A new statistical method for curve group analysis of longitudinal gene expression data illustrated for breast cancer in the NOWAC postgenome cohort as a proof of principle

International audienceA new statistical method for curve group analysis of longitudinal gene expression data illustrated for breast cancer in the NOWAC postgenome cohort as a proof of principle Abstract Background: The understanding of changes in temporal processes related to human carcinogenesis is limited. One approach for prospective functional genomic studies is to compile trajectories of differential expression of genes, based on measurements from many case-control pairs. We propose a new statistical method that does not assume any parametric shape for the gene trajectories. Methods: The trajectory of a gene is defined as the curve representing the changes in gene expression levels in the blood as a function of time to cancer diagnosis. In a nested case–control design it consists of differences in gene expression levels between cases and controls. Genes can be grouped into curve groups, each curve group corresponding to genes with a similar development over time. The proposed new statistical approach is based on a set of hypothesis testing that can determine whether or not there is development in gene expression levels over time, and whether this development varies among different strata. Curve group analysis may reveal significant differences in gene expression levels over time among the different strata considered. This new method was applied as a " proof of concept " to breast cancer in the Norwegian Women and Cancer (NOWAC) postgenome cohort, using blood samples collected prospectively that were specifically preserved for transcriptomic analyses (PAX tube). Cohort members diagnosed with invasive breast cancer through 2009 were identified through linkage to the Cancer Registry of Norway, and for each case a random control from the postgenome cohort was also selected, matched by birth year and time of blood sampling, to create a case-control pair. After exclusions, 441 case-control pairs were available for analyses, in which we considered strata of lymph node status at time of diagnosis and time of diagnosis with respect to breast cancer screening visits. Results: The development of gene expression levels in the NOWAC postgenome cohort varied in the last years before breast cancer diagnosis, and this development differed by lymph node status and participation in the Norwegian Breast Cancer Screening Program. The differences among the investigated strata appeared larger in the year before breast cancer diagnosis compared to earlier years.ConclusionsThis approach shows good properties in term of statistical power and type 1 error under minimal assumptions. When applied to a real data set it was able to discriminate between groups of genes with non-linear similar patterns before diagnosis

Overdiagnosis of breast cancer in the Norwegian Breast Cancer Screening Program estimated by the Norwegian Women and Cancer cohort study

Background: There is increasing ambiguity towards national mammographic screening programs due to varying publicized estimates of overdiagnosis, i.e., breast cancer that would not have been diagnosed in the women’s lifetime outside screening. This analysis compares the cumulative incidence of breast cancer in screened and unscreened women in Norway from the start of the fully implemented Norwegian Breast Cancer Screening Program (NBCSP) in 2005. Methods: Subjects were 53 363 women in the Norwegian Women and Cancer (NOWAC) study, aged 52–79 years, with follow-up through 2010. Mammogram and breast cancer risk factor information were taken from the most recent questionnaire (2002–07) before the start of individual follow-up. The analysis differentiated screening into incidence (52–69 years) and post screening (70–79 years). Relative risks (RR) were estimated by Poisson regression. Results: The analysis failed to detect a significantly increased cumulative incidence rate in screened versus other women 52–79 years. RR of breast cancer among women outside the NBCSP, the “control group”, was non-significantly reduced by 7% (RR = 0∙93; 95% confidence interval 0∙79 to 1∙10) compared to those in the program. The RR was attenuated when adjusted for risk factors; RRadj = 0∙97 (0∙82 to 1∙15). The control group consisted of two subpopulations, those who only had a mammogram outside the program (RRadj =1∙04; 0∙86 to 1∙26) and those who never had a mammogram (RRadj= 0∙77; 0∙59 to 1∙01). These groups differed significantly with respect to risk factors for breast cancer, partly as a consequence of the prescription rules for hormone therapy which indicate a mammogram. Conclusions: In the fully implemented NBCSP, no significant difference was found in cumulative incidence rates of breast cancer between NOWAC women screened and not screened. Naïve comparisons of screened and unscreened women may be affected by important differences in risk factors. The current challenge for the screening program is to improve the diagnostics used at prevalence screenings (ages 50–51)

Validity of self-reported body mass index among middle-aged participants in the Norwegian Women and Cancer study

Background: Body mass index (BMI) based on self-reported height and weight has been criticized as being biased because of an observed tendency for overweight and obese people to overestimate height and underestimate weight, resulting in higher misclassification for these groups. We examined the validity of BMI based on self-reported values in a sample of Norwegian women aged 44–64 years. Methods: The study sample of 1,837 participants in the Norwegian Women and Cancer study self-reported height and weight, and then, within 1 year, either self-reported anthropometric again, or were measured by medical staff. Demographic and anthropometric were compared using t-tests and chi-square tests of independence. Misclassification of BMI categories was assessed by weighted Cohen’s kappa and Bland–Altman plot. Results: On average, the two measurements were taken 8 months apart, and self-reported weight increased by 0.6 kg (P,0.05), and BMI by 0.2 kg/m2 (P,0.05). The distribution of BMI categories did not differ between self-reported and measured values. There was substantial agreement between self-reported values and those measured by medical staff (weighted kappa 0.73). Under-reporting resulting in misclassification of BMI category was most common among overweight women (36%), but the highest proportion of extreme under-reporting was found in obese women (18% outside the 95% limits of agreement). The cumulative distribution curves for the measured and self-reported values closely followed each other, but measurements by medical staff were shifted slightly toward higher BMI values. Conclusion: While there was substantial agreement between self-reported and measured BMI values, there was small but statistically significant under-reporting of weight and thus self-reported BMI. The tendency to under-report was largest among overweight women, while the largest degree of under-reporting was found in the obese group. Self-reported weight and height provide a valid ranking of BMI for middle-aged Norwegian women

Race, Neighborhood Economic Status, Income Inequality and Mortality

<div><p>Mortality rates in the United States vary based on race, individual economic status and neighborhood. Correlations among these variables in most urban areas have limited what conclusions can be drawn from existing research. Our study employs a unique factorial design of race, sex, age and individual poverty status, measuring time to death as an objective measure of health, and including both neighborhood economic status and income inequality for a sample of middle-aged urban-dwelling adults (N = 3675). At enrollment, African American and White participants lived in 46 unique census tracts in Baltimore, Maryland, which varied in neighborhood economic status and degree of income inequality. A Cox regression model for 9-year mortality identified a three-way interaction among sex, race and individual poverty status (p = 0.03), with African American men living below poverty having the highest mortality. Neighborhood economic status, whether measured by a composite index or simply median household income, was negatively associated with overall mortality (p<0.001). Neighborhood income inequality was associated with mortality through an interaction with individual poverty status (p = 0.04). While racial and economic disparities in mortality are well known, this study suggests that several social conditions associated with health may unequally affect African American men in poverty in the United States. Beyond these individual factors are the influences of neighborhood economic status and income inequality, which may be affected by a history of residential segregation. The significant association of neighborhood economic status and income inequality with mortality beyond the synergistic combination of sex, race and individual poverty status suggests the long-term importance of small area influence on overall mortality.</p></div

Characteristics of the Healthy Aging in Neighborhoods of Diversity Across the Life Span Study Participants, Baltimore, Maryland, 2004–2013 (N = 3675).

<p>Characteristics of the Healthy Aging in Neighborhoods of Diversity Across the Life Span Study Participants, Baltimore, Maryland, 2004–2013 (N = 3675).</p

Frailty in a racially and socioeconomically diverse sample of middle-aged Americans in Baltimore.

Frailty is a risk factor for disability and mortality, and is more prevalent among African American (AA) elderly than whites. We examine frailty in middle-aged racially and economically diverse adults, and investigate how race, poverty and frailty are associated with mortality. Data were from 2541 participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span study in Baltimore, Maryland; 35-64 years old at initial assessment (56% women; 58% AA). Frailty was assessed using a modified FRAIL scale of fatigue, resistance, ambulation, illness and weight loss, and compared with difficulties in physical functioning and daily activities. Frailty prevalence was calculated across race and age groups, and associations with survival were assessed by Cox Regression. 278 participants were frail (11%); 924 pre-frail (36%); 1339 not frail (53%). For those aged 45-54, a higher proportion of whites (13%) than AAs (8%) were frail; while the proportions were similar for those 55-64 (14%,16%). Frailty was associated with overall survival with an average follow-up of 6.6 years, independent of race, sex and poverty status (HR = 2.30; 95%CI 1.67-3.18). In this sample of economically and racially diverse older adults, the known association of frailty prevalence and age differed across race with whites having higher prevalence at younger ages. Frailty was associated with survival beyond the risk factors of race and poverty status in this middle-aged group. Early recognition of frailty at these younger ages may provide an effective method for preventing or delaying disabilities

Inflammatory proteins are associated with mortality in a middle‐aged diverse cohort

Abstract Background Recent data indicate a decline in overall longevity in the United States. Even prior to the COVID‐19 pandemic, an increase in midlife mortality rates had been reported. Life expectancy disparities have persisted in the United States for racial and ethnic groups and for individuals living at low socioeconomic status. These continued trends in mortality indicate the importance of examining biomarkers of mortality at midlife in at‐risk populations. Circulating levels of cytokines and inflammatory markers reflect systemic chronic inflammation, which is a well‐known driver of many age‐related diseases. Methods In this study, we examined the relationship of nine different inflammatory proteins with mortality in a middle‐aged socioeconomically diverse cohort of African–American and White men and women (n = 1122; mean age = 47.8 years). Results We found significant differences in inflammatory‐related protein serum levels between African–American and White middle‐aged adults. E‐selectin and fibrinogen were significantly higher in African–American adults. IFN‐γ, TNF‐α trimer, monocyte chemoattractant protein‐1 (MCP‐1), soluble receptor for advanced glycation end‐products (sRAGE) and P‐selectin were significantly higher in White participants compared to African–American participants. Higher levels of E‐selectin, MCP‐1 and P‐selectin were associated with a higher mortality risk. Furthermore, there was a significant interaction between sex and IL‐6 with mortality. IL‐6 levels were associated with an increased risk of mortality, an association that was significantly greater in women than men. In addition, White participants with high levels of sRAGE had significantly higher survival probability than White participants with low levels of sRAGE, while African–American participants had similar survival probabilities across sRAGE levels. Conclusions These results suggest that circulating inflammatory markers can be utilized as indicators of midlife mortality risk in a socioeconomically diverse cohort of African–American and White individuals

Healthy Behaviors Associated with Changes in Mental and Physical Strength in Urban African American and White Adults

Over time, adherence to healthy behaviors may improve physical and mental strength which is essential for successful aging. A plausible mechanism is the reduction of inflammation. Research on the association of risky health behaviors on change in strength with age is limited. This study examined changes in the inflammatory potential of the diet, smoking, illicit drug use with changes in strength in a racially and socioeconomically diverse adult sample from the Healthy Aging in Neighborhoods of Diversity Across the Life Span study. The dietary inflammatory index (DII) was calculated from 35 food components derived from multiple 24-h dietary recalls. Strength was evaluated by handgrip strength (HGS), SF-12 PCS and SF-12 MCS (physical and mental component scores). Repeated measures analyses were used to examine associations. At baseline, mean age was 48.4 ± 0.25 years, 56% of the sample were women, and 58% African American. Significant 4-way interactions were found between age, race, socioeconomic status, and DII for women, on change in HGS (p &lt; 0.05) and in SF-12 PCS (p &lt; 0.05) and for men, in change in SF-12 PCS (p &lt; 0.05). Improvements in SF-12 MCS were associated with all three health behaviors as main effects. This study provided evidence that changes towards improving healthy behaviors, diet with anti-inflammatory potential, not smoking cigarettes and not using illicit drugs, were associated with improved strength. Health professionals, especially registered dietitians and health coaches, should create lifestyle interventions to reduce inflammation targeting change in more than one risky health behavior

Data from: Does the niche-breadth or trade-off hypothesis explain the abundance-occupancy relationship in avian haemosporidia?

Two hypotheses have been proposed to explain the abundance-occupancy relationship (AOR) in parasites. The niche-breadth hypothesis suggests that host generalists are more abundant and efficient at colonizing different host communities than specialists. The trade-off hypothesis argues that host specialists achieve high density across their hosts’ ranges, whereas generalists incur the high cost of adaptation to diverse immuno-defense systems. We tested these hypotheses using 386 haemosporidian cytochrome-b lineages (1894 sequences) recovered from 2318 birds of 103 species sampled in NW Africa, NW Iberia, W Greater Caucasus, and Transcaucasia. The number of regions occupied by lineages was associated with their frequency suggesting the presence of AOR in avian Haemosporidia. However, neither hypothesis provided a better explanation for the AOR. Although, the host-generalist Plasmodium SGS1 was over 3 times more abundant than other widespread lineages, both host specialists and generalists were successful in colonizing all study regions and achieved overall high prevalence