Publications

As there are effective treatments to reduce hip fractures, identification of patients at high risk of hip fracture is important to inform efficient intervention strategies. To obtain a new tool for hip fracture prediction, we developed a protein-based risk score in the Cardiovascular Health Study using an aptamer-based proteomic platform. The proteomic risk score predicted incident hip fractures and improved hip fracture discrimination in two Trøndelag Health Study validation cohorts using the same aptamer-based platform. When transferred to an antibody-based proteomic platform in a UK Biobank validation cohort, the proteomic risk score was strongly associated with hip fractures (hazard ratio per s.d. increase, 1.64; 95% confidence interval 1.53-1.77). The proteomic risk score, but not available polygenic risk scores for fractures or bone mineral density, improved the C-index beyond the fracture risk assessment tool (FRAX), which integrates information from clinical risk factors (C-index, FRAX 0.735 versus FRAX + proteomic risk score 0.776). The developed proteomic risk score constitutes a new tool for stratifying patients according to hip fracture risk; however, its improvement in hip fracture discrimination is modest and its clinical utility beyond FRAX with information on femoral neck bone mineral density remains to be determined.

BACKGROUND: Current cardiovascular magnetic resonance sequences cannot discriminate between different myocardial extracellular space (ECSs), including collagen, noncollagen, and inflammation. We sought to investigate whether cardiovascular magnetic resonance radiomics analysis can distinguish between noncollagen and inflammation from collagen in dilated cardiomyopathy.

METHODS: We identified data from 132 patients with dilated cardiomyopathy scheduled for an invasive septal biopsy who underwent cardiovascular magnetic resonance at 3 T. Cardiovascular magnetic resonance imaging protocol included native and postcontrast T1 mapping and late gadolinium enhancement (LGE). Radiomic features were computed from the midseptal myocardium, near the biopsy region, on native T1, extracellular volume (ECV) map, and LGE images. Principal component analysis was used to reduce the number of radiomic features to 5 principal radiomics. Moreover, a correlation analysis was conducted to identify radiomic features exhibiting a strong correlation (r>0.9) with the 5 principal radiomics. Biopsy samples were used to quantify ECS, myocardial fibrosis, and inflammation.

RESULTS: Four histopathological phenotypes were identified: low collagen (n=20), noncollagenous ECS expansion (n=49), mild to moderate collagenous ECS expansion (n=42), and severe collagenous ECS expansion (n=21). Noncollagenous expansion was associated with the highest risk of myocardial inflammation (65%). Although native T1 and ECV provided high diagnostic performance in differentiating severe fibrosis (C statistic, 0.90 and 0.90, respectively), their performance in differentiating between noncollagen and mild to moderate collagenous expansion decreased (C statistic: 0.59 and 0.55, respectively). Integration of ECV principal radiomics provided better discrimination and reclassification between noncollagen and mild to moderate collagen (C statistic, 0.79; net reclassification index, 0.83 [95% CI, 0.45-1.22]; P<0.001). There was a similar trend in the addition of native T1 principal radiomics (C statistic, 0.75; net reclassification index, 0.93 [95% CI, 0.56-1.29]; P<0.001) and LGE principal radiomics (C statistic, 0.74; net reclassification index, 0.59 [95% CI, 0.19-0.98]; P=0.004). Five radiomic features per sequence were identified with correlation analysis. They showed a similar improvement in performance for differentiating between noncollagen and mild to moderate collagen (native T1, ECV, LGE C statistic, 0.75, 0.77, and 0.71, respectively). These improvements remained significant when confined to a single radiomic feature (native T1, ECV, LGE C statistic, 0.71, 0.70, and 0.64, respectively).

CONCLUSIONS: Radiomic features extracted from native T1, ECV, and LGE provide incremental information that improves our capability to discriminate noncollagenous expansion from mild to moderate collagen and could be useful for detecting subtle chronic inflammation in patients with dilated cardiomyopathy.

INTRODUCTION: Metabolite signatures for blood pressure (BP) may reveal biomarkers, elucidate pathogenesis, and provide prevention targets for high BP. Knowledge regarding metabolites associated with BP in adolescence remains limited.

OBJECTIVES: Investigate the associations between metabolites and adolescent BP, both cross-sectionally (in early and late adolescence) and prospectively (from early to late adolescence).

METHODS: Participants are from the Project Viva prospective cohort. During the early (median: 12.8 years; N = 556) and late (median: 17.4 years; N = 501) adolescence visits, we conducted untargeted plasma metabolomic profiling and measured systolic (SBP) and diastolic BP (DBP). We used linear regression to identify metabolites cross-sectionally associated with BP at each time point, and to assess prospective associations of changes in metabolite levels from early to late adolescence with late adolescence BP. We used Weighted Gene Correlation Network Analysis and Spearman's partial correlation to identify metabolite clusters associated with BP at each time point.

RESULTS: In the linear models, higher androgenic steroid levels were consistently associated with higher SBP and DBP in early and late adolescence. A cluster of 59 metabolites, mainly composed of androgenic steroids, correlated with higher SBP and DBP in early adolescence. A cluster primarily composed of fatty acid lipids was marginally associated with higher SBP in females in late adolescence. Multiple metabolites, including those in the creatine and purine metabolism sub-pathways, were associated with higher SBP and DBP both cross-sectionally and prospectively.

CONCLUSION: Our results shed light on the potential metabolic processes and pathophysiology underlying high BP in adolescents.

INTRODUCTION: At mammography screening invitation, the Danish Health Authority recommends women aged 50 to 69 y make an informed decision about whether to be screened. Previous studies have shown that women have very positive attitudes about screening participation. Therefore, we hypothesized that Danish women may already have decided to participate in breast cancer screening prior to receiving their screening invitation at age 50 y.

METHODS: We invited a random sample of 2,952 Danish women aged 44 to 49 y (prescreening age) to complete an online questionnaire about barriers to informed screening decision making using the official digital mailbox system in Denmark. We asked participants about their screening intentions using 3 different questions to which women were randomized: screening presented 1) as an opportunity, 2) as a choice, and 3) as an opportunity plus a question about women's stage of decision making. All women completed questions about background characteristics, intended participation in the screening program, use and impact of screening information, and preferences for the decision-making process. Data were linked to sociodemographic register data.

RESULTS: A total of 790 (26.8%) women participated in the study. Herein, 97% (95% confidence interval: 96%-98%) reported that they wanted to participate in breast cancer screening when invited at age 50 y. When presented with the choice compared with the opportunity framing, more women rejected screening. When asked about their stage of decision making, most (87%) had already made a decision about screening participation and were unlikely to change their mind.

CONCLUSION: In our study, almost all women of prescreening age wanted to participate in breast cancer screening, suggesting that providing information at the time of screening invitation may be too late to support informed decision making.

HIGHLIGHTS: Almost all women of prescreening age (44-49 y) in our study wanted to participate in the Danish national mammography screening program starting at age 50 y.Early decision making represents a barrier for informed decision making as women in this study had intentions to participate in breast cancer screening prior to receiving an official screening invitation, and therefore, providing information at the time of screening invitation may be too late to support informed decision making.Very few women rejected screening participation; however, more women rejected screening when the information was framed as an active choice between having or declining breast cancer screening (continue with usual care) compared with presenting only the option of screening with no description of the alternative.Two-thirds of women reading the screening information in this study had unchanged attitudes toward screening after reading the presented information.

BACKGROUND: Metabolic syndrome is linked to an increased risk of incident cardiovascular disease (CVD) and all-cause mortality. Notable associations exist between hysterectomy with bilateral salpingo-oophorectomy and metabolic syndrome. However, there is emerging evidence that even with ovarian conservation, hysterectomy may be independently associated with long-term CVD risk.

OBJECTIVE: To examine the associations between hysterectomy with ovarian preservation and metabolic syndrome risk in a multi-ethnic cohort.

METHODS: We studied 3,367 female participants in the Multi-Ethnic Study of Atherosclerosis who had data on self-reported history of hysterectomy, oophorectomy, hystero-oophorectomy and metabolic syndrome at baseline (2000-2002). We used adjusted logistic regression to assess the cross-sectional associations between hysterectomy/oophorectomy subgroups and prevalent metabolic syndrome at baseline. Furthermore, we investigated 1,355 participants free of baseline metabolic syndrome and used adjusted Cox regression models to evaluate incident metabolic syndrome from exams 2 (2002-2004) to 6 (2016-2018).

RESULTS: The mean±SD age was 59.0±9.5 years, with 42% White, 27% Black, 19% Hispanic, and 13% Chinese American participants. 29% and 22% had a history of hysterectomy and oophorectomy, respectively. Over a median follow-up period of 10.5 (3.01-17.62) years, there were 750 metabolic syndrome events. Hysterectomy [HR, 1.32 (95%CI, 1.01-1.73)] and hystero-oophorectomy [1.40 (1.13-1.74)] were both strongly associated with incident metabolic syndrome compared to having neither hysterectomy or oophorectomy.

CONCLUSION: Hysterectomy, even with ovarian preservation, may be independently associated with a higher risk of metabolic syndrome. If other studies confirm these findings, screening and preventive strategies focused on females with ovary-sparing hysterectomy and the mechanisms underpinning these associations may be explored.

BACKGROUND: Guidelines recommend antihypertensive medication for adults with both stage 1 hypertension (systolic blood pressure, 130-139 mm Hg or diastolic blood pressure, 80-89 mm Hg) and 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥10%. Cardiac biomarkers could facilitate a more targeted approach to the treatment of stage 1 hypertension.

METHODS: We studied 1999 to 2004 National Health and Nutrition Examination Survey participants aged ≥20 years with untreated stage 1 hypertension without heart failure or ASCVD. hs-cTnI (high-sensitivity cardiac troponin I) and hs-cTnT (high-sensitivity cardiac troponin T) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) were measured in stored serum. We used the Pooled Cohort Equations to predict 10-year ASCVD risk. All participants had linked mortality follow-up through December 31, 2019.

RESULTS: Overall, 17.5% of US adults (32.2 million) had untreated stage 1 hypertension. Among these 32.2 million persons, 15.7% had ASCVD risk ≥10%, 5.6% had elevated hs-cTnI, 4.7% had elevated hs-cTnT, and 9.5% had elevated NT-proBNP. Among adults aged 65 to 79 years with untreated stage 1 hypertension, 80.5% had ASCVD risk ≥10%, 13.0% had elevated hs-cTnI, 15.2% had elevated hs-cTnT, and 29.4% had elevated NT-proBNP. Less than half of the adults aged ≥80 years with untreated stage 1 hypertension had elevated biomarkers. The cardiovascular disease mortality rates among all adults with untreated stage 1 hypertension and with either ASCVD risk ≥10%, elevated hs-cTnI, elevated hs-cTnT, or elevated NT-proBNP were 7.51, 7.74, 8.75, and 5.87 per 1000 person-years, respectively.

CONCLUSIONS: Cardiac biomarkers may be more selective for informing risk-based treatment decisions in stage 1 hypertension, particularly among adults aged ≥65 years.

Background: There is a yet unmet opportunity to utilize data on taxes and individual behaviors to yield insight for analyzing studies involving alcohol and cigarette use.Objectives: To inform the direction and strength of their mutual associations by leveraging the fact that taxation can affect individual consumption, but individual consumption cannot affect taxation.Methods: We linked state-level data on cigarette and beer taxes in 2009-2020 with individual-level data on self-reported current cigarette and alcohol use from the Behavioral Risk Factor Surveillance System, a telephone survey by the Centers for Disease Control and Prevention that is representative of the population of each state in the United States. We constructed linear and logistic models to examine associations between a $1 increase in cigarette taxes per pack and a $1 increase in beer taxes per gallon and self-reported cigarette use and alcohol consumption (assessed as any current intake, average drinks/day, heavy drinking, and binge drinking), adjusting for survey year and individual characteristics.Results: Among 2,968,839,352 respondents (49% male), a $1 increase in beer taxes was associated with .003 (95% confidence interval [CI] -.013, .008) fewer drinks/day and lower odds of any drinking (odds ratio [OR] = .81 95%CI .80, .83), heavy drinking (OR = .96 95%CI .93, .99), binge drinking (OR = .82 95%CI .80, .83), and smoking (OR = .98 95%CI .96, 1.00). In contrast, a $1 increase in cigarette taxes was associated with lower odds of smoking (OR = .94 95%CI .94, .95) but .007 (95%CI .005, .010) more drinks/day, and higher odds of any drinking (OR = 1.10 95%CI 1.10, 1.11), heavy drinking (OR = 1.02 95%CI 1.01, 1.02), and binge drinking (OR = .82 95%CI .80, .83).Conclusion: Higher beer taxes were associated with lower odds of drinking and smoking, but higher cigarette taxes were associated with lower odds of smoking and higher alcohol consumption. These results suggest that alcohol intake may be a determinant of cigarette use rather than cigarette use as a determinant of alcohol intake.

OBJECTIVE: Proteomics may discover pathophysiological changes related to hepatocellular carcinoma (HCC), an aggressive and lethal type of cancer with low sensitivity for early-stage diagnosis.

DESIGN: We measured 1,305 pre-diagnostic (median 12.7 years) SOMAscan proteins from 54 pairs of healthy individuals who subsequently developed HCC and matched non-HCC controls from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Candidate proteins were validated in the independent, prospective UK Biobank Pharma Proteomics Project (UKB-PPP).

RESULTS: In NHS/HPFS, we identified 56 elevated proteins in HCC with absolute fold-change >1.2 and Wald test P < .05 in conditional logistic regression analysis. Ingenuity Pathway Analysis identified enrichment of pathways associated with cell viability, adhesion, proteolysis, apoptosis, and inflammatory response. Four proteins, chitinase-3-like protein 1, growth/differentiation factor 15, interleukin-1 receptor antagonist protein, and E-selectin, showed strong positive associations with HCC and were thus validated by ELISA (odds ratio ranged 2.48-14.7, all P < .05) in the NHS/HPFS and by Olink platform (hazard ratio ranged 1.90-3.93, all P < .05) in the UKB-PPP. Adding these four proteins to a logistic regression model of traditional HCC risk factors increased the area under the curve (AUC) from 0.67 to 0.87 in the NHS/HPFS. Consistently, model AUC was 0.88 for HCC risk prediction in the UKB-PPP.

CONCLUSION: However, the limited number of HCC cases in the cohorts necessitates caution in interpreting our findings, emphasizing the need for further validation in high-risk populations.

In Vietnam and the Philippines, viral hepatitis is the leading cause of cirrhosis and liver cancer. This study aims to understand the barriers and enablers of people receiving care for hepatitis B and C to support both countries' efforts to eliminate viral hepatitis as a public health threat by 2030. Retrospective, semi-structured interviews were conducted with a purposive, quota-based sample of 63 people living with hepatitis B or C in one province of Vietnam and one region of the Philippines. A rapid deductive approach to thematic analysis produced key findings among the three phases of care: (1) pre-awareness and testing, (2) linkage and treatment initiation and (3) ongoing treatment and recovery. The research found that participants followed five typical journeys, from a variety of entry points. Barriers during the pre-awareness and testing phase included limited awareness about hepatitis and its management, stigma and psychological impacts. Enablers included being familiar with the health system and/or patients benefiting from social connections within the health systems. During the linkage and treatment initiation phase, barriers included difficult physical access, complex navigation and inadequate counselling. In this phase, family support emerged as a critical enabler. During the ongoing treatment and recovery phase, the cost of care and socially and culturally informed perceptions of the disease and medication use were both barriers and enablers. Exploring peoples' journeys with hepatitis B and C in Vietnam and the Philippines revealed many similarities despite the different cultural and health system contexts. Insights from this study may help generate a contextualized, people-centred evidence base to inform the design and improvement of primary care services for hepatitis in both research sites.