Individual Trajectories in Asthma and COPD : A Longitudinal Perspective to Obstructive Lung Disease

Managing chronic respiratory conditions such as asthma and Chronic Obstructive Pulmonary Disease (COPD) forms a notable burden on the healthcare system while the burden on an individual is equally notable as patients might suffer from a symptomatic disease for decades. However, not all asthma and COPD patients develop a disabling disease with frequent disease exacerbations and highest cost (in Quality Adjusted Life Years lost or healthcare spending). This variation in disease trajectories enables the analytical identification of distinct phenotypes over time. Retrospective data collected from a large number of patients could be used efficiently as the electronic health records are increasingly made available to researchers around the world. The aim of this project is to develop disease models based on longitudinal data to better capture the essential characteristics of obstructive lung disease, mainly focusing on COPD. Projects I III in this thesis are based on 2398 asthma and COPD patients retrospectively followed through electronic health records from year 2000 onwards. We aimed to analyse this real-world hospital based data using Hierarchical Models to assess the variation of development between individual patients over time. Unpublished Project IV is based on Health 2000 to 2011 follow-up study consisting of 1113 subjects from random Finnish population. The aim was to estimate Single Nucleotide Polymorphism (SNP) based heritability of Forced Expiratory Volume in 1 s (FEV1) level and development and to perform a Genome-Wide Association Study (GWAS) to identify possible genetic markers associated with FEV1 development over time. Our results suggest that the major determinants of Health Related Quality of Life (HRQoL) in mild or moderate COPD are the common comorbidities associated with COPD while in severe diseases the accentuated lung function has a major role. Over time, observable individual trajectories of HRQoL are presented in Asthma and COPD. Significant decline of HRQoL in Asthma was found to associate with obesity related diseases and states while the main determinants in COPD were poor lung function and increasing age. Psychiatric conditions were found associated in both Asthma and COPD. Using an unbalanced data (varying number of measurements and length of follow-up time) of lung function measurements, we were able to observe significant individual trajectories of FEV1 based on the past development. Significant and rapid decline was seen in 30% of the COPD cohort in the study while significant improvement was extremely rare. Rapid decline was associated with numerous exacerbation related markers. Our unpublished results suggest that development of FEV1 is significantly affected by common variants in DNA as genetic effects were estimated to explain 1/3 of the phenotypic variance in random Finnish population. One locus previously associated with the level of FEV1 was found associated with the development of FEV1. Suggestive evidence for two novel loci associated with FEV1 development was also identified. The findings underline the varying trajectories of HRQoL and lung function seen in a homogenous cohort of Asthma and COPD patients. This thesis aims to provide approaches and aspects to better understand the trajectories of a chosen parameter in asthma and COPD. The variation of e.g. lung function development is abundant, and we should not consider this variation as an obstacle but as a useful source of information as there might be genetic or environmental determinants causing this variation.Krooniset ahtauttavat keuhkosairaudet, kuten keuhkoahtaumatauti (COPD) ja astma ovat merkittäviä kansansairauksia Suomessa. Jopa lähes kymmenys maan aikuisväestöstä kärsii astmasta, COPD:n esiintyvyys ikääntyneillä miehillä saattaa olla vielä tätäkin suurempi. Kroonisina tiloina ahtauttavat keuhkosairaudet aiheuttavat huomattavan taakan niitä sairastaville potilaille sekä suuria kustannuksia yhteiskunnalle. Merkittävä riskitekijä vaikealle keuhkosairaudelle on tupakointi, joka on tunnettu riskitekijä myös monelle muulle krooniselle sairaudelle. Kuitenkin vain osa tupakoivista ahtauttavaa keuhkosairautta sairastavista omaa voimakkaasti etenevän sairauden, joka pahimmillaan johtaa toistuviin intensiivistä hoitoa vaativiin sairauden pahenemisvaiheisiin ja ennenaikaiseen kuolemaan. Nykyisellään suuri osa resursseista kulutetaan intensiivisessä hoidossa, eikä niiden ennaltaehkäisyssä. On mahdollista, että etenevän ja huomattavia kustannuksia aiheuttavan keuhkosairauden taustalla on sille ominaisia perinnöllisiä tai ympäristöllisiä riskitekijöitä. Nämä riskitekijät ovat kuitenkin nykyisellään huonosti tunnettuja. Keuhkosairaus aiheuttaa oireita vasta keuhkojen toiminnan heikennyttyä jo merkittävästi, jonka jälkeen potilaan toimintakyky heikkenee nopeasti, mikäli sairaus edelleen etenee. Mikäli huonosti kehittyvät potilaat kyettäisiin paremmin tunnistamaan aikaisessa vaiheessa, olisi mahdollista kohdistaa hoito ja interventiot niitä eniten tarvitsevaan ryhmään. Tässä työssä on tutkittu erityisesti COPD:tä ja astmaa sairastavien potilaiden terveyteen liittyvän elämänlaadun ja keuhkojen toiminnan kehitystä yli ajan. Noin 30 %:lla COPD-potilaista nähtiin tilastollisesti merkitsevää laskua keuhkojen toiminnassa. Heikosti kehittyvät potilaat kärsivät myös muita useammin sairauden pahenemisvaiheista. Huonolle elämänlaadulle COPD:ssä ja elämän laadun kehitykselle astmassa ja COPD:ssä tunnistettiin useita kliinisiä riskitekijöitä. Työssä tarkasteltiin lisäksi väestöaineistossa nähtyä keuhkojen toiminnan muutosta, jolloin noin kolmanneksen vaihtelusta nähtiin selittyvän geneettisillä tekijöillä. Väitöstyön aineisto on kerätty takautuvasti, mutta kattavasti erilaisista sairaala- ja rekisterilähteistä sekä toistuvin kyselytutkimuksin. Sairaala-aineisto edustaa aitoa potilasmateriaalia, jota ei ole tutkimusta käynnistettäessä merkittävästi rajattu. Ainutlaatuisen materiaalin analysoimiseksi on käytetty kehittyneitä tilastollisia menetelmiä, jotka mahdollistavat yksittäisten potilaiden kehityskulun arvioimisen yli ajan. Nämä menetelmät ovat helposti käyttöönotettavissa myös sairaaloiden tietokannoissa, jolloin hoitava henkilökunta saa paremmin tietoa mahdollisista korkean riskin potilaista entistä aikaisemmin

Digital Games as a Source of English Vocabulary for Finnish Writers

Peer reviewe

Kalatalouden tulevaisuus – 2. väliraportti: ”Mitkä ovat mahdolliset maailmat?”

Julkaisussa väärä ISBN. Oikea ISBN-numero on 951-776-485-5

Kalatalouden tulevaisuus – 3. väliraportti: ”Minne voimme mennä ja kuinka?”

Julkaisussa väärä ISBN. Oikea ISBN-numero on 951-776-493-6

Persistence of antibodies to pneumococcal vaccine in patients with chronic renal failure

Persistence of antibodies to pneumococcal vaccine in patients with chronic renal failure and renal allograft recipients. Antibody response to the 14-valent pneumococcal capsular polysaccharide vaccine was measured by the enzyme-linked immunosorbent assay (EIA) in 17 renal allograft recipients, 29 azotemic, 11 hemodialysis, and 33 control patients. The IgG, IgM, and IgA antibodies were measured against six pneumococcal antigen types 1, 3, 4, 6A, 8, and 19F. The control patients had the best antibody responses in the IgG and IgA antibody classes and the renal allograft recipients in the IgM class. The renal allograft recipients had significantly stronger antibody responses than the azotemic and hemodialysis patients. The hemodialysis patients had significantly weaker antibody responses than the control patients and the renal allograft recipients, and they also lost their antibodies most rapidly. Thus, the hemodialysis patients and probably some azotemic patients should be considered for re vaccination

HLA RNA Sequencing With Unique Molecular Identifiers Reveals High Allele-Specific Variability in mRNA Expression

The HLA gene complex is the most important single genetic factor in susceptibility to most diseases with autoimmune or autoinflammatory origin and in transplantation matching. Most studies have focused on the vast allelic variation in these genes; only a few studies have explored differences in the expression levels of HLA alleles. In this study, we quantified mRNA expression levels of HLA class I and II genes from peripheral blood samples of 50 healthy individuals. The gene- and allele-specific mRNA expression was assessed using unique molecular identifiers, which enabled PCR bias removal and calculation of the number of original mRNA transcripts. We identified differences in mRNA expression between different HLA genes and alleles. Our results suggest that HLA alleles are differentially expressed and these differences in expression levels are quantifiable using RNA sequencing technology. Our method provides novel insights into HLA research, and it can be applied to quantify expression differences of HLA alleles in various tissues and to evaluate the role of this type of variation in transplantation matching and susceptibility to autoimmune diseases.Peer reviewe