Novel Multiple Sclerosis Predisposing Genetic Variants Outside the HLA Region

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Both environmental factors and several predisposing genes are required to generate MS. Despite intensive research these risk factors are still largely unknown, the pathogenesis of MS demyelination is poorly understood, and no curative treatment exists. Both prevalence and familial occurrence of MS are exceptionally high in a Finnish population subisolate, Southern Ostrobothnia, presumably due to enrichment of predisposing genetic variants within this region. Previous linkage scan on MS pedigrees from Southern Ostrobothnia detected three main MS loci on chromosomes 5p, 6p (HLA) and 17q. Linkage studies in other populations have also provided independent evidence for the location of MS susceptibility genes in these regions. Further, these loci are syntenic to the experimental autoimmune encephalomyelitis (EAE) susceptibility loci of rodents. In this thesis work an effort was made to localize MS predisposing alleles of the linked loci outside the HLA region by studying familial MS cases from the Southern Ostrobothnia isolate. Analysis of the 5p locus revealed one region, flanking the complement component 7 (C7) gene. The identified relatively rare haplotype seems to have a fairly large effect on genetic susceptibility of MS (frequency MS 12%, controls 4%; p=0.000003, OR=2.73). Evidence for association with alleles of the region and MS was seen also in more heterogeneous populations. Convincingly, plasma C7 protein levels and complement activity correlated with the risk haplotype identified. The finding stimulated us to study other complement cascade genes in MS. No evidence for association could be observed with the complement component coding genes outside 5p. A scan of the 17q locus provided evidence for association with variants of the protein kinase C alpha (PRKCA) gene (p=0.0001). Modest evidence for association with PRKCA was observed also in Canadian MS families. Finally we used a candidate gene based approach to identify potential MS loci. Mutations of DAP12 and TREM2 cause a recessively inherited CNS white matter disease PLOSL. Interestingly, DAP12 and TREM2 are located in MS regions on 6p and 19q, and we tested them as potential candidate genes in the Finnish MS sample. No evidence for association with MS was observed. This thesis provides an example of how extended families from special populations can be utilized in fine-mapping of the linked loci. A first relatively rare MS variant was identified utilizing the strength of a Finnish population subisolate. This variant seems to have an effect on activity of the complement system, which has previously been suggested to have an important role in the pathogenesis of MS.

Digitoitujen väri-infrailmakuvien numeerinen monikuvatulkinta metsäninventoinnissa

The use of remote sensing imagery as auxiliary data in forest inventory is based on the correlation between features extracted from the images and the ground truth. The bidirectional reflectance and radial displacement cause variation in image features located in different segments of the image but forest characteristics remaining the same. The variation has so far been diminished by different radiometric corrections. In this study the use of sun azimuth based converted image co-ordinates was examined to supplement auxiliary data extracted from digitised aerial photographs. The method was considered as an alternative for radiometric corrections. Additionally, the usefulness of multi-image interpretation of digitised aerial photographs in regression estimation of forest characteristics was studied. The state owned study area located in Leivonmäki, Central Finland and the study material consisted of five digitised and ortho-rectified colour-infrared (CIR) aerial photographs and field measurements of 388 plots, out of which 194 were relascope (Bitterlich) plots and 194 were concentric circular plots. Both the image data and the field measurements were from the year 1999. When examining the effect of the location of the image point on pixel values and texture features of Finnish forest plots in digitised CIR photographs the clearest differences were found between front-and back-lighted image halves. Inside the image half the differences between different blocks were clearly bigger on the front-lighted half than on the back-lighted half. The strength of the phenomenon varied by forest category. The differences between pixel values extracted from different image blocks were greatest in developed and mature stands and smallest in young stands. The differences between texture features were greatest in developing stands and smallest in young and mature stands. The logarithm of timber volume per hectare and the angular transformation of the proportion of broadleaved trees of the total volume were used as dependent variables in regression models. Five different converted image co-ordinates based trend surfaces were used in models in order to diminish the effect of the bidirectional reflectance. The reference model of total volume, in which the location of the image point had been ignored, resulted in RMSE of 1,268 calculated from test material. The best of the trend surfaces was the complete third order surface, which resulted in RMSE of 1,107. The reference model of the proportion of broadleaved trees resulted in RMSE of 0,4292 and the second order trend surface was the best, resulting in RMSE of 0,4270. The trend surface method is applicable, but it has to be applied by forest category and by variable. The usefulness of multi-image interpretation of digitised aerial photographs was studied by building comparable regression models using either the front-lighted image features, back-lighted image features or both. The two-image model turned out to be slightly better than the one-image models in total volume estimation. The best one-image model resulted in RMSE of 1,098 and the two-image model resulted in RMSE of 1,090. The homologous features did not improve the models of the proportion of broadleaved trees. The overall result gives motivation for further research of multi-image interpretation. The focus may be improving regression estimation and feature selection or examination of stratification used in two-phase sampling inventory techniques. Keywords: forest inventory, digitised aerial photograph, bidirectional reflectance, converted image co­ordinates, regression estimation, multi-image interpretation, pixel value, texture, trend surface

Health-Related Quality of Life, Costs and Treatment of Inflammatory Rheumatic Diseases in Routine Practice : With special emphasis on biological drugs

Rheumatoid arthritis (RA) and other chronic inflammatory joint diseases already begin to affect patients health-related quality of life (HRQoL) in the earliest phases of these diseases. In treatment of inflammatory joint diseases, the last two decades have seen new strategies and treatment options introduced. Treatment is started at an earlier phase; combinations of disease-modifying anti-rheumatic drugs (DMARDs) and corticosteroids are used; and in refractory cases new drugs such as tumour necrosis factor (TNF) inhibitors or other biologicals can be started. In patients with new referrals to the Department of Rheumatology of the Helsinki University Central Hospital, we evaluated the 15D and the Stanford Health Assessment Questionnaire (HAQ) results at baseline and approximately 8 months after their first visit. Altogether the analysis included 295 patients with various rheumatic diseases. The mean baseline 15D score (0.822, SD 0.114) was significantly lower than for the age-matched general population (0.903, SD 0.098). Patients with osteoarthritis (OA) and spondyloarthropathies (SPA) reported the poorest HRQoL. In patients with RA and reactive arthritis (ReA) the HRQoL improved in a statistically significant manner during the 8-month follow-up. In addition, a clinically important change appeared in patients with systemic rheumatic diseases. HAQ score improved significantly in patients with RA, arthralgia and fibromyalgia, and ReA. In a study of 97 RA patients treated either with etanercept or adalimumab, we assessed their HRQoL with the RAND 36-Item Health Survey 1.0 (RAND-36) questionnaire. We also analysed changes in clinical parameters and the HAQ. With etanercept and adalimumab, the values of all domains in the RAND-36 questionnaire increased during the first 3 months. The efficacy of each in improving HRQoL was statistically significant, and the drug effects were comparable. Compared to Finnish age- and sex-matched general population values, the HRQoL of the RA patients was significantly lower at baseline and, despite the improvement, remained lower also at follow-up. Our RA patients had long-standing and severe disease that can explain the low HRQoL also at follow-up. In a pharmacoeconomic study of patients treated with infliximab we evaluated medical and work disability costs for patients with chronic inflammatory joint disease during one year before and one year after institution of infliximab treatment. Clinical and economic data for 96 patients with different arthritis diagnoses showed, in all patients, significantly improved clinical and laboratory variables. However, the medical costs increased significantly during the second period by 12 015 (95% confidence interval, 6 496 to 18 076). Only a minimal decrease in work disability costs occurred mean decrease 130 (-1 268 to 1 072). In a study involving a switch from infliximab to etanercept, we investigated the clinical outcome in 49 patients with RA. Reasons for switching were in 42% failure to respond by American College of Rheumatology (ACR) 50% criteria; in 12% adverse event; and in 46% non-medical reasons although the patients had responded to infliximab. The Disease Activity Score with 28 joints examined (DAS28) allowed us to measure patients disease activity and compare outcome between groups based on the reason for switching. In the patients in whom infliximab was switched to etanercept for nonmedical reasons, etanercept continued to suppress disease activity effectively, and 1-year drug survival for etanercept was 77% (95% CI, 62 to 97). In patients in the infliximab failure and adverse event groups, DAS28 values improved significantly during etanercept therapy. However, the 1-year drug survival of etanercept was only 43% (95% CI, 26 to 70) and 50% (95% CI, 33 to 100), respectively. Although the HRQoL of patients with inflammatory joint diseases is significantly lower than that of the general population, use of early and aggressive treatment strategies including TNF-inhibitors can improve patients HRQoL effectively. Further research is needed in finding new treatment strategies for those patients who fail to respond or lose their response to TNF-inhibitors.

A Nationwide Study on Breast Cancer Risk in Postmenopausal Women Using Hormone Therapy in Finland

Since national differences exist in genes, environment, diet and life habits and also in the use of postmenopausal hormone therapy (HT), the associations between different hormone therapies and the risk for breast cancer were studied among Finnish postmenopausal women. All Finnish women over 50 years of age who used HT were identified from the national medical reimbursement register, established in 1994, and followed up for breast cancer incidence (n= 8,382 cases) until 2005 with the aid of the Finnish Cancer Registry. The risk for breast cancer in HT users was compared to that in the general female population of the same age. Among women using oral or transdermal estradiol alone (ET) (n = 110,984) during the study period 1994-2002 the standardized incidence ratio (SIR) for breast cancer in users for < 5 years was 0.93 (95% confidence interval (CI) 0.80–1.04), and in users for ≥ 5 years 1.44 (1.29–1.59). This therapy was associated with similar rises in ductal and lobular types of breast cancer. Both localized stage (1.45; 1.26–1.66) and cancers spread to regional nodes (1.35; 1.09–1.65) were associated with the use of systemic ET. Oral estriol or vaginal estrogens were not accompanied with a risk for breast cancer. The use of estrogen-progestagen therapy (EPT) in the study period 1994-2005 (n= 221,551) was accompanied with an increased incidence of breast cancer (1.31;1.20-1.42) among women using oral or transdermal EPT for 3-5 years, and the incidence increased along with the increasing duration of exposure (≥10 years, 2.07;1.84-2.30). Continuous EPT entailed a significantly higher (2.44; 2.17-2.72) breast cancer incidence compared to sequential EPT (1.78; 1.64-1.90) after 5 years of use. The use of norethisterone acetate (NETA) as a supplement to estradiol was accompanied with a higher incidence of breast cancer after 5 years of use (2.03; 1.88-2.18) than that of medroxyprogesterone acetate (MPA) (1.64; 1.49-1.79). The SIR for the lobular type of breast cancer was increased within 3 years of EPT exposure (1.35; 1.18-1.53), and the incidence of the lobular type of breast cancer (2.93; 2.33-3.64) was significantly higher than that of the ductal type (1.92; 1.67-2.18) after 10 years of exposure. To control for some confounding factors, two case control studies were performed. All Finnish women between the ages of 50-62 in 1995-2007 and diagnosed with a first invasive breast cancer (n= 9,956) were identified from the Finnish Cancer Registry, and 3 controls of similar age (n=29,868) without breast cancer were retrieved from the Finnish national population registry. Subjects were linked to the medical reimbursement register for defining the HT use. The use of ET was not associated with an increased risk for breast cancer (1.00; 0.92-1.08). Neither was progestagen-only therapy used less than 3 years. However, the use of tibolone was associated with an elevated risk for breast cancer (1.39; 1.07-1.81). The case-control study confirmed the results of EPT regarding sequential vs. continuous use of progestagen, including progestagen released continuously by an intrauterine device; the increased risk was seen already within 3 years of use (1.65;1.32-2.07). The dose of NETA was not a determinant as regards the breast cancer risk. Both systemic ET, and EPT are associated with an elevation in the risk for breast cancer. These risks resemble to a large extent those seen in several other countries. The use of an intrauterine system alone or as a complement to systemic estradiol is also associated with a breast cancer risk. These data emphasize the need for detailed information to women who are considering starting the use of HT.

Use of Customer Information: An Ethnography in Service Development

Service researchers have repeatedly claimed that firms should acquire customer information in order to develop services that fit customer needs. Despite this, studies that would concentrate on the actual use of customer information in service development are lacking. The present study fulfils this research gap by investigating information use during a service development process. It demonstrates that use is not a straightforward task that automatically follows the acquisition of customer information. In fact, out of the six identified types of use, four represent non usage of customer information. Hence, the study demonstrates that the acquisition of customer information does not guarantee that the information will actually be used in development. The current study used an ethnographic approach. Consequently, the study was conducted in the field in real time over an extensive period of 13 months. Participant observation allowed direct access to the investigated phenomenon, i.e. the different types of use by the observed development project members were captured while they emerged. In addition, interviews, informal discussions and internal documents were used to gather data. A development process of a bank’s website constituted the empirical context of the investigation. This ethnography brings novel insights to both academia and practice. It critically questions the traditional focus on the firm’s acquisition of customer information and suggests that this focus ought to be expanded to the actual use of customer information. What is the point in acquiring costly customer information if it is not used in the development? Based on the findings of this study, a holistic view on customer information, “information in use” is generated. This view extends the traditional view of customer information in three ways: the source, timing and form of data collection. First, the study showed that the customer information can come explicitly from the customer, from speculation among the developers or it can already exist implicitly. Prior research has mainly focused on the customer as the information provider and the explicit source to turn to for information. Second, the study identified that the used and non-used customer information was acquired both previously, and currently within the time frame of the focal development process, as well as potentially in the future. Prior research has primarily focused on the currently acquired customer information, i.e. within the timeframe of the development process. Third, the used and non-used customer information was both formally and informally acquired. In prior research a large number of sophisticated formal methods have been suggested for the acquisition of customer information to be used in development. By focusing on “information in use”, new knowledge on types of customer information that are actually used was generated. For example, the findings show that the formal customer information acquired during the development process is used less than customer information already existent within the firm. With this knowledge at hand, better methods to capture this more usable customer information can be developed. Moreover, the thesis suggests that by focusing stronger on use of customer information, service development processes can be restructured in order to facilitate the information that is actually used.

Dementiakuolleisuuden sosiaaliset determinantit - rekisteriaineistoon pohjautuva tutkimus dementiakuolleisuuteen vaikuttavista sosiodemografisista tekijöistä

Tutkimuksessa tarkastellaan dementiakuolleisuutta sekä siihen vaikuttavia sosiaalisia tekijöitä. Dementia on oireyhtymä, jota pääasiassa sairastavat yli 65 -vuotiaat henkilöt. Väestön ikääntyessä sekä elinajanodotteen kasvaessa on odotettavissa, että dementiaa sairastavien määrä tulee kasvamaan merkittävästi lähivuosina. On viitteitä siitä, että dementiaan sairastumisen riskiin vaikuttavat erilaiset sosiaaliset tekijät kuten koulutus, mutta varsinkin dementiakuolleisuudesta tiedetään vähän. Tutkielman aineistona käytettiin Tilastokeskuksen muodostamaa Elinolot ja kuolinsyyt -rekisteriaineistoa, joka koostuu väestölaskentatiedoista sekä työssäkäyntitilaston pitkittäisaineistosta, johon on liitetty kuolinsyytietoja. Peruskuolinsyyn lisäksi aineistossa oli tieto korkeintaan kolmesta myötävaikuttavasta syystä. Dementiakuolleisuuden on esitetty aliarvioituvan peruskuolinsyynä, joten dementiakuolleisuuden määrittelyssä käytettiin myös tietoa myötävaikuttavista syistä. Rajausten jälkeen aineistossa on 317 944 henkilöä, joista 128 562 on miehiä ja 189 382 naisia. Pääanalyysimenetelmänä on käytetty elinaikamalleihin kuuluvaa Coxin regressiota. Dementiakuolleisuudessa oli vaihtelua kaikkien tutkimuksessa käytettyjen muuttujien, eli koulutuksen, sosiaaliluokan, tulojen, siviilisäädyn sekä perhemuodon mukaan. Koulutuksen vaikutus välittyi osin ammattiasemaan perustuvan sosiaaliluokan kautta. Suurimpia ryhmien väliset suhteelliset erot olivat nuoremmissa ikäryhmissä sekä sosiaaliluokan ja siviilisäädyn kohdalla. Eronneilla ja naimattomilla oli selvästi kohonnut riski suhteessa naimisissa oleviin. Myös työntekijöillä havaittiin kohonnut riski suhteessa ylempiin toimihenkilöihin. Siviilisääty vaikutti olevan merkittävä tekijä siinä mielessä, että koulutuksen, sosiaaliluokan ja tulojen tuominen malliin ei juuri vaikuttanut siviilisäätyryhmien välillä havaittuun vaihteluun. Dementiakuolleisuudessa havaitut ryhmien väliset suhteelliset erot olivat hieman pienempiä kuin muissa syissä, mutta kuitenkin hyvin samaa suuruusluokkaa. Tulosten perusteella on identifioitavissa tekijöitä, jotka suojaavat dementialta. Erityisesti avioliitto, korkea koulutus sekä ylemmät toimihenkilöammatit vaikuttavat olevan dementialta suojaavia tekijöitä. Avioliiton suojaavan vaikutuksen voidaan tulkita liittyvän sosiaaliseen kanssakäymiseen sekä puolison tukeen ja läsnäoloon. Korkea koulutus sekä toimihenkilöammatit indikoivat virikkeellisempää työympäristöä, mutta niiden vaikutus voi myös kulkea ylipäänsä aktiivisemman ja kognitiivisesti virikkeellisemmän elämäntavan kautta. Aktiivisen ja kognitiivisesti haastavan elämäntavan on esitetty suojaavan dementiaan sairastumiselta. Tuloksia voidaan tulkita elämänkaarinäkökulman kautta. Jo nuoruudessa vaikuttavilla tekijöillä, kuten koulutuksella, on vaikutusta. Tämän lisäksi elämänkaaren aikana myöhemmin vaikuttavat tekijät ovat merkityksellisiä. Näiden tekijöiden on esitetty vaikuttavan aivojen hermoverkostoon ja -yhteyksiin ja luovan kognitiivista reserviä, minkä on esitetty ehkäisevän tai lykkäävän dementiaan sairastumista.