The anadromous Atlantic salmon (Salmo salar) is dependent on river connectivity to reach spawning and rearing habitats in rivers. Most rivers are today fragmented by artificial barriers such as hydroelectric powerplants (HEP) which impede this migratory movement. As an effort to mitigate river fragmentation, upstream passages have been built at some impediments, but passage facilitating downstream migration has been commonly disregarded until recently. The increased mortality associated with downstream movement through hydroelectric turbines have caused population declines and extirpation in some areas. A common first measure to improve downstream passage is to increase spill discharge during critical time periods. In this study we aim to evaluate the efficiency of increased spill as a management tool and investigate the effect on environmental and physiological factors on fish passage in River Mörrumsån, Sweden. This was done by tracking salmon smolt using high resolution acoustic telemetry and time-to-event models. The results were then further explored in relation to 2D-hydraulic models of different spill scenarios. The results show that increasing the spill at Upper Hemsjö HEP resulted in a relatively high impediment passage efficiency. Spill gate passage was best explained by the proportion of spill in relation to intake channel discharge and diel period. Increased spill and nights without ambient lights where positively associated with spill gate passage rate. Increased levels of spill seamed to increase the attraction to the spill gate passage zone which could be explained by the increased area of flow directed toward the spill gate observed in the hydraulic model, showing the usefulness of hydraulic models as an additional tool in evaluation and planning of remedial measures. The result in this study shows that increased spill can be an effective way to ameliorate river fragmentation, however this should be put in relation to the goal of the mitigation measure as increased spill only creates a temporary solution for a permanent problem. / Den anadroma Atlantlaxen (Salmo salar) är beroende av fria vandringsvägar mellan hav och älv, då de nyttjar olika habitat under olika delar av livscykeln. Laxen vandra mellan dess tillväxt område i havet och deras parnings samt uppväxt område i älvar. Det flesta vattendrag är i dag fragmenterade av artificiella barriärer som tillexempel vattenkraftverk. För att minska de negativa effekterna av dessa har uppströmspassager konstruerats, men passage för nedströmsvandring har ofta åsidosatts. Den ökade dödligheten associerad med nedströmspassage genom vattenkraftturbiner har haft kraftig påverkan på många populationer. En vanlig första åtgärd för att förbättra nedströmspassagen är att öka mängden vatten som spills under kritiska perioder, som laxsmoltens nedströmsvandring under våren. Målet med denna studie är att utvärdera ökat spill som en förvaltningsåtgärd och analyserar hur olika miljöfaktorer och fysiologiska faktorer påverkar passageeffektiviteten för nedströmsmigrerande smolt. Detta undersöktes genom att använda högupplöst hydroakustisk telemetri för att spåra fisken och genom att analysera rörelsen med hjälp av time-to-event modeller. Tvådimensionella hydrauliska modeller skapades för att ytterligare utforska resultaten i förhållande till olika spill regimer. Den ökade spill regimen resulterade i relativt hög passage effektivitet förbi hindret. Passage genom spill porten kunde bäst förklaras av period på dygnet samt proportionen av spill i förhållande till flödet genom intagskanalen. Ökad passage effektivitet kunde associeras med passage under natten när belysningen på dammen var avstängd samt ökad andel spill i förhållande till flödet genom intagaskanalen. Ökat spill verkade resultera i ökad attraktion till området framför spill porten, vilket skulle kunna förklaras av den ökade ytan av vatten som rör sig mot spill porten som observerades i den hydrauliska modellen. Dessa resultat visar hur hydrauliskmodellering kan användas som ytterligare ett förvaltningsverktyg för att utvärdera eller planera förbättringsåtgärder. Resultaten Vidare indikerar studien att ökat spill är en metod som kan förbättrar laxsmoltens möjligheter till nedströms passage, detta bör dock sättas i relation till vad som är målet med åtgärden, ökat spill gynnar ett fåtal arter under en begränsad tid på året. Således kvarstår problemet med begränsad konnektivitet i vattendraget under resterande delar av året.

Time-to-event data is very common in medical research. Thus, clinicians and patients need analysis of this data to be accurate, as it is often used to interpret disease screening results, inform treatment decisions, and identify at-risk patient groups (ie, sex, race, gene expressions, etc.). This thesis tackles three statistical issues pertaining to time-to-event data. The first issue was incurred from an Institute for Clinical and Evaluative Sciences lung cancer registry data set, which was de-identified by censoring patients at an earlier date. This resulted in an underestimate of the observed times of censored patients. Five methods were proposed to account for the underestimation incurred by de-identification. A subsequent simulation study was conducted to compare the effectiveness of each method in reducing bias, and mean squared error as well as improving coverage probabilities of four different KM estimates. The simulation results demonstrated that situations with relatively large numbers of censored patients required methodology with larger perturbation. In these scenarios, the fourth proposed method (which perturbed censored times such that they were censored in the final year of study) yielded estimates with the smallest bias, mean squared error, and largest coverage probability. Alternatively, when there were smaller numbers of censored patients, any manipulation to the altered data set worsened the accuracy of the estimates. The second issue arises when investigating model validation via the concordance (c) statistic. Specifically, the c-statistic is intended for measuring the accuracy of statistical models which assess the risk associated with a binary outcome. The c-statistic estimates the proportion of patient pairs where the patient with a higher predicted risk had experienced the event. The definition of a c-statistic cannot be uniquely extended to time-to-event outcomes, thus many proposals have been made. The second project developed a parametric c-statistic which assumes to the true survival times are exponentially distributed to invoke the memoryless property. A simulation study was conducted which included a comparative analysis of two other time-to-event c-statistics. Three different definitions of concordance in the time-to-event setting were compared, as were three different c-statistics. The c-statistic developed by the authors yielded the smallest bias when censoring is present in data, even when the exponentially distributed parametric assumptions do not hold. The c-statistic developed by the authors appears to be the most robust to censored data. Thus, it is recommended to use this c-statistic to validate prediction models applied to censored data. The third project in this thesis developed and assessed the appropriateness of an empirical time-to-event c-statistic that is derived by estimating the survival times of censored patients via the EM algorithm. A simulation study was conducted for various sample sizes, censoring levels and correlation rates. A non-parametric bootstrap was employed and the mean and standard error of the bias of 4 different time-to-event c-statistics were compared, including the empirical EM c-statistic developed by the authors. The newly developed c-statistic yielded the smallest mean bias and standard error in all simulated scenarios. The c-statistic developed by the authors appears to be the most appropriate when estimating concordance of a time-to-event model. Thus, it is recommended to use this c-statistic to validate prediction models applied to censored data. / Thesis / Doctor of Philosophy (PhD)

Many breast cancer diagnoses and second cancers are associated with BRCA gene mutations. Early detection of cancer is necessary to improve health outcomes, particularly with second cancers. Little is known about the influence of risk factors on time to diagnosis of second primary cancers after diagnosis with BRCA-related breast cancer. The purpose of this cohort study was to examine the risk of diagnosis of second primary cancers among women diagnosed with breast cancer after adjusting for BRCA status, age, and ethnicity. The study was guided by the empirical evidence supporting the mechanism of action in the mutation of BRCA leading to the development of cancer. Composite endpoint was used to define second primary cancer occurrences, and Kaplan-Meier survival curves were used to compare the median time-to-event among comparison groups and BRCA gene mutation status. Cox proportional hazards was used to examine the relationships between age at diagnosis, ethnicity, BRCA gene mutation status, and diagnosis of a second primary cancer. The overall median time to event for diagnosis of second primary cancers was 14 years. The hazard ratios for BRCA2 = 1.47, 95% CI [1.03 - 2.11], White = 1.511, 95% CI [1.18 - 1.94], and American Indian/Hawaiian = 1.424, 95% CI [1.12 -1.81] showing positive significant associations between BRCA2 mutation status and risk of diagnosis of second primary colorectal, endometrial, cervical, kidney, thyroid, and bladder cancers. Data on risk factors for development of second cancers would allow for identification of appropriate and timely screening procedures, determining the best course of action for prevention and treatment, and improving quality of life among breast cancer survivors.

Males and age group 1 to 5 years show a much higher risk for childhood acute lymphoblastic leukemia (ALL). We performed a case-only genome-wide association study (GWAS), using the Illumina Infinium HumanCoreExome Chip, to unmask gender- and age-specific risk variants in 240 non-Hispanic white children with ALL recruited at Texas Children’s Cancer Center, Houston, Texas. Besides statistically most significant results, we also considered results that yielded the highest effect sizes. Existing experimental data and bioinformatic predictions were used to complement results, and to examine the biological significance of statistical results. Our study identified novel risk variants for childhood ALL. The SNP, rs4813720 (RASSF2), showed the statistically most significant gender-specific associations (P < 2 x 10-6). Likewise, rs10505918 (SOX5) yielded the lowest P value (P < 1 x 10-5) for age-specific associations, and also showed the statistically most significant association with age-at-onset (P < 1 x 10-4). Two SNPs, rs12722042 and 12722039, from the HLA-DQA1 region yielded the highest effect sizes (odds ratio (OR) = 15.7; P = 0.002) for gender-specific results, and the SNP, rs17109582 (OR = 12.5; P = 0.006), showed the highest effect size for age-specific results. Sex chromosome variants did not appear to be involved in gender-specific associations. The HLA-DQA1 SNPs belong to DQA1*01:07and confirmed previously reported male-specific association with DQA1*01:07. Twenty one of the SNPs identified as risk markers for gender- or age-specific associations were located in the transcription factor binding sites and 56 SNPs were non-synonymous variants, likely to alter protein function. Although bioinformatic analysis did not implicate a particular mechanism for gender- and age-specific associations, RASSF2 has an estrogen receptor-alpha binding site in its promoter. The unknown mechanisms may be due to lack of interest in gender- and age-specificity in associations. These results provide a foundation for further studies to examine the gender- and age-differential in childhood ALL risk. Following replication and mechanistic studies, risk factors for one gender or age group may have a potential to be used as biomarkers for targeted intervention for prevention and maybe also for treatment.

In Sweden, there has been an long term effort to allow as heavy traffic as possible, provided thatthe road network can handle it. This is because heavy traffic offers a competitive advantage withsocio-economic gains. In July 2018, the Swedish Transport Administration made 12 percent ofthe Swedish road network avaliable for the new maximum vehicle weight of 74 tonnes, basedon a legislative change from 2017. It is known that heavy traffic has a negative effect on thedegradation of the road, but it prevails divided opinions on whether 74 tonnes have a greaterimpact on the degradation rate compared to previous maximum gross weights of 64 tonnes.The 74 tonne vehicles have the same allowed axle load, which means more axles per vehicle. Some argue that an increased total load and more axles affect the degradation associated withtime-dependent material properties, while others argue that 74 tonnes mean fewer heavy vehiclesoverall, and thus should have a positive impact on the road’s lifespan. The construction companySkanska therefore requests a statistical analysis that enables to nuance the effects that heavytraffic has on the Swedish state road network. Since there is very limited data on the effect of 74 tonne traffic, this Master thesis instead focuseson modeling heavy traffic in general in order to be able to draw conclusions on which variablesare significant for a road’s lifetime. The method used is survival analysis where the lifetimeof the road is defined as the time between two maintenance treatments. The model selectedis the semi-parametric ’Cox Proportional Hazard Model’. The model is fitted with data froman open source database called LTPP (Long Term Pavement Performance) which is providedby the National Road and Transport Research Institute (VTI). The result of the modeling ispresented with hazard ratios, which is the relative risk that a road will require maintance atthe next time stamp compared to a reference category. The covariates that turned out to besignificant for a road’s lifetime and thus are included in the model are; lane width, undergroundtype, speed limit, asphalt layer thickness, bearing layer thickness and proportion of heavy traffic. Survival curves estimated by the model are also presented. In addition, a sensitivity analysis ismade by exploring survival curves estimated for different scenarios, with different combinationsof covariate levels.The results is then compared with previous studies on the subject. The most interesting finding isa case study from Finland since Finland allow 76 tonne vehicles since 2013. In the comparison,the model’s significant variables are confirmed, but the significance of precipitation and thenumber of axes for a roads lifetime is also highlighted

Die Beurteilung der Wirkung von Cariporide auf dieEreignis-Wahrscheinlichkeit eines Herzinfarktes oder des Todes imRahmen einer Bypass-Operation ist Gegenstand der Arbeit. DasNHE-Austauschersystem in der Herzmuskelzelle induziert den unterIschämie durch den intrazellulären Protonenüberschusshervorgerufenen Na(+)- und Ca(2+)-Einstrom. Cariporide ist einNHE-Inhibitor, der den unter Ischämie durch die Ca(2+)-Überladunginduzierten Herzmuskelzelltod verzögern soll. In einer kombinierten Phase-II/III-Studie (GUARDIAN, n=11590) war derEinfluss verschiedener intravenöser Dosen von Cariporide auf dieHäufigkeit von Herzinfarkt oder Tod in ACS/NQMI, PTCA undCABG-Patientenkollektiven untersucht worden. Nur die höchstdosierteCABG-Gruppe zeigte eine signifikante Reduktion der Ereignisrate um24,7% (p=0,027) gegenüber Placebo. Diese schwacheDosis-Wirkungs-Beziehung konnte durch eine pharmakokinetische undpharmakodynamische Populationsanalyse in eineKonzentrations-Wirkungs-Beziehung überführt werden. Zur Entwicklungdes Populationsmodells waren verschiedene Submodelle notwendig: 1. Modell für den Zeitverlauf der Ereignisrate: Durch Kombination zweier Weibull-Verteilungen ist es möglich, die beobachteten Daten als Überlebenszeitfunktion nach CABG zu beschreiben. Ein akutes, unmittelbar auf die CABG-Operation zurückzuführendes Risiko wird hier von einem chronischen Risiko unterschieden. 2. Pharmakokinetisches Modell: Ein multiexponentielles populationspharmakokinetisches Modell ist notwendig zur Beschreibung der PK nach iv-Applikation von Cariporide bei Probanden und Patienten. 3. Pharmakodynamisches Modell: Über ein empirisches logistisches Modell wird die Reduktion des akuten Risikos mit der mittleren Cariporide Plasmakonzentration unter der Bypass-Operation verknüpft. In einer Substudie der GUARDIAN-Hauptstudie konnte daspopulationspharmakokinetische Modell aus der früherenPhase-I-Entwicklung mit Probanden für die Patienten validiert werden.Die mit Hilfe der individüllen Dosierung, der demographischen Datenund dem Populationsmodell für die Periode mit dem höchsten Risikowährend der CABG-Operation vorhergesagten mittlerenPlasmakonzentrationen flossen in die Analyse derKonzentrations-Zeit-Abhängigkeit der Ereignis-Wahrscheinlichkeit ein. Eine untere Schwellenkonzentration (0,5mg/l), unterhalb der mitkeinem Effekt zu rechnen ist, wurde bestimmt. Die Daten erlaubten dieSchätzung des maximalen Effekts nur unzureichend. Die maximaleRisikoreduktion von 60% wurde mit einem Konfidenzintervall von29% bis 100% geschätzt. Unter Einsatz einer linearen Näherungdes Hill-Modells wurde eine obere Schwellenkonzentration bei 0,9mg/lbestimmt. Nur 37% aller Patienten der 80mg-Dosisgruppe erreichtenmittlere Konzentrationen oberhalb der unteren Schwellenkonzentration,in der 120mg-Dosisgruppe waren es immerhin schon 75% allerPatienten. Die Infusion von 120mg Cariporide über eine Stunde gefolgt voneiner Erhaltungsdosis von 20mg/h für weitere 47 Stunden sollte bei95% der Patienten während der CABG-Operation zu mittlerenKonzentrationen über der minimal effektiven Konzentration von0,5mg/l führen. Eine auf diese Weise mittels Simulationenoptimierte Dosierungsregel sollte während der CABG-Operation zu einemerhöhten Schutz der Patienten gegen die Folgen ischämischerEreignisse führen. Eine weitere Erhöhung der Erhaltungsdosis aufbis zu 40mg/h mit einer entsprechenden Anpassung der Initialdosissollte 95% der Patienten sogar über die bisher nur unsicher zubestimmende obere Grenzkonzentration von 0,9mg/l bringen. Solltenkeine dosislimitierenden Nebenwirkungen auftreten, kann dieseErhöhung sowohl der Initialdosis als auch der Erhaltungsdosis zueiner weiteren Verbesserung während der Risikoperiode führen undeinen weiteren potentiellen klinischen Vorteil für Cariporideerbringen. / Subject of this analysis is the assessment of the effect of cariporideon the event probability of a myocardial infarction (MI) or death inthe scope of a coronary artery bypass graft. Thesodium-hydrogen-exchange system (NHE) in the myocardial cell inducesthe sodium and calcium influx caused by an ischaemia induced hydrogenoverload. Cariporide is a NHE-inhibitor which is seen to be delayingthe necrosis of myocardial cells caused by the ischaemia inducedcalcium influx. The influence of different intravenous doses of cariporide on thefrequency of MI and death in ACS/NQMI, PTCA, and CABG patients hadbeen investigated in a combined phase II/III trial (GUARDIAN,n=11590). Only the highest dosed CABG-subgroup showed a significantreduction of the event-rate compared to placebo of 24.7% (p=0.027).This weak dose-effect-relationship could be translated into aconcentration-effect relationship by using a populationpharmacokinetic/pharmacodynamic (PK/PD) analysis. To develop thispopulation model a series of sub-models were established: 1) Model for the time-to-event progression: using a combination of two Weibull-distributions, it was possible to describe the observed data following the CABG procedure by means of a survival-function. An acute risk, likely to be related to the CABG-procedure could be discriminated from a chronic risk. 2) Pharmacokinetic model: a multi-exponential population PK model was necessary to describe the PK after iv-application of cariporide in volunteers as well patients. 3) Pharmacodynamic model: using an empirical logistic model the reduction of the acute risk was linked to the cariporide plasma-concentrations. In a sub-study of the GUARDIAN-main study, the population PK model ofthe phase I development in volunteers had been be validated. Usingthe individual dosing, the individual demographic information and thepopulation PK model mean concentrations were calculated for the periodof the highest risk during the CABG procedure. Those concentrationswere then introduced into the analysis of the concentration timedependency of the event probability. A lower threshold concentration (0.5mg/l) was estimated beneath thatno effect would be expected. The data permitted the estimation of themaximum effect only insufficiently. A maximum risk reduction of 60%was estimated with a confidence interval from 29% to 100%. Using thelinear approximation of the Hill-model an upper thresholdconcentration of 0.9mg/l could be determined. Mean concentrationsunder risk were reached above the lower threshold concentration inonly 37% of all patients in the 80mg dose group, whereas in the 120mgdose-group already 75% of the patients exceeded the lower thresholdconcentration. The infusion of 120mg cariporide for an hour followed by a maintenancedose of 20mg/h for further 47 hours should maintain in 95% of thepatients during the CABG-procedure mean concentrations above theminimal effective concentration of 0.5mg/l. A dose regimen optimisedin this sense by means of simulations should lead to an increasedprotection against ischemic events during and after theCABG-operation. A further increase of the maintenance dose up to40mg/h with a corresponding adaptation of the initial dose shouldshift at least 95% of the patients above the so far impreciseestimated upper threshold concentration of 0.9mg. If no dose limitingside-effects occur, this increase of both the initial dose and themaintenance dose may lead to a further improvement during the riskperiod and may result in a further potential clinical advantage forcariporide.

<p><br></p> <p>Police use of force has become a topic of significant concern, particularly given the disparate impact on communities of color. Research has shown that police officer involved shootings, misconduct and excessive use of force complaints exhibit network effects, where officers are at greater risk of being involved in these incidents when they socialize with officers who have a history of use of force and misconduct. Given that use of force and misconduct behavior appear to be transmissible across police networks, we are attempting to address if police networks can be altered to reduce use of force and misconduct events in a limited scope.</p> <p><br></p> <p>In this work, we analyze a novel dataset from the Indianapolis Metropolitan Police Department on officer field training, subsequent use of force, and the role of network effects from field training officers. We construct a network survival model for analyzing time-to-event of use of force incidents involving new police trainees. The model includes network effects of the diffusion of risk from field training officers (FTOs) to trainees. We then introduce a network rewiring algorithm to maximize the expected time to use of force events upon completion of field training. We study several versions of the algorithm, including constraints that encourage demographic diversity of FTOs. The results show that FTO use of force history is the best predictor of trainee's time to use of force in the survival model and rewiring the network can increase the expected time (in days) of a recruit's first use of force incident by 8%. </p> <p>We then discuss the potential benefits and challenges associated with implementing such an algorithm in practice.</p> <p><br></p>