KaryoCreate: A CRISPR-based technology to study chromosome-specific aneuploidy by targeting human centromeres.

Aneuploidy, the presence of chromosome gains or losses, is a hallmark of cancer. Here, we describe KaryoCreate (karyotype CRISPR-engineered aneuploidy technology), a system that enables the generation of chromosome-specific aneuploidies by co-expression of an sgRNA targeting chromosome-specific CENPA-binding ɑ-satellite repeats together with dCas9 fused to mutant KNL1. We design unique and highly specific sgRNAs for 19 of the 24 chromosomes. Expression of these constructs leads to missegregation and induction of gains or losses of the targeted chromosome in cellular progeny, with an average efficiency of 8% for gains and 12% for losses (up to 20%) validated across 10 chromosomes. Using KaryoCreate in colon epithelial cells, we show that chromosome 18q loss, frequent in gastrointestinal cancers, promotes resistance to TGF-ß, likely due to synergistic hemizygous deletion of multiple genes. Altogether, we describe an innovative technology to create and study chromosome missegregation and aneuploidy in the context of cancer and beyond.

Proteogenomic analysis of cancer aneuploidy and normal tissues reveals divergent modes of gene regulation across cellular pathways.

How cells control gene expression is a fundamental question. The relative contribution of protein-level and RNA-level regulation to this process remains unclear. Here, we perform a proteogenomic analysis of tumors and untransformed cells containing somatic copy number alterations (SCNAs). By revealing how cells regulate RNA and protein abundances of genes with SCNAs, we provide insights into the rules of gene regulation. Protein complex genes have a strong protein-level regulation while non-complex genes have a strong RNA-level regulation. Notable exceptions are plasma membrane protein complex genes, which show a weak protein-level regulation and a stronger RNA-level regulation. Strikingly, we find a strong negative association between the degree of RNA-level and protein-level regulation across genes and cellular pathways. Moreover, genes participating in the same pathway show a similar degree of RNA- and protein-level regulation. Pathways including translation, splicing, RNA processing, and mitochondrial function show a stronger protein-level regulation while cell adhesion and migration pathways show a stronger RNA-level regulation. These results suggest that the evolution of gene regulation is shaped by functional constraints and that many cellular pathways tend to evolve one predominant mechanism of gene regulation at the protein level or at the RNA level.

Crossover Effects of Education on Health within Married Couples.

Although empirical work has shown that personal and spousal education are both related to health, the nature of these associations has been harder to establish. People select into marriages on the basis of observed and hard-to-observe characteristics, complicating the job of the researcher who wishes to make causal inferences. In this article, we implement a within-sibling-pair design that exploits variation within pairs in spousal education to generate estimates of spousal crossover effects. Results-based on a long-term study of siblings and their spouses-suggest that spousal education is positively related to health, but to a greater degree for women than men. Sensitivity analyses show that these patterns are unlikely to derive from measured differences between individuals or unmeasured characteristics that sort them into unions. These results are consistent with network-based theories of social capital, which view education as a resource that can be mobilized by network ties to enhance health.

Health decisions amidst controversy: Prenatal alcohol consumption and the unequal experience of influence and control in networks.

Individuals avoid stigma by looking to members of their networks for guidance on how to behave. Health controversies complicate this process by exposing people to inconsistent norms, influence, and control within their networks. To understand this process, we meld perspectives on networks and social psychology. Using the case of light/moderate drinking during pregnancy, we examine how people make health decisions in the face of controversy. Through in-depth interviews with first-time pregnant individuals and their health care providers, we reveal that individuals' decisions about controversial health behaviors depend on 1) the consistency of the influence and control they encounter, 2) their status relative to enforcers, and 3) the strength of their ties to enforcers. These processes give people from higher social positions more power to resist influence and control. These findings illuminate how medical recommendations and public health interventions should account for the unequal experience of influence and control within networks.

Moving Upstream: The Effect of Tobacco Clean Air Restrictions on Educational Inequalities in Smoking Among Young Adults.

Education affords a range of direct and indirect benefits that promote longer and healthier lives and stratify health lifestyles. We use tobacco clean air policies to examine whether policies that apply universally-interventions that bypass individuals' unequal access and ability to employ flexible resources to avoid health hazards-have an effect on educational inequalities in health behaviors. We test theoretically informed but competing hypotheses that these policies either amplify or attenuate the association between education and smoking behavior. Our results provide evidence that interventions that move upstream to apply universally regardless of individual educational attainment-here, tobacco clean air policies-are particularly effective among young adults with the lowest levels of parental or individual educational attainment. These findings provide important evidence that upstream approaches may disrupt persistent educational inequalities in health behaviors. In doing so, they provide opportunities to intervene on behaviors in early adulthood that contribute to disparities in morbidity and mortality later in the life course. These findings also help assuage concerns that tobacco clean air policies increase educational inequalities in smoking by stigmatizing those with the fewest resources.

Social Networks and the Emergence of Health Inequalities Following a Medical Advance: Examining Prenatal H1N1 Vaccination Decisions.

Health inequalities persist, in part, because people in socioeconomically advantageous positions possess resources to avoid new health risks when medicine advances. Although these health decisions rarely occur in isolation, we know less about the specific role of networks. We examine whether social capital mediates the relationship between individual educational attainment and decisions about a medical advance: H1N1 vaccination during pregnancy. Building on prior work that defines social capital as the resources of network members, we examine two mechanisms through which social capital may affect health decisions, facilitating information flow and exerting influence. Using egocentric network data collected from 225 pregnant women during the 2009-10 H1N1 pandemic, we measure social capital as the proportion of networks that are college-educated H1N1 discussants (information flow) and the proportion of college-educated H1N1 supporters (influence). Findings reveal that college-educated women knew more college-educated H1N1 discussants and supporters. Further, both measures of social capital predicted higher probabilities of vaccination, with the latter mechanism emerging as a particularly strong predictor. Our findings provide evidence that health decisions are shaped by individual resources as well as social capital available through network ties, offering a unique perspective of the ways that social networks contribute to producing, and potentially reproducing, unequal health.

Denormalization, smoke-free air policy, and tobacco use among young adults.

Smoke-free air laws and the denormalization of smoking are important contributors to reductions in smoking during the 21st century. Yet, tobacco policy and denormalization may intersect in numerous ways to affect smoking. We merge data from the National Longitudinal Survey of Youth 1997, Tobacco Use Supplement of the Current Population Survey, American Nonsmokers' Right Foundation, and Census to produce a unique examination of the intersection of smoking bans and denormalization and their influence on any smoking and heavy smoking among young adults. Operationalizing denormalization as complete unacceptability of smoking within nightlife venues, we examine 1) whether smoking bans and denormalization have independent effects on smoking, 2) whether denormalization mediates the influence of smoking bans on smoking, and 3) whether denormalization moderates the impact of smoking bans on smoking. For any smoking, denormalization has a significant independent effect beyond the influence of smoking bans. For heavy smoking, denormalization mediates the relationship between smoking bans and habitual smoking. Denormalization does not moderate the relationship of smoking bans with either pattern of smoking. This research identifies that the intersection of denormalization and smoking bans plays an important role in lowering smoking, yet they remain distinct in their influences. Notably, smoking bans are efficacious even in locales with lower levels of denormalization, particularly for social smoking.

Educational and Gender Differences in Health Behavior Changes After a Gateway Diagnosis.

OBJECTIVE: Hypertension represents a gateway diagnosis to more serious health problems that occur as people age. We examine educational differences in three health behavior changes people often make after receiving this diagnosis in middle or older age, and test whether these educational differences depend on (a) the complexity of the health behavior change and (b) gender. METHOD: We use data from the Health and Retirement Study and conduct logistic regression analysis to examine the likelihood of modifying health behaviors post diagnosis. RESULTS: We find educational differences in three behavior changes-antihypertensive medication use, smoking cessation, and physical activity initiation-after a hypertension diagnosis. These educational differences in health behaviors were stronger among women compared with men. DISCUSSION: Upon receiving a hypertension diagnosis, education is a more important predictor of behavior changes for women compared with men, which may help explain gender differences in the socioeconomic gradient in health in the United States.

Provider and patient influences on the formation of socioeconomic health behavior disparities among pregnant women.

Socially advantaged individuals are better positioned to benefit from advances in biomedicine, which frequently results in the emergence of social inequalities in health. I use survey and in-depth interviews with pregnant women and their health care providers from four Midwestern clinics in the United States, conducted in 2009 and 2010. I compare socioeconomic differences in intake of two new prenatal supplements: Vitamin D and omega-3 fatty acid. Although socioeconomic differences in omega-3 fatty acid supplementation emerged, there were no differences in the use of vitamin D. I argue that providers may have contributed to the prevention of a health disparity in vitamin D supplementation by implementing an aggressive uniform protocol. These results suggest that providers not only serve as a conduit for the dissemination of new biomedical information, the strength and uniformity of their recommendations have the potential to prevent or exacerbate socioeconomic differences in health behaviors.

The impact of childhood sickness on adult socioeconomic outcomes: evidence from late 19th century America.

We use family fixed-effects models to estimate the impact of childhood health on adult literacy, labor force outcomes, and marital status among pairs of white brothers observed as children in the 1880 U.S. Census and then as adults in the 1900-1930 Censuses. Given our focus on the 19th century, we observed a wider array of infectious, chronic, and traumatic health problems than is observed using data that are more recent; our results thus provide some insights into circumstances in modern developing countries where similar health problems are more frequently observed. Compared to their healthy siblings, sick brothers were less likely to be located (and thus more likely to be dead) 20-50 years after their 1880 enumeration. Sick brothers were also less likely to be literate, to have ever been married, and to have reported an occupation. However, among those with occupations, sick and healthy brothers tended to do similar kinds of work. We discuss the implications of our results for research on the impact of childhood health on socioeconomic outcomes in developed and developing countries.

Institutions, Politics, and Mental Health Parity.

Mental health parity laws require insurers to extend comparable benefits for mental and physical health care. Proponents argue that by placing mental health services alongside physical health services, such laws can help ensure needed treatment and destigmatize mental illness. Opponents counter that such mandates are costly or unnecessary. The authors offer a sociological account of the diffusion and spatial distribution of state mental health parity laws. An event history analysis identifies four factors as especially important: diffusion of law, political ideology, the stability of mental health advocacy organizations and the relative health of state economies. Mental health parity is least likely to be established during times of high state unemployment and under the leadership of conservative state legislatures.

Did socioeconomic inequalities in morbidity and mortality change in the United States over the course of the twentieth century?

In this article we present two sets of empirical analyses that consider the extent to which socioeconomic gradients in self-assessed health and child mortality changed since the beginning of the twentieth century in the United States. This empirical issue has important and wide-ranging research and policy implications. In particular, our results speak to the value of considering the role of broader social, economic, and political inequalities in generating and maintaining socioeconomic disparities in morbidity and mortality. Despite dramatic declines in morbidity and mortality rates in the United States across the twentieth century, we find that socioeconomic-status gradients in morbidity and mortality declined only modestly (if at all) during that period.