A causal investigation of soy isoflavone intake for primary prevention of post-menopausal breast cancer among Asian women

The incidence of breast cancer is increasing at an alarming rate across Asia, by up to 6% annually, compared to near stable incidence rates in many Western countries. While selective oestrogen receptor modulators and aromatase inhibitors are actively being studied as chemoprevention among high-risk Caucasian women, the risks may outweigh the benefits among Asian women with lower population risk of breast cancer. Modifiable lifestyle targets for primary prevention have long been identified, such as post-menopausal obesity, alcohol intake, and hormone replacement therapy use, but these risk factors are less prevalent among women in Asian countries. There remains an urgent need to find primary prevention strategies that are low risk, acceptable, and effective for Asian women. Epidemiological evidence in Asian women suggests that high soy intake is associated with lower risk of breast cancer, but these findings were not observed in epidemiological studies of Caucasian women nor in clinical trials of soy isoflavone supplements. To date, there are no clinical trials that examine the effect of soy isoflavone intake from diet nor supplement on breast cancer risk among Asian women. In this thesis, I present the research studies undertaken to investigate if soy isoflavone intake is causally and inversely associated with post-menopausal breast cancer risk among Asian women. The objective of the first research study was to identify mammographic density measures that are suitable biomarkers of breast cancer risk in the target population (Chapter 3). In this study, volume-based mammographic density measures and breast cancer risk factors were compared between 1,501 Malaysian women and 4,501 age- and BMI-matched Swedish women with no personal history of cancer. The analysis demonstrated that absolute dense volume, rather than percent density, may be a better biomarker of breast cancer risk among post-menopausal Asian women. Based on the above findings, the second research study sought to determine if mammographic density mediates the association between soy intake and breast cancer risk in the target population (Chapter 4). A cross-sectional analysis of 3,277 healthy Malaysian women showed that mammographic density was lower among women with frequent soy intake compared to non-consumers, by up to 2.5cm3 dense volume or 2.0cm2 dense area, but this was not statistically significant. Intriguingly, regular soy intake was associated with lower mammographic density among overweight or obese women, but for leaner women, regular soy intake was associated with higher mammographic density. This interaction was statistically significant among pre-menopausal women (pinteraction = 0.029). Prior to designing a robust clinical trial to test the causal association between soy intake and mammographic density as a biomarker of breast cancer risk, the feasibility of a dietary soy intervention was assessed in a small sample of the target population (n=10, Chapter 5). Overall, women in the study were able to maintain a diet of 70-90mg/day of soy isoflavones for 2 months, but the target of 100mg/day was not feasible and may have led to some adverse events. Thematic analysis of semi-structured interviews revealed that women participated in the study for altruistic reasons and due to emotional attachments to the cause, and that adherence was largely influenced by the practicability of the new diet or routine. Building from the results of the previous three chapters, the primary objective of the last research study was to test the effect of daily soy isoflavone intake for 1 year on breast cancer risk among Asian women, using mammographic density as a biomarker of risk (Chapter 6). In this clinical trial, 57 healthy post-menopausal Malaysian women were randomized into the Supplement arm (100mg/day isoflavones, with >90% daidzein), the Dietary Soy arm (50mg/day isoflavones), or the Control arm. After 1 year of intervention, women in the Supplement arm experienced 4.1cm2 lower dense area and 2.4% lower area-based percent density compared to women in the Control arm, but these associations were not statistically significant. The associations were weaker for women in the Dietary Soy arm and for volume-based mammographic density measures. Interestingly, stronger associations were observed when the analysis was limited to women with high BMI or low dietary fat intake, but the sample size was too small for robust analyses. In conclusion, the data presented in this thesis suggest a causal association between soy isoflavone intake and lower post-menopausal breast cancer risk among Asian women. However, due to the small sample size, the analysis was underpowered to show statistically significant effects and will require confirmation in a larger trial. Nonetheless, the research undertaken here adds to existing evidence that the soy isoflavone daidzein may be responsible for the protective effect of soy. Furthermore, it proposes new hypotheses in understanding the association between soy intake and breast cancer risk across populations, including possible effect modification by BMI or dietary fat intake

A causal investigation of soy isoflavone intake for primary prevention of post-menopausal breast cancer among Asian women

The incidence of breast cancer is increasing at an alarming rate across Asia, by up to 6% annually, compared to near stable incidence rates in many Western countries. While selective oestrogen receptor modulators and aromatase inhibitors are actively being studied as chemoprevention among high-risk Caucasian women, the risks may outweigh the benefits among Asian women with lower population risk of breast cancer. Modifiable lifestyle targets for primary prevention have long been identified, such as post-menopausal obesity, alcohol intake, and hormone replacement therapy use, but these risk factors are less prevalent among women in Asian countries. There remains an urgent need to find primary prevention strategies that are low risk, acceptable, and effective for Asian women. Epidemiological evidence in Asian women suggests that high soy intake is associated with lower risk of breast cancer, but these findings were not observed in epidemiological studies of Caucasian women nor in clinical trials of soy isoflavone supplements. To date, there are no clinical trials that examine the effect of soy isoflavone intake from diet nor supplement on breast cancer risk among Asian women. In this thesis, I present the research studies undertaken to investigate if soy isoflavone intake is causally and inversely associated with post-menopausal breast cancer risk among Asian women. The objective of the first research study was to identify mammographic density measures that are suitable biomarkers of breast cancer risk in the target population (Chapter 3). In this study, volume-based mammographic density measures and breast cancer risk factors were compared between 1,501 Malaysian women and 4,501 age- and BMI-matched Swedish women with no personal history of cancer. The analysis demonstrated that absolute dense volume, rather than percent density, may be a better biomarker of breast cancer risk among post-menopausal Asian women. Based on the above findings, the second research study sought to determine if mammographic density mediates the association between soy intake and breast cancer risk in the target population (Chapter 4). A cross-sectional analysis of 3,277 healthy Malaysian women showed that mammographic density was lower among women with frequent soy intake compared to non-consumers, by up to 2.5cm3 dense volume or 2.0cm2 dense area, but this was not statistically significant. Intriguingly, regular soy intake was associated with lower mammographic density among overweight or obese women, but for leaner women, regular soy intake was associated with higher mammographic density. This interaction was statistically significant among pre-menopausal women (pinteraction = 0.029). Prior to designing a robust clinical trial to test the causal association between soy intake and mammographic density as a biomarker of breast cancer risk, the feasibility of a dietary soy intervention was assessed in a small sample of the target population (n=10, Chapter 5). Overall, women in the study were able to maintain a diet of 70-90mg/day of soy isoflavones for 2 months, but the target of 100mg/day was not feasible and may have led to some adverse events. Thematic analysis of semi-structured interviews revealed that women participated in the study for altruistic reasons and due to emotional attachments to the cause, and that adherence was largely influenced by the practicability of the new diet or routine. Building from the results of the previous three chapters, the primary objective of the last research study was to test the effect of daily soy isoflavone intake for 1 year on breast cancer risk among Asian women, using mammographic density as a biomarker of risk (Chapter 6). In this clinical trial, 57 healthy post-menopausal Malaysian women were randomized into the Supplement arm (100mg/day isoflavones, with >90% daidzein), the Dietary Soy arm (50mg/day isoflavones), or the Control arm. After 1 year of intervention, women in the Supplement arm experienced 4.1cm2 lower dense area and 2.4% lower area-based percent density compared to women in the Control arm, but these associations were not statistically significant. The associations were weaker for women in the Dietary Soy arm and for volume-based mammographic density measures. Interestingly, stronger associations were observed when the analysis was limited to women with high BMI or low dietary fat intake, but the sample size was too small for robust analyses. In conclusion, the data presented in this thesis suggest a causal association between soy isoflavone intake and lower post-menopausal breast cancer risk among Asian women. However, due to the small sample size, the analysis was underpowered to show statistically significant effects and will require confirmation in a larger trial. Nonetheless, the research undertaken here adds to existing evidence that the soy isoflavone daidzein may be responsible for the protective effect of soy. Furthermore, it proposes new hypotheses in understanding the association between soy intake and breast cancer risk across populations, including possible effect modification by BMI or dietary fat intake

Mutual Aid Parkdale

The commentary includes an introduction to the political values, principles and activities of Mutual Aid Parkdale (M.A.P.) in Toronto, Ontario, during the COVID pandemic, followed by a panel discussion at York University of mutual aid leaders from M.A.P. discussing the history and purpose of mutual aid

Measurement challenge : protocol for international case–control comparison of mammographic measures that predict breast cancer risk

Introduction: For women of the same age and body mass index, increased mammographic density is one of the strongest predictors of breast cancer risk. There are multiple methods of measuring mammographic density and other features in a mammogram that could potentially be used in a screening setting to identify and target women at high risk of developing breast cancer. However, it is unclear which measurement method provides the strongest predictor of breast cancer risk. Methods and analysis: The measurement challenge has been established as an international resource to offer a common set of anonymised mammogram images for measurement and analysis. To date, full field digital mammogram images and core data from 1650 cases and 1929 controls from five countries have been collated. The measurement challenge is an ongoing collaboration and we are continuing to expand the resource to include additional image sets across different populations (from contributors) and to compare additional measurement methods (by challengers). The intended use of the measurement challenge resource is for refinement and validation of new and existing mammographic measurement methods. The measurement challenge resource provides a standardised dataset of mammographic images and core data that enables investigators to directly compare methods of measuring mammographic density or other mammographic features in case/control sets of both raw and processed images, for the purposes of the comparing their predictions of breast cancer risk. Ethics and dissemination: Challengers and contributors are required to enter a Research Collaboration Agreement with the University of Melbourne prior to participation in the measurement challenge. The Challenge database of collated data and images are stored in a secure data repository at the University of Melbourne. Ethics approval for the measurement challenge is held at University of Melbourne (HREC ID 0931343.3)

International Consortium on Mammographic Density:methodology and population diversity captured across 22 countries

Mammographic density (MD) is a quantitative trait, measurable in all women, and is among the strongest markers of breast cancer risk. The population-based epidemiology of MD has revealed genetic, lifestyle and societal/environmental determinants, but studies have largely been conducted in women with similar westernized lifestyles living in countries with high breast cancer incidence rates. To benefit from the heterogeneity in risk factors and their combinations worldwide, we created an International Consortium on Mammographic Density (ICMD) to pool individual-level epidemiological and MD data from general population studies worldwide. ICMD aims to characterize determinants of MD more precisely, and to evaluate whether they are consistent across populations worldwide. We included 11755 women, from 27 studies in 22 countries, on whom individual-level risk factor data were pooled and original mammographic images were re-read for ICMD to obtain standardized comparable MD data. In the present article, we present (i) the rationale for this consortium; (ii) characteristics of the studies and women included; and (iii) study methodology to obtain comparable MD data from original re-read films. We also highlight the risk factor heterogeneity captured by such an effort and, thus, the unique insight the pooled study promises to offer through wider exposure ranges, different confounding structures and enhanced power for sub-group analyses

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. Methods: We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting. Findings: Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3·9% (95% uncertainty interval [UI] 3·1-4·6) from 1990 to 2017; however, the all-age YLD rate increased by 7·2% (6·0-8·4) while the total sum of global YLDs increased from 562 million (421-723) to 853 million (642-1100). The increases for males and females were similar, with increases in all-age YLD rates of 7·9% (6·6-9·2) for males and 6·5% (5·4-7·7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782-3252] per 100 000 in males vs 1400 [1279-1524] per 100 000 in females), transport injuries (3322 [3082-3583] vs 2336 [2154-2535]), and self-harm and interpersonal violence (3265 [2943-3630] vs 5643 [5057-6302]). Interpretation: Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury

Global, regional, and national age-sex-specific mortality and life expectancy, 1950-2017: a systematic analysis for the Global Burden of Disease Study 2017

Background: Assessments of age-specific mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Affairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally. Methods: The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analysed separately and then incorporated into the estimation. We analyse the relationship between age-specific mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in different components of the analysis have been further standardised and improved; and the analysis has been extended backwards in time by two decades to start in 1950. Findings: Globally, 18·7% (95% uncertainty interval 18·4–19·0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58·8% (58·2–59·3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48·1 years (46·5–49·6) to 70·5 years (70·1–70·8) for men and from 52·9 years (51·7–54·0) to 75·6 years (75·3–75·9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49·1 years (46·5–51·7) for men in the Central African Republic to 87·6 years (86·9–88·1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216·0 deaths (196·3–238·1) per 1000 livebirths in 1950 to 38·9 deaths (35·6–42·83) per 1000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5·4 million (5·2–5·6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development. Interpretation: This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing

Addressing food insecurity and climate change in Malaysia: Current Evidence and Way Forward

Access to sufficient, nutritious food is an urgent, mounting global problem that has been exacerbated by the COVID-19 pandemic. In 2020, up to 30% of the global population faced food insecurity, a 4% increase from the preceding year, with great variation across regions (1). The highest levels of food insecurity were reported in the African continent, where more than half the population (59%) reported poor access to food (1). The largest impact of the pandemic, however, was observed in Latin America and the Caribbean, where the pandemic led to an almost 10% increase in food insecurity in just over a year, resulting in 41% of the population living with food insecurity (1). In Asia, the prevalence of food insecurity increased by 3% to 26% in 2020 (1). The pandemic highlighted how vulnerable current food systems are, especially in emerging economies that rely on large-scale agriculture and international food trade. Without intervention, the global food-insecure population is expected to rise by another 10% by 2050 (2), or more if another global catastrophe strikes

Performance of a subsidised mammographic screening programme in Malaysia, a middle-income Asian country

Abstract Background The incidence of breast cancer in Asia is increasing because of urbanization and lifestyle changes. In the developing countries in Asia, women present at late stages, and mortality is high. Mammographic screening is the only evidence-based screening modality that reduces breast cancer mortality. To date, only opportunistic screening is offered in the majority of Asian countries because of the lack of justification and funding. Nevertheless, there have been few reports on the effectiveness of such programmes. In this study, we describe the cancer detection rate and challenges experienced in an opportunistic mammographic screening programme in Malaysia. Methods From October 2011 to June 2015, 1,778 asymptomatic women, aged 40–74 years, underwent subsidised mammographic screening. All patients had a clinical breast examination before mammographic screening, and women with mammographic abnormalities were referred to a surgeon. The cancer detection rate and variables associated with a recommendation for adjunct ultrasonography were determined. Results The mean age for screening was 50.8 years and seven cancers (0.39%) were detected. The detection rate was 0.64% in women aged 50 years and above, and 0.12% in women below 50 years old. Adjunct ultrasonography was recommended in 30.7% of women, and was significantly associated with age, menopausal status, mammographic density and radiologist’s experience. The main reasons cited for recommendation of an adjunct ultrasound was dense breasts and mammographic abnormalities. Discussion The cancer detection rate is similar to population-based screening mammography programmes in high-income Asian countries. Unlike population-based screening programmes in Caucasian populations where the adjunct ultrasonography rate is 2–4%, we report that 3 out of 10 women attending screening mammography were recommended for adjunct ultrasonography. This could be because Asian women attending screening are likely premenopausal and hence have denser breasts. Radiologists who reported more than 360 mammograms were more confident in reporting a mammogram as normal without adjunct ultrasonography compared to those who reported less than 180 mammograms. Conclusion Our subsidised opportunistic mammographic screening programme is able to provide equivalent cancer detection rates but the high recall for adjunct ultrasonography would make screening less cost-effective