumococcal bacteremias were healthcare-associated, and mortality among these patients was over twice as high as among patients with community-associated bacteremia. Most patients with nosocomial infections had underlying conditions for which PPV23 is recommended. The incidence of IPI in Finland has increased and the overall disease burden is higher than previously reported. The findings of this study underscore the urgent need for improved prevention efforts against pneumococcal infections in Finland through increased use of PPV23 in adult risk groups and introduction of childhood immunization with pneumococcal conjugate vaccine.

Oral Health among Young Adults and the Middle-aged in Iran

The aim of the present study was to assess oral health and treatment needs among adult Iranians according to socio-demographic status, smoking, and oral hygiene, and to investigate the relationships between these determinants and oral health. Data for 4448 young adult (aged 18) and 8301 middle-aged (aged 35 to 44) Iranians were collected in 2002 as part of a national survey using the World Health Organization (WHO) criteria for sampling and clinical diagnoses, across 28 provinces by 33 calibrated examiners. Gender, age, place of residence, and level of education served as socio-demographic information, smoking as behavioural and modified plaque index (PI) as the biological risk indicator for oral hygiene. Number of teeth, decayed teeth (DT), filled teeth (FT), decayed, missing, filled teeth (DMFT), community periodontal index (CPI), and prosthodontic rehabilitation served as outcome variables of oral health. Mean number of DMFT was 4.3 (Standard deviation (SD) = 3.7) in young adults and 11.0 (SD = 6.4) among middle-aged individuals. Among young adults the D-component (DT = 70%), and among middle-aged individuals the M-component (60%) dominated in the DMFT index. Among young adults, visible plaque was found in nearly all subjects. Maximum (max) PI was associated with higher mean number of DT, and higher periodontal treatment needs. A healthy periodontium was a rare condition, with 8% of young adults and 1% of middle-aged individuals having a max CPI = 0. The majority of the CPI findings among young adults consisted of calculus (48%) and deepened periodontal pockets (21%). Respective values for middle-aged individuals were 40% and 53%. Having a deep pocket (max CPI = 4) was more likely among young adults with a low level of education (Odds ratio (OR) = 2.7, 95% Confidence interval (CI) = 1.9–4.0) than it was among well-educated individuals. Among middle-aged individuals, having calculus or a periodontal pocket was more likely in men (OR = 1.8, 95% CI = 1.6–2.0) and in illiterate subjects (OR = 6.3, 95% CI = 5.1–7.8) than it was for their counterparts. Among young adults, having 28 teeth was more (p < 0.05) prevalent among men (72% vs. 68% for women), urban residents (71% vs. 67% for rural residents), and those with a high level of education (73% vs. 60% for those with a low level). Among middle-aged individuals, having a functional dentition was associated with younger age (OR = 2.0, 95% CI = 1.7−2.5) and higher level of education (OR = 1.8, 95% CI = 1.6−2.1). Of middle-aged individuals, 2% of 35- to 39-year-olds and 5% of those aged 40 to 44 were edentulous. Among the dentate subjects (n = 7,925), prosthodontic rehabilitation was more prevalent (p < 0.001) among women, urban residents, and those with a high level of education than it was among their counterparts. Among those having 1 to 19 teeth, a removable denture was the most common type of prosthodontic rehabilitation. Middle-aged individuals lacking a functional dentition were more likely (OR = 6.0, 95% CI = 4.8−7.6) to have prosthodontic rehabilitation than were those having a functional dentition. In total, 81% of all reported being non-smokers, and 32% of men and 5% of women were current smokers. Heavy smokers were the most likely to have deepened periodontal pockets (max CPI ≥ 3, OR = 2.9, 95% CI = 1.8−4.7) and to have less than 20 teeth (OR = 2.3, 95% CI = 1.5−3.6). The findings indicate impaired oral health status in adult Iranians, particularly those of low socio-economic status and educational level. The high prevalence of dental plaque and calculus and considerable unmet treatment needs call for a preventive population strategy with special emphasis on the improvement of oral self-care and smoking cessation to tackle the underlying risk factors for oral diseases in the Iranian adult population.