Self-reported Family History Research Articles

Pathogenic Germline Mutations of DNA Repair Pathway Components in Early-Onset Sporadic Colorectal Polyp and Cancer Patients.

Simple SummaryColorectal cancer (CRC) screening by immuno-fecal occult blood tests (iFOBTs) begins at age 50 in average-risk persons. However, the incidence of early-onset CRC has risen; of the cases, at least half are sporadic CRC without a family history. The authors of this study found a high percentage of de novo germline mutation in young sporadic CRC patients, as well as in sporadic colorectal polyp and control groups. All the mutated genes contribute to various DNA-repair pathways, hinting that a loss of genomic integrity play a crucial role in the development of CRC. The early identification of cancer-susceptible individuals by multigene panels in younger individuals who may be missed under current iFOBT screening could contribute to preventing CRC.Given recent increases in the proportion of early-onset colorectal cancer (CRC), researchers are urgently working to establish a multi-gene screening test for both inherited and sporadic cancer-susceptible individuals. However, the incidence and spectrum of germline mutations in young sporadic CRC patients in East Asian countries and, especially, in sporadic polyp carriers and normal individuals are unknown. Peripheral blood samples were collected from 43 colonoscopy-proved normal controls and from 50 polyp patients and 49 CRC patients with no self-reported family history of cancer. All participants were under 50 years old. Next-generation sequencing with a panel of 30 CRC-associated susceptibility genes was employed to detect pathogenic germline mutations. The germline mutation carrier rates were 2.3%, 4.0%, and 12.2% in the normal, polyp, and cancer groups, respectively. A total of seven different mutations in six DNA repair pathway-related genes (MLH1, BRCA1, BRCA2, CHEK2, BLM, and NTHL1) were detected in nine participants. One frameshift mutation in BRCA2 and one frameshift mutation in the CHEK2 gene were found in a normal control and two colorectal polyp patients, respectively. One young sporadic CRC patient carried two heterozygous mutations, one in MLH1 and one in BRCA1. Three mutations (MLH1 p.Arg265Cys, MLH1 p.Tyr343Ter and CHEK2 p.Ile158TyrfsTer10) were each found in two independent patients and were considered “founder” mutations. This is the first report to demonstrate high percentage of germline mutations in young sporadic colorectal polyp, CRC, and general populations. A multi-gene screening test is warranted for the proactive identification of cancer-predisposed individuals.

Family history is a predictor of current preterm birth

Reliable prediction of spontaneous preterm birth remains limited, particularly for nulliparous and multiparous women without a personal history of preterm birth. Although previous preterm birth is a risk factor for recurrent preterm birth, most spontaneous preterm births occur in women with no previous history of preterm birth. This study aimed to determine whether patients' self-reported maternal family history of preterm births among siblings and across 3 generations was an independent risk factor for spontaneous preterm births after controlling for potential confounders. This was a retrospective analysis of a prospectively acquired cohort using a comprehensive single, academic center database of deliveries from August 2011 to July 2017. The objective of the current analysis was to evaluate the risk of preterm birth among women with and without a family history of preterm birth. All subjects in the database were directly queried regarding familial history across 3 generations, inclusive of obstetrical morbidities. Index subjects with probable indicated preterm birth (eg, concurrent diagnosis of preeclampsia; hemolysis, elevated liver enzymes, and low platelet count; or placenta previa or placenta accreta) were excluded, as were nonsingleton pregnancies. Univariate and multivariate analyses with logistic regression were used to determine significance and adjusted relative risk. In this study, 23,816 deliveries were included, with 2345 (9.9%) born prematurely (<37 weeks' gestation). Across all subjects, preterm birth was significantly associated with a maternal family history of preterm birth by any definition (adjusted relative risk, 1.44; P<.001), and the fraction of preterm birth occurring in women with a positive family history increased with decreasing gestational age at which the index subjects of preterm birth occurred. For nulliparous women, a history in the subject's sister posed the greatest risk (adjusted relative risk, 2.25; P=.003), whereas for multiparous women with no previous preterm birth, overall family history was most informative (P=.003). Interestingly, a personal history of the index subject herself being born preterm presented the greatest individual risk factor (adjusted relative risk, 1.94; P=.004). Spontaneous preterm birth in the current pregnancy was significantly associated with a maternal family history of preterm birth among female relatives within 3 generations and notably sisters. The risk persisted among gravidae without a previous preterm birth, demonstrating the capacity for familial history to independently predict risk of spontaneous preterm birth even in the context of a negative personal history. This study provides evidence that self-reported maternal family history is relevant in a US population cohort and across more distant generations than has previously been reported.

Abstract 2319: Pan-cancer analysis of polygenic risk scores reveals improvement in risk prediction and stratification

Abstract Genome-wide association studies (GWAS) have identified a wealth of germline risk variants, but the clinical impact of these findings has been modest. In response, GWAS results have been used to create polygenic risk scores (PRS) that summarize an individual's genetic susceptibility profile. We assembled PRS for 16 cancers in the UK Biobank (n=413753, 52 to 4170 incident cases) to quantify the extent to which common, low-penetrance risk variants improve upon risk discrimination provided by family history and modifiable exposures. PRS were derived by abstracting variants with minor allele frequency ≥0.01 and P&amp;lt;5 × 10−8 from the literature and selecting independent (LD r2&amp;lt;0.3) variants with the smallest p-value. To account for uncertainty in the reported effect sizes (β), we combined risk alleles in the PRS using inverse variance weights: β/SE(β). Cancer-specific PRS, modifiable risk factors, and family history were modelled using Cox regression accounting for competing risks. All models were well-calibrated and each PRS was associated with the target cancer (P&amp;lt;0.01). Risk discrimination was assessed using Harrell's C-index between 1 and 5 years of follow-up time. An interesting initial observation was that replacing self-reported family history of cancer with the PRS improved prediction accuracy for prostate (C=0.763, ΔC=0.047), breast (C=0.618, ΔC=0.060), and colorectal (C=0.708, ΔC=0.029) cancers. Incorporating the PRS in addition to all risk factors available in our data resulted in substantial gains in risk discrimination for several cancer sites: testes (CPRS=0.766, ΔC=0.138), thyroid (CPRS=0.692, ΔC=0.099), leukemia (CPRS=0.756, ΔC=0.061), breast (CPRS=0.631, ΔC=0.060), prostate (CPRS=0.768, ΔC=0.051), melanoma (CPRS=0.664, ΔC=0.042), and colon/rectum (CPRS=0.716, ΔC=0.030). Next, we assessed risk stratification by examining 5-year absolute risk trajectories. Stratifying by percentiles of PRS (high: ≥80%, average: &amp;gt;20% to &amp;lt;80%, low: ≤20%) and modifiable risk factor profiles revealed significantly diverging risk trajectories (P&amp;lt;10−10) for 15 out of 16 cancers. There was also evidence of PRS-environment interaction, with larger than additive risk differences observed for melanoma (P=3.3 × 10−122), post-menopausal breast (P=1.3 × 10−21), colorectal (P=1.3 × 10−208), lung (P=1.1 × 10−37), bladder (P=1.5 × 10−50), and kidney (P=5.5 × 10−29) cancers. Lastly, we quantified the proportion of cancer risk at the population level that is attributed to genetic vs. modifiable risk factors. High genetic risk (PRS≥80th percentile) explained between 4.0% (lung) and 30.3% (testicular) of new cases. For many cancers the attributable fraction (AF) for PRS exceeded the AF for modifiable risk factors or family history: thyroid (AFPRS=0.268, P=1.7 × 10−9), prostate (AFPRS=0.232, P=5.5 × 10−158), colorectal (AFPRS=0.167, P=9.2 × 10−50), breast (AFPRS=0.166, P=2.6 × 10−85), and melanoma (AFPRS=0.139, P=1.3 × 10−23). PRS was the only significant contributor to cancer risk, other than age and sex, for testicular cancer (AFPRS=0.303, P=4.5 × 10−4), leukemia (AFPRS=0.269, P=4.5 × 10−4), and lung cancer in never smokers (AFPRS=0.077, P=0.045). In summary, we provide evidence from an independent validation cohort that supports the potential clinical utility of PRS in complementing conventional cancer risk factors to improve and refine risk prediction. Citation Format: Linda Kachuri, Rebecca E. Graff, Karl Smith-Byrne, Travis J. Meyers, Sara R. Rashkin, Elad Ziv, John S. Witte, Mattias Johansson. Pan-cancer analysis of polygenic risk scores reveals improvement in risk prediction and stratification [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2319.

Minority Stress and Cardiovascular Disease Risk Among Sexual Minorities: Mediating Effects of Sense of Mastery.

Sexual minority adults are at greater risk for cardiovascular disease (CVD) risk factors than heterosexual adults. There is a dearth of research identifying factors that are associated with CVD risk among sexual minorities. This study examined the associations between distal and proximal minority stressors and CVD risk. We also tested a sense of mastery as one mechanism that might explain the link between minority stressors and CVD risk. Participants were 670 sexual minority adults (53.6% male; 76% White), ages 18 to 76years (M = 41.19, SD = 14.73), obtained from a non-probability sample. Using an online survey, participants self-reported family history of CVD risk, physiological conditions (diabetes mellitus, high cholesterol, hypertension), and health behaviors (e.g., tobacco use, diet, exercise) that confer or protect against CVD risk. A weighted CVD risk index was computed. Linear and logistic regressions were conducted to test the effects of minority stressors on the CVD risk index and its specific indicators and to examine mediation. Minority stressors were associated with a sense of mastery, and mastery was associated with lower CVD risk index scores. Proximal and distal minority stressors were not directly associated with the overall CVD risk index but were associated with some specific risk indicators. Mediation analyses revealed that both distal and proximal minority stressors were indirectly associated with the CVD risk index through mastery. Research and interventions should aim to reduce CVD risk factors and target minority stressors and mastery to improve the cardiovascular health of sexual minorities.

The Evaluation of Retinal Nerve Fiber Layer and Ganglion Cell Complex Thickness in Adult Offspring of Primary Open-angle Glaucoma Patients.

In the adult offspring of glaucoma patients, retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thickness, especially in the inferior quadrant, were significantly decreased. This finding in the adult offspring of glaucoma patients may be important in evaluating the course of glaucoma disease. The aim of this study was to investigate RNFL and GCC thickness in adult offspring of primary open-angle glaucoma (POAG) patients and to compare the results with individuals without a family history for glaucoma disease. This was a cross-sectional observational study. Forty eyes of 40 individuals with self-reported family history for proven POAG and 40 eyes of 40 healthy individuals without a family history for glaucoma disease were included in the study. RNFL and macular GCC thickness were measured by spectral-domain optical coherence tomography, and the results were compared between the 2 groups. In adult offspring of patients with POAG, RNFL and GCC thickness were thinner in all quadrants. Average RNFL and GCC decreased significantly in adult offspring of patients with POAG (P=0.039 and 0.015, respectively). Thinning in RNFL and GCC thickness was especially significant in the inferior quadrant (P=0.024 and 0.039, respectively). There was no significant difference between the groups in terms of mean deviation and pattern standard deviation values (P=0.064 and 0.091, respectively). In adult offspring of POAG patients, especially in the inferior quadrant, the RNFL and GCC thickness are significantly lower than in subjects without a family history. Prospective, controlled clinical trials with longer follow-up are needed to better understand whether these changes are an early indicator of glaucoma, and the progression of glaucoma disease.

Family history of cardiovascular disease and risk of premature coronary heart disease: A matched case-control study.

Background: Self-reported family history of cardiovascular disease (CVD) is an independent risk factor for future coronary heart disease (CHD) events. However, inclusion of family history of CVD in the traditional risk scores failed to improve risk prediction of CHD. It is proposed that family history of CVD may substantially increase the risk of CHD among younger individuals. Methods: We conducted a matched case-control study with 170 hospital-based premature CHD patients (<55 years in men and <65 years in women) from a tertiary care centre in Thiruvananthapuram, Kerala and age and sex matched community-based controls in 1:1 ratio. Conditional logistic regression analysis was conducted to assess the independent association of family history of cardiovascular disease (CVD) and premature CHD. We estimated McNemar's odds ratios and their 95 percent confidence intervals. Results: The prevalence of any family history of CVD and CHD in the control population was 24% and 21%, respectively. The family history of CVD was independently associated with premature CHD (odds ratio (OR) = 9.0; 95% confidence interval (CI) 4.7-17.3). There was a dose-response relationship between family history and premature CHD as the risk increased linearly with increase in number of affected family members. Conclusions: Family history of CVD is an independent risk factor for premature CHD. The risk of premature CHD increases linearly with increase in number of affected family members. Collecting family history beyond parental history of CVD is important for risk stratification. Targeting young individuals with family history of CVD for intensive risk reduction interventions may help to prevent future events.

Family history of cardiovascular disease and risk of premature coronary heart disease: A matched case-control study

Background: Self-reported family history of cardiovascular disease (CVD) is an independent risk factor for future coronary heart disease (CHD) events. However, inclusion of family history of CVD in the traditional risk scores failed to improve risk prediction of CHD. It is proposed that family history of CVD may substantially increase the risk of CHD among younger individuals. Methods: We conducted a matched case-control study with 170 hospital-based premature CHD patients (<55 years in men and <65 years in women) from a tertiary care centre in Thiruvananthapuram, Kerala and age and sex matched community-based controls in 1:1 ratio. Conditional logistic regression analysis was conducted to assess the independent association of family history of cardiovascular disease (CVD) and premature CHD. We estimated McNemar's odds ratios and their 95 percent confidence intervals. Results: The prevalence of any family history of CVD and CHD in the control population was 24% and 21%, respectively. The family history of CVD was independently associated with premature CHD (odds ratio (OR) = 9.0; 95% confidence interval (CI) 4.7–17.3). There was a dose-response relationship between family history and premature CHD as the risk increased linearly with increase in number of affected family members. Conclusions: Family history of CVD is an independent risk factor for premature CHD. The risk of premature CHD increases linearly with increase in number of affected family members. Collecting family history beyond parental history of CVD is important for risk stratification. Targeting young individuals with family history of CVD for intensive risk reduction interventions may help to prevent future events.

Abstract C038: First- and second-degree family history of ovarian and breast cancers in relation to risk of invasive ovarian cancer in African American and White women

Abstract Background: Family history of ovarian and breast cancers is a well-established risk factor for ovarian cancer and recent findings suggest that the risk of ovarian cancer may be higher for African American (AA) women compared to other racial/ethnic groups. Few studies have been able to examine this association in both AA and White participants taking into account histotype. Methods: The Ovarian Cancer in Women of African Ancestry Consortium harmonized data from four case-control studies and two case-control studies nested within cohort studies. Each study collected self-reported first-degree family history of ovarian and breast cancers; the four case-control studies also collected self-reported data on second-degree family history of ovarian and breast cancers. For cases, data on age at diagnosis, tumor grade, and tumor histology were abstracted from medical records and cancer registry reports. Race-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multilevel logistic regression with control for covariates. Results: Our sample included 1,052 AA cases, 2,328 AA controls, 2,380 White cases, and 3,982 White controls. The prevalence of first-degree history of ovarian or breast cancer was higher among AA than White ovarian cancer cases (28% vs. 21%) and similar among AA and White controls (15% vs. 16%). The prevalence of second-degree family history of ovarian or breast cancer was similar among AA and White ovarian cancer cases (38% vs. 34%) and among AA and White controls (28% vs. 32%). First-degree family history of ovarian cancer was significantly associated with high-grade serous ovarian cancer in both AA (OR=2.33; 95% CI: 1.48, 3.69) and White participants (OR=2.86; 95% CI: 2.03, 4.02). In AA women, first-degree family history of breast cancer was associated with increased risk of high-grade serous ovarian cancer (OR=1.80; 95% CI: 1.38, 2.34) and all other histotypes combined (OR=1.62; 95% CI: 1.16, 2.25). In White women, first degree family history of breast cancer was associated with high-grade serous ovarian cancer only (OR=1.40; 95% CI: 1.16, 1.68). Second-degree family history of ovarian cancer was associated with high-grade serous ovarian cancer among White women (OR=1.95; 95% CI: 1.32, 2.90) and second-degree family history of breast cancer was associated with high-grade serous ovarian cancer in AA women (OR=1.48; 95% CI: 1.11, 1.98). Second-degree family history of ovarian or breast cancer was not associated with the other histotypes. Estimates across studies were compatible with overall estimates (pheterogeneity&amp;gt;0.05). Conclusion: First-degree family history of ovarian cancer may be more strongly associated with high-grade serous ovarian cancer than other histotypes in AA and White women. Second-degree family history of cancer may differ by race in the associations with ovarian cancer, but potential underreporting of second-degree family history and inability to account for family size limit interpretation of these data. Citation Format: Traci N. Bethea, Heather M. Ochs-Balcom, Elisa V. Bandera, Alicia Beeghly-Fadiel, Fabian Camancho, Emily K. Cloyd, Holly R. Harris, Charlotte E. Joslin, Evan Myers, Patricia G. Moorman, Lauren C. Peres, Veronica W. Setiawan, Anna H. Wu, Lynn Rosenberg, Joellen M. Schildkraut. First- and second-degree family history of ovarian and breast cancers in relation to risk of invasive ovarian cancer in African American and White women [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C038.

Low accuracy of self-reported family history of melanoma in high-risk patients.

Family history of melanoma is a major melanoma risk factor. However, self-reported family histories for some cancers, including melanoma, are commonly inaccurate. We used a unique database, the Utah Population Database (UPDB), as well as the Utah Cancer Registry to determine the accuracy of self-reported family history of melanoma in a large cohort of high-risk patients. Patient charts were reviewed and compared to records in the UPDB and the UCR to confirm personal and family history of melanoma in 1780 patients enrolled in a total body photography monitoring program. Self-reported family history of melanoma in first-degree relatives had an overall sensitivity of 71%, specificity of 79%, PPV of 31%, and NPV of 95%, with decreased accuracy (PPV) for second-degree relatives. A personal history of melanoma was the only factor significantly associated with accuracy in self-reported family history of melanoma. Patient age, sex, estimated nevus count, and number of prior personal melanomas were not significant predictors. Dermatologists should educate patients on the differences between melanomas, keratinocyte carcinomas, and pre-cancers. Confirming self-reported family history of melanoma may improve risk assessment for patients undergoing screening.

Comparison of germline mutations in African American and Caucasian men with metastatic prostate cancer.

5568 Background: The relevance of germline mutations in metastatic prostate cancer is well established; however, comparison of germline genetics in African American (AA) versus Caucasian (CA) men with metastatic prostate cancer (PCa) is limited. Methods: Germline data from self-identified AA and CA metastatic PCa patients (pts) were collected from 5 academic cancer centers. Various commercial cancer-specific germline testing panels were used to evaluate 12-86 genes. Pathogenic (P) or likely pathogenic (LP) mutations, and variants of unknown significance (VUS), were reported according to ACMG guidelines. Self-reported family history (FH) was annotated for 99% of pts. Statistical analyses included Chi-squared and Fischer’s exact tests. Results: A total of 821 metastatic PCa pts were assessed: 152 AAs and 669 CAs. For P/LP alterations, AAs had a frequency of 11.2% (17/152) as compared to a frequency of 14.6% (98/669) in CAs (p = 0.302). AA pts were more likely to have a VUS than CA pts, 61% vs 43% respectively (OR = 2.09, 95%CI [1.45, 2.99], p &lt; 0.001). BRCA mutations were similar between races, but AA were more likely to have a BRCA1 P/LP alteration (OR = 6.00, 95% CI [1.33, 27.09], p = 0.025). AA pts were less likely to have a P/LP alteration in a non-BRCA gene (OR = 0.34, 95% CI [0.15, 0.80], p = 0.013). Among DNA repair genes, there were no significant difference between AA and CA pts (p = 0.574); however, there was a trend toward AA pts having fewer P/LP alteration in a non-BRCA DNA repair genes (OR = 0.26, 95% CI [0.06, 1.08], p = 0.071). In pts with &gt;1 first degree relative (FDR) with ovarian cancer, P/LP germline alterations were more likely in CAs (OR = 2.33, 95% CI [1.05, 5.17], p = 0.043); but there were no significant differences in AAs (p = 0.098). Those with &gt;2 FDRs with PCa were more likely to have a P/LP change in CAs (OR = 2.32, 95% CI [1.04, 5.15], p = 0.043), but there were no difference in AAs (p = 0.700). In pts with ≥2 FDRs with breast cancer, P/LP germline alterations were more likely in both AAs (OR = 9.36, 95% CI [1.72, 50.84], p = 0.019) and CAs (OR = 3.92, 95% CI [1.79, 8.59], p = 0.001). Conclusions: We did not observe a difference in the overall frequency of germline P/LP alterations between AA and CA men with metastatic PCa but VUSs were more common in AA men. These AA men have an overall frequency of BRCA mutations similar to CA men; however, BRCA1 mutations were more prevalent in these AAs. Non-BRCA P/LP mutations are significantly less frequent in AA pts. A positive family history of &gt;2 FDRs with breast cancer was associated with P/LP alterations in both AA and CA pts.

Identifying Ashkenazi Jewish BRCA1/2 founder variants in individuals who do not self-report Jewish ancestry

Current guidelines recommend BRCA1 and BRCA2 genetic testing for individuals with a personal or family history of certain cancers. Three BRCA1/2 founder variants — 185delAG (c.68_69delAG), 5382insC (c.5266dupC), and 6174delT (c.5946delT) — are common in the Ashkenazi Jewish population. We characterized a cohort of more than 2,800 research participants in the 23andMe database who carry one or more of the three Ashkenazi Jewish founder variants, evaluating two characteristics that are typically used to recommend individuals for BRCA testing: self-reported Jewish ancestry and family history of breast, ovarian, prostate, or pancreatic cancer. Of the 1,967 carriers who provided self-reported ancestry information, 21% did not self-report Jewish ancestry; of these individuals, more than half (62%) do have detectable Ashkenazi Jewish genetic ancestry. In addition, of the 343 carriers who provided both ancestry and family history information, 44% did not have a first-degree family history of a BRCA-related cancer and, in the absence of a personal history of cancer, would therefore be unlikely to qualify for clinical genetic testing. These findings may help inform the discussion around broader access to BRCA genetic testing.

Differences in attitude toward prevention of suicide between nursing and medicine students: A study in Mexican population

The aim of the present study was to evaluate the attitude toward suicide prevention in medicine and nursing students attending University in south Mexico, considering their family and personal history of suicide. Demographic features and self-reported personal and family history of suicide were evaluated in 355 Mexican students at the Health Sciences School. Their views toward suicide prevention was assessed using the Attitude Toward Suicide Prevention scale. Comparisons between medicine and nursing students were performed, as well as between had or had-not previous personal or family history of suicide. Our results support that nursing students showed the most negative attitude toward suicide prevention. Therefore, training programs and strategies encouraging a better attitude in suicide prevention are necessary to be implemented. It is also necessary to consider cultural, ethnic and family backgrounds of the students/of the population when developing new strategies.

Family history of cardiovascular disease and risk of premature coronary heart disease: A matched case-control study

Background: Self-reported family history of cardiovascular disease (CVD) is an independent risk factor for future coronary heart disease (CHD) events. However, inclusion of family history of CVD in the traditional risk scores failed to improve risk prediction of CHD. It is proposed that family history of CVD may substantially increase the risk of CHD among younger individuals. Methods: We conducted a matched case-control study with 170 hospital-based premature CHD patients (&lt;55 years in men and &lt;65 years in women) from a tertiary care centre in Thiruvananthapuram, Kerala and age and sex matched community-based controls in 1:1 ratio. Conditional logistic regression analysis was conducted to assess the independent association of family history of cardiovascular disease (CVD) and premature CHD. We estimated McNemar's odds ratios and their 95 percent confidence intervals. Results: The prevalence of any family history of CVD and CHD in the control population was 24% and 21%, respectively. The family history of CVD was independently associated with premature CHD (odds ratio (OR) = 9.0; 95% confidence interval (CI) 4.7–17.3). There was a dose-response relationship between family history and premature CHD as the risk increased linearly with increase in number of affected family members. Conclusions: Family history of CVD is an independent risk factor for premature CHD. The risk of premature CHD increases linearly with increase in number of affected family members. Collecting family history beyond parental history of CVD is important for risk stratification. Targeting young individuals with family history of CVD for intensive risk reduction interventions may help to prevent future events.

Disruption of cholinergic neurotransmission, within a cognitive challenge paradigm, is indicative of A\u03b2-related cognitive impairment in preclinical Alzheimer\u2019s disease after a 27-month delay interval

BackgroundAbnormal beta-amyloid (Aβ) is associated with deleterious changes in central cholinergic tone in the very early stages of Alzheimer’s disease (AD), which may be unmasked by a cholinergic antagonist (J Prev Alzheimers Dis 1:1–4, 2017). Previously, we established the scopolamine challenge test (SCT) as a “cognitive stress test” screening measure to identify individuals at risk for AD (Alzheimer’s & Dementia 10(2):262–7, 2014) (Neurobiol. Aging 36(10):2709-15, 2015). Here we aim to demonstrate the potential of the SCT as an indicator of cognitive change and neocortical amyloid aggregation after a 27-month follow-up interval.MethodsOlder adults (N = 63, aged 55–75 years) with self-reported memory difficulties and first-degree family history of AD completed the SCT and PET amyloid imaging at baseline and were then seen for cognitive testing at 9, 18, and 27 months post-baseline. Repeat PET amyloid imaging was completed at the time of the 27-month exam.ResultsSignificant differences in both cognitive performance and in Aβ neocortical burden were observed between participants who either failed vs. passed the SCT at baseline, after a 27-month follow-up period.ConclusionsCognitive response to the SCT (Alzheimer’s & Dementia 10(2):262–7, 2014) at baseline is related to cognitive change and PET amyloid imaging results, over the course of 27 months, in preclinical AD. The SCT may be a clinically useful screening tool to identify individuals who are more likely to both have positive evidence of amyloidosis on PET imaging and to show measurable cognitive decline over several years.

Abstract P534: Is a Positive Family History of Cardiovascular Diseases Associated With Ideal Cardiovascular Health in the Community? The Polish Norwegian Study

Introduction: Self-reported family history of cardiovascular diseases (FHxCVD) is associated with an increased cardiovascular risk. In contrast to genetic profiling, FHxCVD has the advantage that it reflects not only genetic susceptibility, but also factors related to a shared environment and behaviors. Ideal cardiovascular health (ICVH) is a summary indicator of behavioral and major subsequent biological factors. FHxCVD is presumed to motivate the adoption of a healthy lifestyle, yet little evidence exists to support this hypothesis in a community setting. Hypothesis: We assessed the hypothesis that self-reported family history of cardiovascular diseases is associated with ICVH in a community based study. Methods: We used cross-sectional, baseline data of 10934 participants, age 45 to 64 years free of cardiovascular diseases in an ongoing cohort study (PONS). Data were collected through structured questionnaires and fasting blood samples. Ideal cardiovascular health was defined according to the American Heart Association criteria (7 metrics assessed at 3 levels: ideal, intermediate, and poor). FHxCVD was self-reported, based on three questions inquiring about coronary heart disease, stroke, hypertension in parents and siblings. We considered a positive FHxCVD if an affirmative answer to any of these three questions was reported. We used multivariable logistic models and adjusted for age, sex, education, place of residence, health care services. Results: The prevalence of poor CVH (0-2 ideal metrics) was 63% and of ideal CVH (6, 7 ideal metrics) was 0.07%. The prevalence of a positive FHxCVD was 77%. Mean (SD) for ICVH score was 2.20 (1.06), with no difference between those with positive and negative FHxCVD. A positive FHxCVD was associated with increased odds of a poor cardiovascular health (0-2 health components), OR (95%CI) 1.12 (1.01-1.23), after adjusting for age, sex, education, rural residence and health care services. Among participants with known history of hypertension, having a positive family history of HTN (but not of CHD or stroke) was associated with lower odds of having their blood pressure controlled (OR 0.83 , 95%CI 0.71-0.96), after multivariable adjustment. Conclusion: In this community-based study we found that self-reported FHxCVD is not accompanied by healthy behaviors. In spite of its personal value, simple knowledge of one’s FHxCVD may not suffice as motivator for lifestyle changes.

Abstract P2-12-08: Triaging breast care center patients to supportive care services based on the Athena Breast Health Network online intake form and the patient-reported outcomes measurement information system (PROMIS)

Abstract Background: The Athena Breast Health Network is a multi-site effort aimed at integrating cutting-edge research and clinical care for breast cancer screening and treatment. At the University of California, San Francisco (UCSF) Breast Care Center (BCC), an Athena-based electronic Health Questionnaire System (eHQS) is distributed to all new patients. This questionnaire assesses self-reported personal and familial health history, comorbidities, and Patient-Reported Outcome Measurement and Information System (PROMIS) quality of life domains. Based on these responses, patients are proactively triaged to genetic counseling, psycho-oncology, onco-fertility, smoking cessation, peer support, nutritional counseling, behavioral sleep, and social work. These referrals are based on pre-defined thresholds, such as Ashkenazi Jewish Ancestry (referral to Genetic Counseling), or PROMIS Depression and Anxiety scores greater than or equal to 9 and 11, respectively. This analysis aims to assess the eHQS as a means to refer patients to supportive care services and assess if high-need patients (those with the highest symptom burden as assessed by quality of life PROMIS scores) are referred to services more frequently. Patients and Methods: Since Athena’s launch in 2013, over 6,000 patients have completed the online intake questionnaire at the UCSF BCC, 4,984 of whom have consented to research. 3,627 patients completed all relevant data to this study and were used in our analysis. A review of patient referrals was conducted to assess the number of referrals as a result of eHQS completion. PROMIS T-Scores in 8 domains (depression, anxiety, fatigue, sleep-related impairment and disturbance, cognitive function, applied cognition and physical function) were calculated with the Health Measures system and compared across patients stratified by age and cancer type and against the US general population. Results: When compared to the US population as a whole, PROMIS scores indicate that UCSF BCC patients have impaired quality of life in every assessed PROMIS domain except for depression. As age increases, PROMIS scores across multiple domains (depression, anxiety, sleep disturbance, cognitive function) increase, signifying lower symptom burden. Importantly, high symptom burden in the anxiety PROMIS domain was suggestive of lower quality of life scores in 6 out of the other 7 assessed PROMIS domains. 39% (1408 patients) of all analyzed BCC patients received at least one referral to a supportive care service. 721 of 1450 (50%) patients with an Invasive Breast Cancer (IBC) diagnosis and 246 of 571 (43%) patients with a DCIS diagnosis triggered at least one referral. 31% of all patients received a referral to genetic counseling, 16.3% to psycho-oncology, 11% to behavioral sleep, 8% to nutritional counseling, 7.6% to social work, 2.4% to smoking cessation, and 1.6% to onco-fertility. When compared to patients with DCIS or without a cancer diagnosis, patients with IBC are most likely to receive a referral to genetic counseling and psychosocial services. Referrals to supportive care services are less frequent as age increases. Conclusion: The Athena online intake form at the UCSF BCC effectively triages patients with high levels of anxiety (PROMIS &amp;gt; 8) and depression (PROMIS &amp;gt;10) to supportive care services. Preliminary results regarding the correlation between anxiety and overall poor quality of life suggest that referrals to psycho-oncology may be most efficacious in decreasing symptom burden. Using these analyses, we aim to refine our use of the eHQS to tailor the most relevant and effective referrals to the highest-need patients. Citation Format: Madeline Matthys, André Dempsey, Amrita Basu, Emily Wong, Nickolas Dreher, Irene Acerbi, Suzanne Ackerson, Laura Esserman, Athena Breast Health Network Investigators and Advocate Partners, Michelle Melisko, Laura van 't Veer. Triaging breast care center patients to supportive care services based on the Athena Breast Health Network online intake form and the patient-reported outcomes measurement information system (PROMIS) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-12-08.

Hostility, depression and incident cardiac events in the GAZEL cohort

BackgroundPsychological factors such as hostility and depression have been associated with cardiovascular disease. However, their role in predicting incident cardiac events independently one of another is not clear. MethodsAmong 10,304 GAZEL middle-aged workers free of cardiovascular diseases in 1993, 581 incident cardiac events were validated from 1994–2014. Hostile traits (cognitive hostility, behavioral hostility, irritability and negativism) were assessed with the Buss and Durkee Hostility Inventory at baseline. Depressive symptoms were assessed at baseline and every three years with the Center for Epidemiological Studies Depression scale. We used Cox proportional hazards models to calculate hazard ratios (HR) of hostile traits for incident cardiac events adjusting for baseline self-reported socio-demographics and family history of coronary heart diseases (model 1), then additionally for time-dependent depressive symptoms (either as a binary or continuous variable) (model 2) and for yearly self-reported modifiable cardiovascular risk factors (physical activity, smoking, body mass index, diabetes, dyslipidemia and hypertension) (model 3). ResultsIn Model 1, the only hostile trait associated with incident cardiac events was irritability (HR for one interquartile range: 1.16, 95% confidence interval: 1.02–1.32). This association was no longer statistically significant when further adjusting for depressive symptoms. Depressive symptoms, in turn, remained significant predictors of cardiac events with HRs ranging from 1.40–1.49 (binary). LimitationsHostility traits were measured only once. ConclusionsDepressive symptoms might explain the association between irritability and cardiac events and should therefore be prioritized in interventions aiming to prevent cardiovascular disease. Further research is needed to identify the mechanisms underlying this association.

White matter connectometry among individuals with self-reported family history of drug and alcohol use disorders

Heredity is an important risk factor for alcoholism. Several studies have been conducted on small groups of alcohol naïve adolescents which show lowered fractional anisotropy of frontal white matter in individuals with a family history of alcohol and substance use disorder (FH+). We compare large adult FH+ and FH− groups using white matter connectometry, different from the previously used global tractography method, as it is more sensitive to regional variability. Imaging and behavioral data from the Human Connectome Project (WU-MINN HCP 1200) was analyzed. Groups of participants were positive (n = 109) and negative (n = 109) for self-reported alcohol and substance use disorders in at least one parent, and stringently matched. Connectometry was performed on diffusion MRI in DSI-Studio using q-space diffeomorphic reconstruction, and multiple regression was completed with 5000 permutations. Analyses showed decreased major tract (>40 mm) connectivity in the FH+ group in left inferior longitudinal fasciculus, bilateral cortico-striatal pathway, left cortico-thalamic pathway, and corpus callosum, compared to the FH− group. For cognitive tasks related to reward processing, inhibition, and monitoring, there were a number of interactions, such that the relationship between identified tracts and behavior differed significantly between groups. Self-reported family history was associated with decreased connectivity in reward signaling pathways, controlling for alcohol consumption and alcohol use disorder. This is the first connectometry study of FH+, and extends the neural basis of the hereditary diathesis of alcoholism beyond that demonstrated with global tractography. Regions associated with FH+ are similar to those associated with alcohol use disorder.

Self- Reported Personal and Family History of Cancers in Brunei Darussalam: Result of an Integrated Health Survey.

Introduction:Cancers remain an important cause of mortality and morbidity, and overall incidence of cancers continues to increase worldwide with some cancers increasing while others decreasing. Understanding the epidemiology of cancer burden is important for health care planning. Most studies to date have reported incidence based on cancer registry. This aim of this study is to report the incidence of self-reported personal and family history of cancers. Materials and Methods:Data on cancers were extracted from an anonymized database of a survey (Integrated Health Screening Survey) for civil servants conducted between 2008 and 2013 (N=21,437, mean age 40.61 ± 9.46 years old, men 45.1%). Results:The overall incidence of self-reported cancers was 11.2%; personal and family histories were 0.6% and 9.4% respectively (1.2% did not state if cancers were either personal or family history). Commonly self-reported personal history of cancers were cancer of the breast, cervix and colorectal and for self-reported family history were cancers of the gastrointestinal tract, pulmonary, breast, head/neck and gynecological system. Common associations were with first degree relatives (single parent affected 50.8%, both parents affected 1.8%, siblings affected 21.9% and parents and siblings affected 3.1%). Involvement of grandparents accounted for 13.4%. The numbers affected ranged from one to three family members. For self-reported personal history of cancers, older age and gender were significant on univariate analysis and remained on multivariate analyses (p<0.05). For self–reported family history of cancers, older age, gender, professionals employment and smoking status were significant on univariate analysis but only older age, gender, race and professional employments remained significant factors on multivariate analyses (p<0.05). Conclusions:Our study showed that more than one in nine of participants reported personal or family histories of cancers, and certain characteristics were predictive of self-reporting history of cancers. Associations of cancers were mainly with first degree relatives.

Race/Ethnicity and Accuracy of Self-Reported Female First-Degree Family History of Breast and Other Cancers in the Northern California Breast Cancer Family Registry.

Few studies have evaluated accuracy of self-reported family history of breast and other cancers in racial/ethnic minorities. We assessed the accuracy of cancer family history reports by women with breast cancer (probands) from the Northern California Breast Cancer Family Registry compared with 2 reference standards: personal cancer history reports by female first-degree relatives and California Cancer Registry records. Probands reported breast cancer in first-degree relatives with high accuracy, but accuracy was lower for other cancers. Sensitivity (percentage correctly identifying relatives with cancer) was 93% [95% confidence interval (CI), 89.5-95.4] when compared with the relatives' self-report of breast cancer as the reference standard and varied little by proband race/ethnicity and other demographic factors, except for marginally lower sensitivity for Hispanic white probands (87.3%; 95% CI, 78.0-93.1; P = 0.07) than non-Hispanic white probands (95.1%; 95% CI, 88.9-98.0). Accuracy was also high when compared with cancer registry records as the reference standard, with a sensitivity of 95.5% (95% CI, 93.4-96.9) for breast cancer, but lower sensitivity for Hispanic white probands (91.2%; 95% CI, 84.4-95.2; P = 0.05) and probands with low English language proficiency (80%; 95% CI, 52.8-93.5; P < 0.01). Non-Hispanic white, African American, and Asian American probands reported first-degree breast cancer family history with high accuracy, although sensitivity was lower for Hispanic white probands and those with low English language proficiency. Self-reported family history of breast cancer in first-degree relatives is highly accurate and can be used as a reliable standard when other validation methods are not available.