Elucidating the genetic architecture of cystic kidney disease using whole genome sequencing

Cystic kidney disease (CyKD) is the commonest life-threatening monogenic disorder, causing great morbidity and mortality. Whilst there is believed to be a strongly monogenic architecture, an unbiased whole genome sequencing approach to understanding the underlying genetic architecture has never previously been attempted. In this thesis I used statistical genetics and bioinformatics methodology to investigate the genetic architecture of CyKD as well as two other rare disorders, urinary stone disease (USD) and extreme early onset hypertension (EEHTN), using whole genome sequencing data from the 100,000 Genomes Project. I used population-based tools to assess the rare and common variant associations in diverse ancestry matched cohorts seeking enrichment of single nucleotide/indel and structural variants on a genome-wide and per-gene basis. In all three disorders this improved our understanding of the underlying architecture. CyKD is shown to be strongly monogenic as expected but low-frequency and common variants are shown to play an important role in pathogenesis and causation of this disease, revealing a role for polygenic factors. The heritability of USD is shown to be heavily influenced by low-frequency variants in the sodium-phosphate transporter gene SLC34A3, which explains much of the missing heritability not detected by previous large-scale common variant association studies. This finding bridges the gap between the traditional thinking that USD is either monogenic or polygenic/environmental. Finally, EEHTN is shown to likely be an extreme manifestation of primary hypertension, with a strong polygenic basis. These results support the idea that with better sequencing and larger biobanks, an omnigenic model of disease will become more demonstrable for a broader range of phenotypes, consistent with genotype-phenotype heterogeneity, variable expressivity and incomplete penetrance observed in all three diseases. Finally, I demonstrate that population level approaches traditionally used to study common disease are applicable and useful in rare disease research

No-Regret Online Prediction with Strategic Experts

We study a generalization of the online binary prediction with expert advice framework where at each round, the learner is allowed to pick $m\geq 1$ experts from a pool of $K$ experts and the overall utility is a modular or submodular function of the chosen experts. We focus on the setting in which experts act strategically and aim to maximize their influence on the algorithm's predictions by potentially misreporting their beliefs about the events. Among others, this setting finds applications in forecasting competitions where the learner seeks not only to make predictions by aggregating different forecasters but also to rank them according to their relative performance. Our goal is to design algorithms that satisfy the following two requirements: 1) $\textit{Incentive-compatible}$: Incentivize the experts to report their beliefs truthfully, and 2) $\textit{No-regret}$: Achieve sublinear regret with respect to the true beliefs of the best fixed set of $m$ experts in hindsight. Prior works have studied this framework when $m=1$ and provided incentive-compatible no-regret algorithms for the problem. We first show that a simple reduction of our problem to the $m=1$ setting is neither efficient nor effective. Then, we provide algorithms that utilize the specific structure of the utility functions to achieve the two desired goals

Investigation of Emulsion Bitumen Adhesion to Aggregates in Chipseal at Various Temperatures for Low-Cost Pavement Management

Preventive maintenance is recommended by economic models in pavement management. One of the issues that the Chipseal mix is currently dealing with is the degree of separation of the material from the mixture's surface due to a lack of proper adhesion between the emulsion(green) bitumen, and the aggregate. Have and cause an accident. In this study, it was attempted to reduce material separation by increasing the percentage of bitumen in the mixture as well as the percentage of sand as a filler. The results of this study showed that with increasing the percentage of emulsion bitumen in the chipseal mixture and with it increases the percentage of filler in the mixture, the separation rate of aggregates to less than 10% in the temperature range of -15 to +45 ° C, and a Created a more cohesive mixture

Maternal Satisfaction of Spinal Anesthesia for Elective Cesarean Section in an Academic Hospital

Background: Currently, spinal anesthesia is an acceptable method for cesarean section (CS) throughout the world, since general anesthesia is associated with higher maternal morbidity and mortality rates. The current study was performed to survey different factors for maternal satisfaction of spinal anesthesia. Methods: This cross sectional study was performed onwomenwhowere candidates for elective CS at Dr. Shariati hospital. Informed consents were obtained from all the patients, and the risks and side effects of both spinal and general anesthesia were explained preoperatively. The mothers were free to choose the anesthetic technique. One day after the operation, all mothers were examined with respect to the variables. Results: A total of 84 women with the mean age of 30.7 _ 5.63 years and mean body mass index (BMI) of 31.2 _ 4.15 kg/m2 were anesthetized through the spinal method. Overall, 28.6% of the subjects were distressed about perioperative awareness, while 40.5%, 29.8%, and 46.4% reported postoperative pain at the injection site, headache, and lumbar pain, respectively. Maternal satisfaction of the spinal method and willingness to choose this method again in future surgeries were 83.8% and 78.5%, respectively. Conclusions: Women undergoing CS are highly satisfied with spinal anesthesia, and the majority are likely to choose this method in the future. Factors decreasing satisfaction include inadequate preoperative explanations about the anesthesia method by the anesthesiologist, postoperative pain at the injection site, headache, and lumbar pain

Evaluación de Silicio e irrigación en tres cultivares de Cártamo

This study was performed to evaluation of interaction of silicon application and irrigation on agronomic and physiologic traits of safflower at 2018 and 2019. The experiment was conducted as a split plot factorial based on randomized complete block design with 3 replications. The irrigation was main factor (0, 2 and 4 times during growth) and the sub-factor were silicon foliar application (at three levels: 0, 1 and 2 mM) and three safflower cultivars (Goldasht, Padideh and Golmehr). The studied traits were: number of seeds per boll and 1000-grain weight, number and weight of boll, number of lateral branches and branch diameter, plant weight and total plant weight, floret yield, grain yield, chlorophyll a and b, proline and antioxidant enzymes. According to results, treatments had significant effects on studied traits at 5 or 1% statistically level. 2 and 3 times irrigation led to 7 and 24% the increasing of seed yield in compare to control, respectively. It was obtained that 1 and 2mM silicon led to 25 and 15% the increase of seed yield in compare to control. Interaction between treatments showed that the highest seed yield (500g per m2) was observed by Goldasht cultivar under 4-time irrigation and 2mM silicon. Therefore, it can be suggested that Goldasht with 2 mM silicon be used to reduce the effects of dehydration.Este estudio se realizó para evaluar la interacción de la aplicación de silicio y el riego en rasgos agronómicos y fisiológicos del cártamo en 2018 y 2019. El experimento se realizó como un factorial de parcela dividida basado en un diseño de bloques completos al azar con 3 repeticiones. El riego fue el factor principal (0, 2 y 4 veces durante el crecimiento) y el subfactor fue la aplicación foliar de silicio (en tres niveles: 0, 1 y 2 mM) y tres cultivares de cártamo (Goldasht, Padideh y Golmehr). Los rasgos estudiados fueron: número de semillas por cápsula y peso de 1000 granos, número y peso de cápsula, número de ramas laterales y diámetro de rama, peso de la planta y peso total de la planta, rendimiento del florete, rendimiento de grano, clorofila ayb, prolina y enzimas antioxidantes Según los resultados, los tratamientos tuvieron efectos significativos en los rasgos estudiados a un nivel estadístico del 5 o 1%. El riego 2 y 3 veces condujo a un aumento de 7 y 24% en el rendimiento de semillas en comparación con el control, respectivamente. Se obtuvo que el silicio de 1 y 2 mM condujo a un aumento de 25 y 15% del rendimiento de la semilla en comparación con el control. La interacción entre tratamientos mostró que el cultivar Goldasht observó un rendimiento de semilla más alto (500 g por m2) bajo riego por 4 tiempos y silicio 2 mM. Por lo tanto, se puede sugerir que se use Goldasht con silicio 2 mM para reducir los efectos de la deshidratación