Effect measures, their estimation and interpretation : Applications to pneumococcal conjugate vaccination

The direct and indirect effects of pneumococcal vaccination on an individual and the population are of great interest. This study focuses on the definition, estimation and interpretation of different effect measures of vaccines and vaccination against pneumococcal colonisation and disease. Vaccine efficacy, effectiveness and impact are considered as epidemiological parameters of interest which are estimated using observations gathered according to some study design. In this thesis, vaccine efficacy against colonisation is defined through pneumococcal acquisition, which describes the natural process of incident occurrences of colonisation better than prevalence. Moreover, a general definition of vaccine efficacy against a multi-type pathogen is presented, with an epidemiologically meaningful interpretation as a weighted average of strain-specific efficacies. A feasible estimation method is then proposed, based on cross-sectional measurement on the current status of colonisation. When the differences in times at-risk between vaccinated and unvaccinated individuals are taken into account, the estimation of vaccine efficacy against colonisation is shown to be less biased by within-host competition between different serotypes (strains). The estimation method is exemplified with empirical data of pneumococcal colonisation in Israeli children. At the population level, vaccine effectiveness is the measure of vaccine-induced protection during an ongoing vaccination programme when both vaccinated and unvaccinated individuals experience the indirect effects of the vaccination programme. Vaccine impact is the population prevented fraction of the incidence of infection when exposure is the vaccination programme rather than each individual’s own vaccination. Both vaccine effectiveness and impact are parameters that depend on the population dynamics of pneumococcal colonisation and disease after vaccine introduction. In this thesis, the time trends of vaccine effectiveness and impact are described with a pseudo-dynamic model that incorporates the incidences of pneumococcal carriage and disease. The model shows that the effectiveness and impact against vaccine-serotype invasive pneumococcal disease (IPD) are expected to be high and largely of the same magnitude through the post-introduction period. By contrast, the vaccine effectiveness and impact against non-vaccine-serotype IPD follow very divergent paths while the vaccine-type colonisation and disease become eliminated. The practical estimation of vaccine effectiveness is exemplified with register data of Finnish children eligible for pneumococcal conjugate (PCV10) vaccination. Three parallel study designs, the cohort, nested case-control and indirect cohort designs, are shown to provide estimates that are broadly concordant with each other. The parameters of vaccine efficacy as proposed in this thesis can be interpreted as measures of the biological effect of the vaccine on new vaccine-type acquisitions and should therefore allow more robust comparisons across different epidemiological settings with differing levels of exposure by non-vaccine strains. Moreover, the thesis helps to interpret the time-varying parameters of vaccine impact and effectiveness during large-scale vaccinations, and their manifestation in Finnish children.Pneumokokkirokotusten yksilöön ja koko väestöön kohdistuvat suorat ja epäsuorat vaikutukset on tärkeää tuntea. Tämä tutkimus keskittyy pneumokokkirokotteiden tehomittojen määritelmiin, estimointiin ja tulkintaan. Rokotteen teho ennen rokotusohjelman aloittamista sekä teho ja vaikuttavuus ohjelman aikana ovat kiinnostavia parametreja, jotka estimoidaan keräämällä havaintoja jonkin koeasetelman mukaisesti. Työssä tarkastellaan pneumokokkirokotteen tehoa nenänielukantajuutta vastaan kantajuuden ilmaantuvuuden kautta. Ilmaantuvuus kuvaa kantajuuden biologista luonnetta paremmin kuin sen esiintyvyys, mutta vaatii tyypillisesti pitkittäismittauksia. Työssä osoitetaan, että rokotusteho kantajuuden ilmaantuvuutta vastaan voidaan estimoida poikkileikkausaineistosta odds-suhteena. Lisäksi näytetään, että kun rokotusteho määritellään patogeenille, jolla on monta alatyyppiä kuten pneumokokille, on huomioitava eri alatyyppien keskinäinen kilpailu nenänielussa. Tällöin rokotustehon estimaatti vastaa tarkemmin todellista rokotustehoa. Tätä havainnollistetaan israelilaisten päiväkotilasten kantajuusmittausten avulla. Laajamittaisen rokotusohjelman aikana rokotusteho mittaa rokotteen yksilölle tarjoamaa suoraa suojaa tilanteessa, jossa sekä rokotetut että rokottamattomat lapset kokevat myös epäsuoria vaikutuksia (laumasuojaa ja ei-rokotetyyppien korvautumista). Rokotusohjelman vaikuttavuus mittaa kantajuuden tai taudin ilmaantuvuuden muutosta verrattuna tilanteeseen ennen rokotusohjelmaa. Sekä rokotusteho että vaikuttavuus ovat parametreja, jotka riippuvat pneumokkikantajuuden ja -taudin väestödynamiikasta. Rokotustehon ja vaikuttavuuden aikatrendejä kuvataan pseudodynaamisella mallilla, joka ottaa huomioon kantajuuden ja taudin ilmaantuvuuden muutokset ajassa. Mallin mukaan sekä rokotusteho että vaikuttavuus rokotetyypin vakavaa pneumokokkitautia vastaan pysyvät korkeina ja liki samansuuruisina koko rokotusohjelman ajan. Sitä vastoin rokotusteho ja vaikuttavuus ei-rokotetyypin vakavaa pneumokokkitautia vastaan ovat hyvin erisuuruiset silloin, kun rokotetyypin kantajuus on vähentynyt ja poistumassa väestöstä. Rokotustehon estimointia havainnollistetaan käyttäen suomalaista terveysrekisteriaineistoa vakavan pneumokokkitaudin tapauksista lapsilla, jotka ovat oikeutettuja pneumokokkirokotusohjelmaan. Kolmen tutkimusasetelman eli kohortti-, pesäytetyn tapaus-verrokki- ja epäsuoran kohorttiasetelman näytetään tarjoavan likimain samansuuruisia estimaatteja. Esitetyt rokotustehon parametrit nenänielukantajuutta vastaan tarjoavat mahdollisuuden verrata rokotetutkimuksia erilaisissa asetelmissa, vaikka ei-rokotetyypin kantajuuden ilmaantuvuus voi vaihdella paljonkin. Lisäksi tutkimus tarjoaa keinoja tulkita ajassa muuttuvia rokotustehon ja vaikuttavuuden mittoja laajojen rokotusohjelmien aikana, erityisesti suomalaisten lasten näkökulmasta

Relaxed selection when you least expect it: why declining bird populations might fail to respond to phenological mismatches

Ongoing climate change threatens to cause mismatches between the phenology of many organisms and their resources. Populations of migratory birds may need to undergo ‘evolutionary rescue’ if resource availability moves to earlier dates in the year, as shifted arrival dates at the breeding grounds may be required for persistence under new environmental schedules. Here we show a counterintuitive process that can reduce the strength of selection for early arrival when the resource peaks earlier. This happens when two processes combine to determine selection for early arrival: breeding success is higher if a bird does not miss the resource peak, but this occurs together with a ‘zero‐sum game’ where birds acquire good territories ahead of their competitors if they arrive early. The latter process can relax if the population has experienced a recent decline. Therefore, climate change can have two opposing effects: its direct effect on breeding success strengthens selection for early arrival, but this combines with an indirect effect of relaxed selection due to population declines, if territoriality is a significant determinant of population dynamics and fitness. We show that the latter process can predominate, and this can cause a failure for a population to adapt to a new schedule under changing environmental conditions

Sexual conflict and the evolution of asexuality at low population densities

Theories for the evolution of sex rarely include facultatively sexual reproduction. Sexual harassment by males is an underappreciated factor: it should at first sight increase the relative advantage of asexual reproduction by increasing the cost of sex. However, if the same females can perform either sexual or asexual life cycles, then females trying to reproduce asexually may not escape harassment. If resisting male harassment is costly, it might be beneficial for a female to accept a mating and undertake a sexual life cycle rather than ‘insist’ on an asexual one. We investigate the effects of sexual harassment on the maintenance of sex under different population densities. Our model shows that resisting matings pays off at low population densities, which leads to the complete extinction of males, and thus to the evolution of completely asexual populations. Facultative sex persists in a narrow range of slightly higher densities. At high densities, selection favours giving up resisting male mating attempts and thus sexual reproduction takes over. These interactions between the outcomes of sexual conflict and population density suggest an explanation for the rarity of facultative sex and also patterns of geographical parthenogenesis, where marginal environments with potentially low densities are associated with asexuality

Social transmission of avoidance among predators facilitates the spread of novel prey

Warning signals are an effective defence strategy for aposematic prey, but only if they are recognized by potential predators. If predators must eat prey to associate novel warning signals with unpalatability, how can aposematic prey ever evolve? Using experiments with great tits (Parus major) as predators, we show that social transmission enhances the acquisition of avoidance by a predator population. Observing another predator’s disgust towards tasting one novel conspicuous prey item led to fewer aposematic than cryptic prey being eaten for the predator population to learn. Despite reduced personal encounters with unpalatable prey, avoidance persisted and increased over subsequent trials. Next we use a mathematical model to show that social transmission can shift the evolutionary trajectory of prey populations from fixation of crypsis to fixation of aposematism more easily than was previously thought. Therefore, social information use by predators has the potential to have evolutionary consequences across ecological communities.Peer reviewe

Veterinary herd health management-Experiences and perceptions among Swedish dairy cattle veterinarians

Cattle veterinarians have long been encouraged to take on a role as proactive health consultants. How-ever, the process so far has been slow in Sweden and elsewhere, and only a rather small proportion of cattle work conducted by veterinarians involves vet-erinary herd health management (VHHM). The aims of this exploratory study were to explore Swedish cattle veterinarians' interpretation of VHHM services and to understand the factors that might affect the extent to which cattle veterinarians perform VHHM. Six focus group discussions with cattle veterinarians complemented with 5 individual telephone interviews with clinic managers were conducted in 2020. In total, 33 cattle veterinarians participated, all employed by the largest employer of Swedish cattle veterinarians: Distriktsveterinarerna (Swedish Board of Agriculture). Participants were chosen from 6 geographical regions with the aim to present variations in gender, age, coun-try of education, proportion of dairy cattle work at the clinic, experience in the veterinary profession, and ex-perience in work with dairy herds and in VHHM. The focus group discussions and interviews were recorded and these recordings were transcribed and analyzed thematically. Participants interpreted VHHM as work associated with the process of advising and included both ad hoc advising and more strategic forms of ser-vices. Prebooked visits per se were not seen as VHHM. We identified 4 different themes among the factors af-fecting the extent of VHHM services: (1) farmer trust and demand; (2) veterinary competence; (3) time avail-able for VHHM; and (4) the individual veterinarian's commitment and motivation. To gain farmers' trust and to create a demand for VHHM services, the results of VHHM work and the veterinarian's competence were deemed central by the participants. The veterinarians' skills in communication and relation building were considered especially important. Some farmers were perceived as having little interest in, or lacking deeper knowledge about, VHHM services. The promotion of VHHM services was mentioned as an important fac-tor to increase farmer demand. Participants described VHHM as work demanding high skills and continuous capacity development. Veterinarians' personal commit-ment and motivation were also described as important for the extent to which VHHM services were performed. This was in turn affected by the psychosocial work environment (e.g., workload, interest and recognition from farmers and managers, and acceptance, priority, and support by colleagues and managers). Clinic man-agers had a central role in the extent to which VHHM services are offered by an individual veterinarian due to their responsibility for staff scheduling, which highly affects the conditions for capacity development, inter-collegiate networking, and cooperation. Lack of time was a major barrier for VHHM. On-call duty time and subsequent compensatory leave affected the total time available, and participants described time conflicts between VHHM and emergency services; moreover, it was perceived as challenging to find sufficient time for capacity development in several different species for veterinarians working in mixed practice. The slow de-velopment toward more proactive approaches for cattle veterinarians can be explained by the numerous dif-ferent factors that together constrain the veterinarian to the traditional role of diagnosing and treating sick animals

An inordinate fondness for species with intermediate dispersal abilities

J. B. S. Haldane is widely quoted to have quipped that the Creator, if one exists, has an inordinate fondness for beetles. Although Coleoptera may not be the most speciose order once Hymenopteran diversity is fully accounted for, as a whole the very clear differences in species diversity among taxa require an explanation. Here we use stochastic simulations to show that dispersal has eco-evolutionary effects that predict taxa to become particularly species-rich when dispersal is neither too low nor too high. Our model combines recent advances in understanding coexistence in niche space with previously verbally expressed ideas, where too low dispersal imposes biogeographic constraints that prevent a lineage from finding new areas to colonize (reducing opportunities for speciation), while too high dispersal impedes population divergence, leading to few but widely distributed species. We show that this logic holds for species richness and is robust to a variety of model assumptions, but peak diversification rate is instead predicted to increase with dispersal. Our work unifies findings of increasing and decreasing effects of dispersal rate on speciation, and explains why taxa with moderate dispersal abilities have the best prospects for high global species richness.</p