Decision-analytic evaluation of the comparative effectiveness and cost-effectiveness of strategies to prevent breast and ovarian cancer in German women with BRCA-1/2 mutations

Abstract Background Women with inherited mutations in the BRCA1 or BRCA2 genes have increased lifetime risks for developing breast and/or ovarian cancer and may develop these cancers around the age of 30 years. Therefore, prevention of breast and ovarian cancer in these women may need to start relatively early in life. In this study we systematically evaluate the long-term effectiveness and cost effectiveness of different prevention strategies for breast and ovarian cancer in women with BRCA-1/2 mutation in Germany. Methods A decision-analytic Markov model simulating lifetime breast and ovarian cancer development in BRCA-1/2 carriers was developed. Different strategies including intensified surveillance (IS), prophylactic bilateral mastectomy (PBM), and prophylactic bilateral salpingo-oophorectomy (PBSO) alone or in combination at different ages were evaluated. German clinical, epidemiological, and economic (in 2022 Euro) data were used. Outcomes included cancer incidences, mortality, life years (LYs), quality-adjusted life years (QALYs), and discounted incremental cost-effectiveness ratios (ICER). We adopted the German health-care system perspective and discounted costs and health effects with 3% annually. Results All intervention strategies are more effective and less costly than IS alone. Prevention with PBM plus PBSO at age 30 maximizes life expectancy with 6.3 LYs gained, whereas PBM at age 30 with delayed PBSO at age 35 improves quality of life with 11.1 QALYs gained, when compared to IS alone. A further delay of PBSO was associated with lower effectiveness. Both strategies are cost effective with ICERs significantly below 10,000 EUR/LYG or QALY. Conclusion Based on our results, PBM at age 30 plus PBSO between age 30 and 40 prolongs life and is cost effective in women with BRCA-1/2 mutations in Germany. Serial preventive surgeries with delayed PBSO potentially improve quality of life for women. However, delaying PBM and/or PBSO further may lead to increased mortality and reduced QALYs

Upstream Statin Therapy and Long-Term Recurrence of Atrial Fibrillation after Cardioversion: A Propensity-Matched Analysis

The relationship of statin therapy with recurrence of atrial fibrillation (AF) after cardioversion (CV) has been evaluated by several investigations, which provided conflicting results and particularly long-term data is scarce. We sought to examine whether upstream statin therapy is associated with long-term recurrence of AF after CV. This was a single-center registry study including consecutive AF patients (n = 454) undergoing CV. Cox regression models were performed to estimate AF recurrence comparing patients with and without statins. In addition, we performed a propensity score matched analysis with a 1:1 ratio. Statins were prescribed to 183 (40.3%) patients. After a median follow-up period of 373 (207–805) days, recurrence of AF was present in 150 (33.0%) patients. Patients receiving statins had a significantly lower rate of AF recurrence (log-rank p < 0.001). In univariate analysis, statin therapy was associated with a significantly reduced rate of AF recurrence (HR 0.333 (95% CI 0.225–0.493), p = 0.001), which remained significant after adjustment (HR 0.238 (95% CI 0.151–0.375), p < 0.001). After propensity score matching treatment with statins resulted in an absolute risk reduction of 27.5% for recurrent AF (21 (18.1%) vs. 53 (45.7%); p < 0.001). Statin therapy was associated with a reduced risk of long-term AF recurrence after successful cardioversion

Quantitative Trait Evolution in a Changing Environment in a Seed Beetle

During the last decades the climate has been changing more rapidly than in the preceding periods. This is for instance characterized by an increase in temperature. Interestingly, such changes in the environment are not necessarily constant over time as they often show high levels of fluctuation. Organisms are exposed to these changes and respond to them and a recent theoretical model predicts that fluctuations in the environment are important for populations’ response to climate change. The aim of this thesis is to investigate how populations respond to a changing environment, including fluctuations. My thesis is based on the previously mentioned theoretical model and I used a suite of laboratory experiments on the seed beetle Callsosobruchus maculatus, to test the model predictions in a quantitative genetic framework. First, I assessed the genetic architecture of several life history and morphological traits in order to verify that there is sufficient additive genetic variation for the population to respond to changes in the environment. Second, I tested the detailed model predictions explicitly, by investigating whether different types of environmental fluctuations matter for a population’s response. Third, I investigated changes in quantitative genetic variation after i) a rapid shift in temperature and ii) long term selection under increasing temperature including fluctuations. Fourth, I concentrated on sex differences in response to temperature, and finally, I assessed the relative importance of genetic and nongenetic inheritance for traits that differ in their plastic response to a change in the environment. I found that environmental fluctuations are highly important for a population’s response to environmental change. I could detect changes in a set of quantitative genetic parameters, suggesting that a population’s potential to respond to selection, environmental sensitivity and the evolution of phenotypic plasticity are affected by the selective past. I also found that sexes differ in additive genetic variation and plasticity and that parental effects may play an important role in the evolutionary process. Therefore, future studies would benefit greatly from considering details of the selective past and especially environmental fluctuations during attempts to predict how populations respond to a changing environment, particularly with regards to climate change

Quantitative Trait Evolution in a Changing Environment in a Seed Beetle

During the last decades the climate has been changing more rapidly than in the preceding periods. This is for instance characterized by an increase in temperature. Interestingly, such changes in the environment are not necessarily constant over time as they often show high levels of fluctuation. Organisms are exposed to these changes and respond to them and a recent theoretical model predicts that fluctuations in the environment are important for populations’ response to climate change. The aim of this thesis is to investigate how populations respond to a changing environment, including fluctuations. My thesis is based on the previously mentioned theoretical model and I used a suite of laboratory experiments on the seed beetle Callsosobruchus maculatus, to test the model predictions in a quantitative genetic framework. First, I assessed the genetic architecture of several life history and morphological traits in order to verify that there is sufficient additive genetic variation for the population to respond to changes in the environment. Second, I tested the detailed model predictions explicitly, by investigating whether different types of environmental fluctuations matter for a population’s response. Third, I investigated changes in quantitative genetic variation after i) a rapid shift in temperature and ii) long term selection under increasing temperature including fluctuations. Fourth, I concentrated on sex differences in response to temperature, and finally, I assessed the relative importance of genetic and nongenetic inheritance for traits that differ in their plastic response to a change in the environment. I found that environmental fluctuations are highly important for a population’s response to environmental change. I could detect changes in a set of quantitative genetic parameters, suggesting that a population’s potential to respond to selection, environmental sensitivity and the evolution of phenotypic plasticity are affected by the selective past. I also found that sexes differ in additive genetic variation and plasticity and that parental effects may play an important role in the evolutionary process. Therefore, future studies would benefit greatly from considering details of the selective past and especially environmental fluctuations during attempts to predict how populations respond to a changing environment, particularly with regards to climate change

Quantitative Trait Evolution in a Changing Environment in a Seed Beetle

During the last decades the climate has been changing more rapidly than in the preceding periods. This is for instance characterized by an increase in temperature. Interestingly, such changes in the environment are not necessarily constant over time as they often show high levels of fluctuation. Organisms are exposed to these changes and respond to them and a recent theoretical model predicts that fluctuations in the environment are important for populations’ response to climate change. The aim of this thesis is to investigate how populations respond to a changing environment, including fluctuations. My thesis is based on the previously mentioned theoretical model and I used a suite of laboratory experiments on the seed beetle Callsosobruchus maculatus, to test the model predictions in a quantitative genetic framework. First, I assessed the genetic architecture of several life history and morphological traits in order to verify that there is sufficient additive genetic variation for the population to respond to changes in the environment. Second, I tested the detailed model predictions explicitly, by investigating whether different types of environmental fluctuations matter for a population’s response. Third, I investigated changes in quantitative genetic variation after i) a rapid shift in temperature and ii) long term selection under increasing temperature including fluctuations. Fourth, I concentrated on sex differences in response to temperature, and finally, I assessed the relative importance of genetic and nongenetic inheritance for traits that differ in their plastic response to a change in the environment. I found that environmental fluctuations are highly important for a population’s response to environmental change. I could detect changes in a set of quantitative genetic parameters, suggesting that a population’s potential to respond to selection, environmental sensitivity and the evolution of phenotypic plasticity are affected by the selective past. I also found that sexes differ in additive genetic variation and plasticity and that parental effects may play an important role in the evolutionary process. Therefore, future studies would benefit greatly from considering details of the selective past and especially environmental fluctuations during attempts to predict how populations respond to a changing environment, particularly with regards to climate change

JEB-2012-00108_data_fecundity

Collected in the laboratory, based on split brood design, individual based data; split temp = two temperatures of the split brood, Fam = Family, fecundity = number of offsprin

Data from: Selection in a fluctuating environment leads to decreased genetic variation and facilitates the evolution of phenotypic plasticity

Changes in the environment are expected to induce changes in the quantitative genetic variation, which influences the ability of a population to adapt to environmental change. Furthermore, environmental changes are not constant in time, but fluctuate. Here we investigate the effect of rapid, continuous and/or fluctuating temperature changes in the seed beetle Callosobruchus maculatus, using an evolution experiment followed by a split brood experiment. In line with expectations, individuals responded in a plastic way and had an overall higher potential to respond to selection after a rapid change in the environment. After selection in an environment with increasing temperature, plasticity remained unchanged (or decreased) and environmental variation decreased, especially when fluctuations were added; these results were unexpected. As expected, the genetic variation decreased after fluctuating selection. Our results suggest that fluctuations in the environment have major impact on the response of a population to environmental change; in a highly variable environment with low predictability a plastic response might not be beneficial and the response is genetically and environmentally canalized resulting in a low potential to respond to selection and low environmental sensitivity. Interestingly, we found greater variation for phenotypic plasticity after selection, suggesting that the potential for plasticity to evolve is facilitated after exposure to environmental fluctuations. Our study highlights that environmental fluctuations should be considered when investigating the response of a population to environmental change

Data from: Selection in a fluctuating environment and the evolution of sexual dimorphism in the seed beetle Callosobruchus maculatus

Temperature changes in the environment, which realistically include environmental fluctuations, can create both plastic and evolutionary responses of traits. Sexes might differ in either or both of these responses for homologous traits, which in turn has consequences for sexual dimorphism and its evolution. Here we investigate both immediate changes in and the evolution of sexual dimorphism in response to a changing environment (with and without fluctuations) using the seed beetle Callosobruchus maculatus. We investigate sex differences in plasticity and also the genetic architecture of body mass and developmental time dimorphism to test two existing hypothesis on sex differences in plasticity (adaptive canalization hypothesis and condition dependence hypothesis). We found a decreased sexual size dimorphism in higher temperature and females responded more plastically than males, supporting the condition dependence hypothesis. However, selection in a fluctuating environment altered sex specific patterns of genetic and environmental variation, indicating support for the adaptive canalization hypothesis. Genetic correlations between sexes (r_MF) were affected by fluctuating selection, suggesting facilitated independent evolution of the sexes. Thus, the selective past of a population is highly important for the understanding of the evolutionary dynamics of sexual dimorphism

JEB-2012-00106.R1_data_developmental_time

Developmental time of C. maculatus collected in the laboratory. Presented are four selection treatments (C = Control, T = Trend, R = Red noise, W = White noise). split temp = two temperature environments the beetles were exposed to during the split brood experiment. replicate: replicate is nested within treatment (4 replicates per treatment). Fam = Family nested within replicate and treatment, per replicate 10 families were investigated. sex = sex of the individual measured. emergence day = egg to adult developmental time, i.e. number of days after egg laying until emergence of adult beetle