Self-reported Family History Research Articles

Interplay between family History and polygenic risk for coronary heart disease: a cohort study among over 60 thousand individuals

Abstract Background The degree to which background genetic risk adds to self-report of family history of coronary heart disease (CHD) remains an important question. Methods We utilized data from the multiethnic Genetic Epidemiology Resource in Adult Health and Aging (GERA) cohort of 60,070 Kaiser Permanente of Northern California (KPNC) members (mean ± SD age=59 ± 9 years; 67% female; 18% non-white). We characterized the cohort at baseline in 2003-2007. Excluding those with missing self-report of family history of CHD (n=1,718) resulted in a final sample of 61,352. We stratified the cohort into not having (n=42,866; 70%) and having (n=18,486; 30%) self-reported family history of CHD and then (within stratum of family history of CHD) by three groups of CHD polygenic risk (low: quintile 1; intermediate: quintiles 2, 3 and 4 combined; and high: quintile 5) using a validated 12-SNP polygenic risk score (PRS) for CHD (CARDIO inCode-Score®). Incident CHD was based on ICD-9/10 codes for angina pectoris, myocardial infarction, revascularization procedures or CHD death (n=3,040) through 12/31/2022; mean follow-up was 14.5 years. Results Age-adjusted CHD incidence rates per 10,000 person years were estimated using Poisson regression (accounting for death and health plan disenrollment) by absence/presence of family history of CHD and polygenic risk groups. As shown in the Figure, polygenic risk provided additional risk stratification within categories of family history. The hazard ratio of high PRS (vs low PRS) adjusted for age, sex, 10 principal components of ancestry, smoking, body mass index, diabetes, hypertension, total cholesterol/HDL ratio and cholesterol lowering therapy was 1.62 (95% CI, 1.39-1.87; p<0.001) in those with no family history of CHD, and 1.66 (95% CI, 1.37-2.00; p<0.001) in those with family history of CHD (p-interaction PRS continuous*family history of CHD=0.93). Conclusions Our results show that polygenic risk predicts future CHD regardless of the presence of family history of CHD. Thus, it is not enough to rely of family history to fully characterize potential genetic burden. These data are therefore important for the future of precision medicine.

Abstract B090: Assessing the relationship between family history of cancer and self-perceived cancer risk among Black adults in the United States

Abstract Introduction: Cancer family history is a risk factor for multiple cancer types. Knowing and sharing cancer family history can help inform cancer screening and genetic testing which ultimately aids in cancer prevention and early detection. There is limited knowledge about how people with cancer family history appraise their own risk of developing cancer which may influence screening and preventive behaviors, particularly among marginalized populations like Black adults. The objective of this study was to conduct a community-engaged survey to assess the relationship between self-reported cancer family history and perceived risk of developing cancer among Black adults. Methods: Using community-based recruitment methods in partnership with national Black-led organizations we conducted an online survey on cancer family history in Black communities. Individuals could participate if they self-identified as Black or African-American, were 18 or older, resided in the US, and could complete a survey in English. In the survey, participants were asked if members of their immediate families had ever been diagnosed with cancer, and if so which family members. Participant responses were categorized into: No family history, 1 family member with cancer history, 2+ family members with cancer history. Participants without a personal history of cancer were asked “On a scale of 0 to 100, what do you think your chances are of getting cancer? (0 = no chance of getting cancer and 100 = you will definitely get cancer)”, and to rate their level of agreement with the following statement “I feel I will get cancer sometime during my life.” Chi-squared and Kruskal-Wallis tests were used to assess the relationship between the number of family members with cancer and self-perceived cancer risk. Results: Overall, 100 participants from 17 states responded to the survey. Among participants, 93% were women, 84% had a bachelor’s degree or higher, and 16% reported a personal history of cancer. In total, 20% (n=20) reported no cancer family history, 30% (n=30) reported 1 family member with cancer, and 50% (n=50) reported 2 or more relatives with cancer. The mean perceived chance of developing cancer was 41.3% (95% CI: 33.6, 49.0) among people with no family history of cancer, 29.0% (95% CI: 22.2%, 35.6%) among people with one relative with cancer, and 48.2% (95% CI: 42.1, 54.2) among people with multiple relatives with a cancer history (p=0.0002). In addition, 17.6% of people with no family history, 0% with 1 relative family history, and 16.7% with 2 or more relative cancer family history somewhat or strongly agreed to the statement , “I feel I will get cancer sometime during my life,” (p=0.001). Conclusion: In this community-partnered survey of a diverse Black US adults, there was an association between number of family members with a cancer history and self-perceived risk of developing cancer. Understanding the appraisal of perceived cancer risk by level of cancer family history in Black adults could help inform targeted cancer prevention and early detection interventions. Citation Format: Mya L. Roberson, Laura Crandon, Jordyn A. Brown, Jordan Speller, Monique Gary. Assessing the relationship between family history of cancer and self-perceived cancer risk among Black adults in the United States [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B090.

Family history of arthritis, osteoporosis, and carpal tunnel syndrome and risk of these conditions among U.S. adults.

The aim was to estimate odds ratios of associations between family history of arthritis, osteoporosis, and carpal tunnel syndrome and prevalence in a real-world population, uncovering family histories of related conditions that may increase risk due to shared heritability, condition pathophysiology, or social/environmental factors. Using data from 156,307 participants in the All of Us (AoU) Research Program, we examined associations between self-reported first-degree family history of 5 common types of arthritis (fibromyalgia, gout, osteoarthritis (OA), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE)), osteoporosis, and carpal tunnel syndrome and prevalence. We evaluate associations across 7 conditions and performed stratified analyses by race and ethnicity, sex, socioeconomic differences, body mass index, and type of affected relative. Over 38% of AoU participants reported a family history of any arthritis, osteoporosis, or carpal tunnel syndrome. Adults with a family history of any arthritis, osteoporosis, and carpal tunnel syndrome exhibited 3.68 to 7.59 (4.90, on average) odds of having the same condition, and 0.70 to 2.10 (1.24, on average) odds of having a different condition. The strongest associations observed were between family history of OA and prevalence of OA (OR 7.59, 95%CI 7.32-7.88), and family history of SLE and prevalence of SLE (OR 6.34, 95%CI 5.17-7.74). We additionally uncover race and ethnicity and sex disparities in family history associations. Family history of several related conditions was associated with increased risk for arthritis, osteoporosis, and carpal tunnel syndrome, underscoring the importance of family history of related conditions for primary prevention.

Race adjustments in clinical algorithms can help correct for racial disparities in data quality

Despite ethical and historical arguments for removing race from clinical algorithms, the consequences of removal remain unclear. Here, we highlight a largely undiscussed consideration in this debate: varying data quality of input features across race groups. For example, family history of cancer is an essential predictor in cancer risk prediction algorithms but is less reliably documented for Black participants and may therefore be less predictive of cancer outcomes. Using data from the Southern Community Cohort Study, we assessed whether race adjustments could allow risk prediction models to capture varying data quality by race, focusing on colorectal cancer risk prediction. We analyzed 77,836 adults with no history of colorectal cancer at baseline. The predictive value of self-reported family history was greater for White participants than for Black participants. We compared two cancer risk prediction algorithms-a race-blind algorithm which included standard colorectal cancer risk factors but not race, and a race-adjusted algorithm which additionally included race. Relative to the race-blind algorithm, the race-adjusted algorithm improved predictive performance, as measured by goodness of fit in a likelihood ratio test (P-value: <0.001) and area under the receiving operating characteristic curve among Black participants (P-value: 0.006). Because the race-blind algorithm underpredicted risk for Black participants, the race-adjusted algorithm increased the fraction of Black participants among the predicted high-risk group, potentially increasing access to screening. More broadly, this study shows that race adjustments may be beneficial when the data quality of key predictors in clinical algorithms differs by race group.

Risk of Cardiovascular Disease Hospitalization After Common Psychiatric Disorders: Analyses of Disease Susceptibility and Progression Trajectory in the UK Biobank

AbstractWhether associations between psychiatric disorders and hospitalization for cardiovascular diseases (CVDs) can be modified by disease susceptibility and the temporal pattern of these associated CVDs remain unknown. In our study, we conducted a matched cohort study of the UK Biobank including 44,430 patients with common psychiatric disorders (anxiety, depression, and stress-related disorders) between 1997 and 2019, together with 222,150 sex-, Townsend deprivation index-, and birth year- individually matched unexposed individuals. The hazard ratios (HRs) for CVD hospitalization associated with a prior psychiatric disorder were derived from Cox models, adjusted for multiple confounders. We then stratified the analyses by self-reported family history of CVD and CVD polygenic risk score (PRS) calculated based on summary statistics of independent genome-wide association studies. We further conducted disease trajectory analysis and visualized the temporal pattern of CVDs after common psychiatric disorders. During a mean follow-up of 12.28 years, we observed an elevated risk of CVD hospitalization among patients with psychiatric disorders, compared with matched unexposed individuals (hazard ratios [HRs] = 1.20, 95% confidence interval [CI]: 1.18–1.23), especially during the first six months of follow-up (1.72 [1.55–1.91]). The stratification analyses by family history of CVD and by CVD PRS obtained similar estimates between subgroups with different susceptibilities to CVD. We conducted trajectory analysis to visualize the temporal pattern of CVDs after common psychiatric disorders, identifying primary hypertension, acute myocardial infarction, and stroke as three main intermediate steps leading to further increased risk of other CVDs. In conclusion, the association between common psychiatric disorders and subsequent CVD hospitalization is not modified by predisposition to CVD. Hypertension, acute myocardial infarction, and stroke are three initial CVDs linking psychiatric disorders to other CVD sequelae, highlighting a need of timely intervention on these targets to prevent further CVD sequelae among all individuals with common psychiatric disorders.

Using polygenic scores in combination with symptom rating scales to identify attention-deficit/hyperactivity disorder

BackgroundThe inclusion of biomarkers could improve diagnostic accuracy of attention-deficit/hyperactivity disorder (ADHD). One potential biomarker is the ADHD polygenic score (PGS), a measure of genetic liability for ADHD. This study aimed to investigate if the ADHD PGS can provide additional information alongside ADHD rating scales and examination of family history of ADHD to distinguish between ADHD cases and controls.MethodsPolygenic scores were calculated for 576 adults with ADHD and 530 ethnically matched controls. ADHD PGS was used alongside scores from the Wender-Utah Rating Scale (WURS) and the Adult ADHD Self-Report Scale (ASRS) as predictors of ADHD diagnosis in a set of nested logistic regression models. These models were compared by likelihood ratio (LR) tests, Akaike information criterion corrected for small samples (AICc), and Lee R². These analyses were repeated with family history of ADHD as a covariate in all models.ResultsThe ADHD PGS increased the variance explained of the ASRS by 0.58% points (pp) (R2ASRS = 61.11%, R2ASRS + PGS=61.69%), the WURS by 0.61pp (R2WURS = 77.33%, R2WURS + PGS= 77.94%), of ASRS and WURS together by 0.57pp (R2ASRS + WURS=80.84%, R2ASRS + WURS+PGS=81.40%), and of self-reported family history by 1.40pp (R2family = 28.06%, R2family + PGS=29.46%). These increases were statistically significant, as measured by LR tests and AICc.ConclusionWe found that the ADHD PGS contributed additional information to common diagnostic aids. However, the increase in variance explained was small, suggesting that the ADHD PGS is currently not a clinically useful diagnostic aid. Future studies should examine the utility of ADHD PGS in ADHD prediction alongside non-genetic risk factors, and the diagnostic utility of the ADHD PGS should be evaluated as more genetic data is accumulated and computational tools are further refined.

The accuracy of self-reported family history in glaucoma in Brazil.

To evaluate the accuracy of a positive self-reported glaucoma family history. Cross-sectional study. Each subject was asked if they had a first-degree relative diagnosed with glaucoma. If their answer was affirmative, the relative was invited to attend on ophthalmic evaluation and underwent complementary exams to confirm or exclude the glaucoma diagnosis. Only one relative was included per subject. We included 204 subjects in the study (102 subjects and their respective relatives). The accuracy of family history of glaucoma was 76.96% of the cases. In the univariable analysis, subjects with college degree had 2.34 [(P = 0.010; 95% confidence interval (CI) 1.18-4.63)], with higher family income 3.72 (P = 0.003; 95% CI 1.57-8.85) and those with health insurance 3.42 (P = 0.001; 95% CI 1.67-6.98) more chances to have a true positive family history for glaucoma. In the multivariable logistic regression analysis, none of the variables presented significant association. Around 24% of patients may not provide reliable information about family history for glaucoma. When asking about a glaucoma family history, clinicians should consider the real accuracy of this self-reported data.

Predictive models as a clinical decision support tool for genetic cancer risk assessment among Mexican patients at risk of hereditary colorectal cancer.

10617 Background: Hereditary cancer syndromes, including Lynch syndrome (LS) with an increased risk of colorectal cancer (CRC), have prompted the development of clinical criteria and predictive models (PM) to identify at-risk individuals. However, these criteria have been validated with limited representation from the Latino population. Several factors may influence CRC penetrance, potentially leading to variations in PM performance across populations. Given that CRC ranks as the third most prevalent cancer worldwide, the increasing incidence of early-onset disease highlights the need for expanding Genetic Cancer Risk Assessment (GCRA) services. Methods: This prospective study included Mexican patients who were diagnosed with CRC and met NCCN criteria for GCRA. Participants were enrolled at two referral centers in Mexico, the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City and at the Hospital Zambrano Hellion TecSalud, Nuevo Leon. Participants' carrier risk was estimated using the PREMM5 model. Amsterdam II and revised Bethesda criteria, immunohistochemistry (IHC) for DNA mismatch repair (MMR) proteins in tumor tissue and multigene panel testing results were reviewed. For this analysis, only pathogenic and likely pathogenic (P/LP) variants in probands were reported. Results: From April 2016 to October 2023, 194 patients were included, with a median age at diagnosis of 45.0 (range 17-82) years, and 49.5% were women. P/LP variants were identified in 37.6% (n=73). 27.5% (n=50) were carriers of P/LP variants associated with LS (29 MLH1, 13 MSH2, 6 MSH6, and 2 PMS2). 11.8% (n=23) were carriers of P/LP variants in other genes (7 APC, 4 ATM, 3 CHEK2, 2 BRCA1, 2 TP53, 2 STK11, 1 PALB2, 1 BRIP1, and 1 MUTYH). Overall, carriers of PVs were diagnosed with CRC at a younger age than non-carriers (42 vs 46 years, p=0.034). The Amsterdam II criteria proved to be accurate (Sen 55%, Spe 91%, PPV 0.69, NPV 0.85), while the Bethesda criteria (Sen 98%, Spe 18%, PPV 0.29, NPV 0.96) and IHC for MMR proteins (Sen 94%, Spe 67%, PPV 0.61, NPV 0.95) were found to be highly sensitive. The area under the ROC curve for PREMM5 was 0.82 with a mean score 28.5 (2.1 – 50) in patients with LS and 6.0 (0.9 – 50) in non-carriers. Carriers of PVs had a higher rate of multiple primary malignancies than non-carriers (41.0% vs 19.0%, p=0.0014), and self-reported family history of CRC (65.7% vs 24.8%, p&lt;0.001). Conclusions: Our results showed the PREMM5 model and IHC for MMR proteins effectively prioritized patients eligible for germline genetic testing in resource-limited settings. The performance of PREMM5 in this Mexican cohort was similar to that reported in the validation study of this model in other populations. Considering the spectrum of identified P/LP variants, the multigene panel test should be used in the comprehensive evaluation of Mexican patients with CRC.

Utilisation of the health belief model to study the behavioural intentions relating to obesity management among university students: a cross-sectional study

BackgroundOverweight and obesity are excessive fat accumulations linked with many health problems, including heart diseases, type 2 diabetes and cancer. Multiple studies have demonstrated that beliefs about overweight, obesity and...

Non-syndromic supernumerary teeth and association with aself-reported family history of cancer.

Supernumerary teeth are an alteration of dental developmental and result in the formation of teeth above the usual number. Epidemiologic studies suggested that patients with dentofacial anomalies and their family members may present an increased risk of developing cancer, including female breast cancer and gynecologic cancers. These observations indicate that genetic alterations that result in dental anomalies may be related to cancer development. Thus, the aim of the present study was to evaluate the association between supernumerary teeth and afamily history of female breast cancer and gynecologic cancers. The diagnosis of supernumerary teeth was based on clinical and radiographic examinations. For data collection, aquestionnaire asking for information regarding ethnicity, age, gender, and self-reported family history of cancer up to the second generation was used. Statistical analysis was performed using the Χ2 test and Fisher's exact test with an established α of 5%. Atotal of 344 patients were included; 47 of them had one or more non-syndromic supernumerary teeth (not associated with any syndrome or cleft lip and palate) and 297 were control patients. Age, ethnicity, and gender distribution were not statistically different between the group with supernumerary teeth and the control group (p > 0.05). The supernumerary teeth were most commonly observed in the incisors area. Breast cancer (n = 17) was the most commonly self-reported type of cancer, followed by uterine cervical (n = 10), endometrial (n = 2), and ovarian (n = 1) cancers. Endometrial cancer was significantly associated with the diagnosis of supernumerary teeth (p = 0.017). This study suggests that patients with supernumerary teeth possess ahigher risk of having family members with endometrial cancer.

Association Between a First-Degree Family History and Self-Reported Personal History of Obesity, Diabetes, and Heart and Blood Conditions: Results From the All of Us Research Program.

Family history reflects the complex interplay of genetic susceptibility and shared environmental exposures and is an important risk factor for obesity, diabetes, and heart and blood conditions (ODHB). However, the overlap in family history associations between various ODHBs has not been quantified. We assessed the association between a self-reported family history of ODHBs and their risk in the adult population (age ≥20 years) of the AoU (All of Us) Research Program, a longitudinal cohort study of diverse participants across the United States. We conducted a family history-wide association study to systematically assess the association of a first-degree family history of 15 ODHBs in AoU. We performed stratified analyses based on racial and ethnic categories, education, household income and gender minority status, and quantified associations by type of affected relatives. Of 125 430 participants, 76.8% reported a first-degree family history of any ODHB, most commonly hypertension (n=64 982, 51.8%), high cholesterol (49 753, 39.7%), and heart attack (29 618, 23.6%). We use the FamWAS method to estimate 225 familial associations among 15 ODHBs. The results include overlapping associations between family history of different types of cardiometabolic conditions (such as type 2 diabetes and coronary artery disease), and their risk factors (obesity, hypertension), where adults with a family history of 1 ODHB exhibited 1.1 to 5.6 times (1.5, on average) the odds of having a different ODHB. Our findings inform the utility of family history data as a risk assessment and screening tool for the prevention of ODHBs and to provide additional insights into shared risk factors and pathogenic mechanisms.

Incorporating a polygenic risk score into cardiovascular disease examinations to identify subclinical coronary artery disease: rationale and design of the ESCALATE trial

Abstract Background Identifying and targeting established modifiable risk factors such as hyperlipidaemia, blood pressure, smoking, and diabetes have led to a successful reduction in poor outcomes from coronary artery disease (CAD) at the population-level. However, up to one-in-four patients who present with ST elevation myocardial infarction do so in the absence of such risk factors. There is a significant unmet need for new diagnostic strategies independent of these factors to detect CAD in its subclinical phase. Polygenic risk scores (PRS) have demonstrated an ability in cohort studies to improve risk prediction models independent of traditional risk factors and self-reported family history. However, there is a lack of data from implementation and interventional studies demonstrating efficacy, participant and provider experience, and cost effectiveness of utilising PRS. Aim The aim of this study is to examine the incorporation of a CAD PRS during primary care-based cardiovascular disease (CVD) risk assessments to identify low or intermediate risk individuals with newly diagnosed CAD and subsequent impact on shared treatment decisions, participant experience, and provider experience. Our hypothesis is that incorporating a CAD PRS-based decision tool for a coronary calcium scan into CVD risk assessments will identify new, potentially missed individuals with subclinical CAD. Methods The ESCALATE study is a 12-month, prospective, multi-centre implementation study incorporating CAD PRS into otherwise standard primary care CVD risk assessments, identifying patients at increased lifetime CAD risk, for non-invasive CT coronary imaging. 1,000 eligible participants aged 45-65 years old will enter the PPP-CAD Diagnostic Pathway, which applies CAD PRS to those considered low or moderate 5-year absolute CVD risk based on traditional risk factors and triages those with CAD PRS ≥80% for a coronary calcium scan (Figure 1). The primary outcome will be the identification of subclinical CAD, defined as a coronary artery calcium score (CACS) &amp;gt;0 Agatston units (AU). Multiple secondary outcomes will be assessed, including baseline CACS ≥100 AU or ≥75th age-/sex-matched percentile, medical management strategies, cholesterol and blood pressure levels, health-related quality of life (HRQOL), and patient experience. Results Study recruitment was initiated recruitment in August 2022 and is actively recruiting across Australia. 298 participants have been enrolled as of 27th February 2022. Conclusion The ESCALATE study is the first prospectively registered clinical trial testing the ability of a CAD PRS to: a) identify individuals with subclinical CAD by non-invasive coronary imaging; and b) measure the impact of this diagnostic strategy on personalised diagnosis and shared decision-making. The top-line study results are expected in mid-2025.

41 Examining the independent and additive effects of family history of dementia and apolipoprotein e4 on neurocognitive performance among people with HIV

Objective:Among people with HIV (PWH), the apolipoprotein e4 (APOE-e4) allele, a genetic marker associated with Alzheimer’s disease (AD), and self-reported family history of dementia (FHD), considered a proxy for higher AD genetic risk, are independently associated with worse neurocognition. However, research has not addressed the potential additive effect of FHD and APOE-e4 on global and domain-specific neurocognition among PWH. Thus, the aim of the current investigation is to examine the associations between FHD, APOE-e4, and neurocognition among PWH.Participants and Methods:283 PWH (Mage=50.9; SDage=5.6) from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study completed comprehensive neuropsychological and neuromedical evaluations and underwent APOE genotyping. APOE status was dichotomized into APOE-e4+ and APOE-e4-. APOE-e4+ status included heterozygous and homozygous carriers. Participants completed a free-response question capturing FHD of a first- or second-degree relative (i.e., biologic parent, sibling, children, grandparent, grandchild, uncle, aunt, nephew, niece, half-sibling). A dichotomized (yes/no), FHD variable was used in analyses. Neurocognition was measured using global and domain-specific demographically corrected (i.e., age, education, sex, race/ethnicity) T-scores. t-tests were used to compare global and domain-specific demographically-corrected T-scores by FHD status and APOE-e4 status. A 2x2 factorial analysis of variance (ANOVA) was used to model the interactive effects of FHD and APOE-e4 status. Tukey’s HSD test was used to follow-up on significant ANOVAs.Results:Results revealed significant differences by FHD status in executive functioning (t(281)=-2.3, p=0.03) and motor skills (t(278)=-2.0, p=0.03) such that FHD+ performed worse compared to FHD-. Differences in global neurocognition by FHD status approached significance (t(281)=-1.8, p=.069). Global and domain-specific neurocognitive performance were comparable among APOE-e4 carriers and noncarriers (ps&gt;0.05). Results evaluating the interactive effects of FHD and APOE-e4 showed significant differences in motor skills (F(3)=2.7, p=0.04) between the FHD-/APOE-e4+ and FHD+/APOE-e4- groups such that the FHD+/APOE-e4- performed worse than the FHD-/APOE-e4+ group (p=0.02).Conclusions:PWH with FHD exhibited worse neurocognitive performance within the domains of executive functioning and motor skills, however, there were no significant differences in neurocognition between APOE-e4 carriers and noncarriers. Furthermore, global neurocognitive performance was comparable across FHD/APOE-e4 groups. Differences between the FHD-/APOE-e4+ and FHD+/APOE-e4- groups in motor skills were likely driven by FHD status, considering there were no independent effects of APOE-e4 status. This suggests that FHD may be a predispositional risk factor for poor neurocognitive performance among PWH. Considering FHD is easily captured through self-report, compared to blood based APOE-e4 status, PWH with FHD should be more closely monitored. Future research is warranted to address the potential additive effect of FHD and APOE-e4 on rates of global and domain-specific neurocognitive decline and impairment over time among in an older cohort of PWH, where APOE-e4 status may have stronger effects.

OR34-03 Defining Clinical Characteristics Of Patients With Severe Hypoglycemia After Roux-en-Y Gastric Bypass: How Do They Differ From Asymptomatic Patients?

Abstract Disclosure: A. Grover: None. A.L. Sheehan: None. C. Cummings: None. M. Farahmandsadr: None. H. Saeed: None. A.M. Puleio: None. D.C. Simonson: Stock Owner; Self; Phase V Technologies, GI Windows. M. Patti: Consulting Fee; Self; AstraZeneca, MBX-Biosciences, Hanmi Pharmaceutical. Other; Self; DSMB: Fractyl Health, Inc. Introduction: Post-bariatric hypoglycemia (PBH) is a severe, disabling complication of Roux-en-Y gastric bypass (RYGB). We aimed to identify clinical characteristics distinguishing patients with severe PBH vs. post-RYGB patients without symptomatic hypoglycemia (RYGB non-hypo) to help elucidate PBH pathophysiology and potential risk factors. Methods: Adults aged 18-70, without diabetes mellitus (DM), were recruited into 3 groups: (1) PBH with neuroglycopenia (n=33); (2) RYGB non-hypo (n=16); (3) non-surgical weight-matched controls (n=17). Detailed history of hypoglycemia, medical/surgical/family history, medications, Dumping Symptom Rating Scale (DSRS), and Rome IV diagnostic criteria for Irritable Bowel Syndrome (IBS) was completed. Differences between PBH and RYGB non-hypo were evaluated by unpaired t-tests and chi-square analysis as indicated. Results: PBH participants were 90% female, mean age 53±2 y, BMI 32±1 kg/m2, 39±2% body fat, with similar data for RYGB non-hypo (100% female, age 54±2 y, BMI 33±2 kg/m2, 40±2% fat), and controls (65% female, age 45±4 y, BMI 31±2 kg/m2, 35±3% fat). 90% of PBH reported level 3 hypoglycemia, with ER visits in 29% and motor vehicle accidents in 7%. Reduced awareness of hypoglycemia was reported by 80% of PBH, with hypoglycemia awareness at mean glucose of 57±2 mg/dL. 29% of PBH reported hypoglycemic symptoms occurring preoperatively, and 20% reported family history of hypoglycemia. The majority of PBH reported depression, change in driving habits, and adverse impact on employment. When compared with RYGB non-hypo, PBH participants had no difference in postoperative weight loss trajectories but had higher prevalence of revisional surgeries (p&amp;lt;0.05). PBH participants also had a higher score on DSRS (p&amp;lt;0.05) and higher prevalence of IBS (48 vs. 7% meeting Rome IV criteria, p&amp;lt;0.05). Higher rates of orthostatic hypotension, intestinal dysmotility, and vitamin B12 deficiency requiring treatment were reported by PBH (p&amp;lt;0.05 for all). Additionally, PBH participants reported greater gabapentin, PPI, and hormonal contraceptive use (p&amp;lt;0.05 for all); there were no differences in SSRI/SNRI use. Conclusion: PBH participants reported high rates of hypoglycemia unawareness, a likely contributor to hypoglycemia severity, recurrence, and adverse effects on safety and personal life. High rates of IBS, dumping symptoms, and orthostatic hypotension suggest possible disordered autonomic regulation in the pathophysiology of PBH. Self-reported preoperative symptoms and family history of hypoglycemia suggest possible differences in glucose metabolism prior to surgery in at-risk individuals. Preoperative assessment of these and other factors, together with longitudinal follow-up studies to determine incidence of PBH, will be required to identify risk factors for development of post-bariatric hypoglycemia. Presentation: Sunday, June 18, 2023

Daily stair climbing, disease susceptibility, and risk of atherosclerotic cardiovascular disease: A prospective cohort study

Background and aimsThe associations between intensity of stair climbing and atherosclerotic cardiovascular disease (ASCVD) and how these vary by underlying disease susceptibility are not fully understood. We aim to evaluate the intensity of stair climbing and risk of ASCVD types and whether these vary with the presence of ASCVD risk factors. MethodsThis prospective study used data of 458,860 adult participants from the UK Biobank. Information about stair climbing, sociodemographic, and lifestyle factors was collected at baseline and a resurvey 5 years after baseline. ASCVD was defined as coronary artery disease (CAD), ischemic stroke (IS), or acute complications. Associations between flights of stair climbing and ASCVD were examined as hazard ratios (HRs) from Cox proportional hazards models. The modification role of disease susceptibility on such associations was assessed by analyses stratified by levels of genetic risk score (GRS), 10-year risks of ASCVD, and self-reported family history of ASCVD. ResultsDuring a median of 12.5 years of follow-up, 39,043 ASCVD, 30,718 CAD, and 10,521 IS cases were recorded. Compared with the reference group (reported climbing stairs 0 times/day at baseline), the multivariable-adjusted HRs for ASCVD were 0.97 (95% CI, 0.93–1.01), 0.84 (0.82–0.87), 0.78 (0.75–0.81), 0.77 (0.73–0.80) and 0.81 (0.77–0.85) for stair climbing of 1–5, 6–10, 11–15, 16–20 and ≥21 times/day, respectively. Comparable results were obtained for CAD and IS. When stratified by different disease susceptibility based on the GRS for CAD/IS, 10-year risk, and family history of ASCVD, the protection association of stair climbing was attenuated by increasing levels of disease susceptibility. Furthermore, compared with people who reported no stair climbing (<5 times/d) at two examinations, those who climbed stairs at baseline and then stopped at resurvey experienced a 32% higher risk of ASCVD (HR 1.32, 95% CI:1.06–1.65). ConclusionsClimbing more than five flights of stairs (approx 50 steps) daily was associated with a lower risk of ASCVD types independent of disease susceptibility. Participants who stopped stair climbing between baseline and resurvey had a higher risk of ASCVD compared with those who never climbed stairs.

Influence of family history on penetrance of hereditary cancers in a population setting

We sought to investigate how penetrance of familial cancer syndromes varies with family history using a population-based cohort. We analysed 454,712 UK Biobank participants with exome sequence and clinical data (data collected between March 2006 and June 2021). We identified participants with a self-reported family history of breast or colorectal cancer and a pathogenic/likely pathogenic variant in the major genes responsible for hereditary breast cancer or Lynch syndrome. We calculated survival to cancer diagnosis (controlled for sex, death, recruitment centre, screening and prophylactic surgery). Women with a pathogenic BRCA1 or BRCA2 variant had an increased risk of breast cancer that was higher in those with a first-degree family history (relative hazard 10.3 and 7.8, respectively) than those without (7.2 and 4.7). Penetrance to age 60 was also higher in those with a family history (44.7%, CI 32.2-59.3 and 24.1%, CI 17.5-32.6) versus those without (22.8%, CI 15.9-32.0 and 17.9%, CI 13.8-23.0). A similar pattern was seen in Lynch syndrome: individuals with a pathogenic MLH1, MSH2 or MSH6 variant had an increased risk of colorectal cancer that was significantly higher in those with a family history (relative hazard 35.6, 48.0 and 9.9) than those without (13.0, 15.4 and 7.2). Penetrance to age 60 was also higher for carriers of a pathogenic MLH1 or MSH2 variant in those with a family history (30.9%, CI 18.1-49.3 and 38.3%, CI 21.5-61.8) versus those without (20.5% CI 9.6-40.5 and 8.3% CI 2.1-30.4), but not for MSH6 (6.5% CI 2.7-15.1 with family history versus 8.3%, CI 5.1-13.2). Relative risk increases were also observed both within and across conditions. Individuals with pathogenic cancer syndrome variants may be at a less elevated risk of cancer in the absence of a first-degree family history, so in the context of results return, family history should be considered when counselling patients on the risks and benefits of potential follow-up care. The current work is supported by the MRC (grant no MR/T00200X/1). The MRC had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

The value of parental medical records for the prediction of diabetes and cardiovascular disease: a novel method for generating and incorporating family histories.

To determine whether data-driven family histories (DDFH) derived from linked EHRs of patients and their parents can improve prediction of patients' 10-year risk of diabetes and atherosclerotic cardiovascular disease (ASCVD). A retrospective cohort study using data from Israel's largest healthcare organization. A random sample of 200000 subjects aged 40-60years on the index date (January 1, 2010) was included. Subjects with insufficient history (<1year) or insufficient follow-up (<10years) were excluded. Two separate XGBoost models were developed-1 for diabetes and 1 for ASCVD-to predict the 10-year risk for each outcome based on data available prior to the index date of January 1, 2010. Overall, the study included 110734 subject-father-mother triplets. There were 22153 cases of diabetes (20%) and 11715 cases of ASCVD (10.6%). The addition of parental information significantly improved prediction of diabetes risk (P < .001), but not ASCVD risk. For both outcomes, maternal medical history was more predictive than paternal medical history. A binary variable summarizing parental disease state delivered similar predictive results to the full parental EHR. The increasing availability of EHRs for multiple family generations makes DDFH possible and can assist in delivering more personalized and precise medicine to patients. Consent frameworks must be established to enable sharing of information across generations, and the results suggest that sharing the full records may not be necessary. DDFH can address limitations of patient self-reported family history, and it improves clinical predictions for some conditions, but not for all, and particularly among younger adults.

Incorporating a polygenic risk score-triaged coronary calcium score into cardiovascular disease examinations to identify subclinical coronary artery disease (ESCALATE): Protocol for a prospective, nonrandomized implementation trial

Identifying and targeting established modifiable risk factors has been a successful strategy for reducing the burden of coronary artery disease (CAD) at the population-level. However, up to 1-in-4 patients who present with ST elevation myocardial infarction do so in the absence of such risk factors. Polygenic risk scores (PRS) have demonstrated an ability to improve risk prediction models independent of traditional risk factors and self-reported family history, but a pathway for implementation has yet to be clearly identified. The aim of this study is to examine the utility of a CAD PRS to identify individuals with subclinical CAD via a novel clinical pathway, triaging low or intermediate absolute risk individuals for noninvasive coronary imaging, and examining the impact on shared treatment decisions and participant experience. The ESCALATE study is a 12-month, prospective, multicenter implementation study incorporating PRS into otherwise standard primary care CVD risk assessments, to identify patients at increased lifetime CAD risk for noninvasive coronary imaging. One-thousand eligible participants aged 45 to 65 years old will enter the study, which applies PRS to those considered low or moderate 5-year absolute CVD risk and triages those with CAD PRS ≥80% for a coronary calcium scan. The primary outcome will be the identification of subclinical CAD, defined as a coronary artery calcium score (CACS) >0 Agatston units (AU). Multiple secondary outcomes will be assessed, including baseline CACS ≥100 AU or ≥75th age-/sex-matched percentile, the use and intensity of lipid- and blood pressure-lowering therapeutics, cholesterol and blood pressure levels, and health-related quality of life (HRQOL). This novel trial will generate evidence on the ability of a PRS-triaged CACS to identify subclinical CAD, as well as subsequent differences in traditional risk factor medical management, pharmacotherapy utilization, and participant experience. Australian New Zealand Clinical Trials Registry, ACTRN12622000436774. Trial was prospectively registered on March 18, 2022. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=383134.

Genetic and clinical factors underlying a self-reported family history of heart disease.

To estimate how much information conveyed by self-reported family history of heart disease (FHHD) is already explained by clinical and genetic risk factors. Cross-sectional analysis of UK Biobank participants without pre-existing coronary artery disease using a multivariable model with self-reported FHHD as the outcome. Clinical (diabetes, hypertension, smoking, apolipoprotein B-to-apolipoprotein AI ratio, waist-to-hip ratio, high sensitivity C-reactive protein, lipoprotein(a), triglycerides) and genetic risk factors (polygenic risk score for coronary artery disease [PRSCAD], heterozygous familial hypercholesterolemia [HeFH]) were exposures. Models were adjusted for age, sex, and cholesterol-lowering medication use. Multiple logistic regression models were fitted to associate FHHD with risk factors, with continuous variables treated as quintiles. Population attributable risks (PAR) were subsequently calculated from the resultant odds ratios. Among 166 714 individuals, 72 052 (43.2%) participants reported an FHHD. In a multivariable model, genetic risk factors PRSCAD (OR 1.30, CI 1.27-1.33) and HeFH (OR 1.31, 1.11-1.54) were most strongly associated with FHHD. Clinical risk factors followed: hypertension (OR 1.18, CI 1.15-1.21), lipoprotein(a) (OR 1.17, CI 1.14-1.20), apolipoprotein B-to-apolipoprotein AI ratio (OR 1.13, 95% CI 1.10-1.16), and triglycerides (OR 1.07, CI 1.04-1.10). For the PAR analyses: 21.9% (CI 18.19-25.63) of the risk of reporting an FHHD is attributed to clinical factors, 22.2% (CI% 20.44-23.88) is attributed to genetic factors, and 36.0% (CI 33.31-38.68) is attributed to genetic and clinical factors combined. A combined model of clinical and genetic risk factors explains only 36% of the likelihood of FHHD, implying additional value in the family history.

Mode of HIV acquisition among adolescents living with HIV in resource-limited settings: A data-driven approach from South Africa.

Adolescents living with HIV (ALHIV) face unique treatment and care challenges which may differ by how they acquired HIV, whether vertically (in-utero, perinatal or postnatal exposure during breastfeeding) or sexually (sexual exposure). Distinguishing and documenting the mode of HIV acquisition (MOHA) is crucial to further research on the different needs and outcomes for ALHIV and to tailor HIV services to their needs. Age-based cut-offs have been used to attribute MOHA but have not been validated. We analysed data from a three-wave cohort of n = 1107 ALHIV part of a longitudinal study in South Africa. Age-based MOHA was allocated using age at ART initiation, validated against a logic-tree model based on literature-hypothesised factors: self-reported HIV, sexual, and family history. After testing six ART initiation age cut-offs (10 to 15 years old), we determined the optimal MOHA cut-off age by calculating the sensitivity and specificity for each cut-off, measured against the final logic-tree allocation. Following validation using this longitudinal study, the methodology is extended to 214 additional third-wave participants-adolescent girls and young women living with HIV who became mothers before the age of 20. Finally, descriptive statistics of the final allocations are presented. Among the 1,063 (96.0%) cohort study participants classified, 68.7% acquired HIV vertically, following validation. ART initiation before cut-off age 10 had the highest sensitivity (58.9%) but cut-off age 12 had the largest area under the curve (AUC) (0.712). Among the additional young mothers living with HIV, 95.3% were estimated to have acquired it sexually, following the same algorithm. For this group, while cut-off ages 10 to 12 had the highest sensitivity (92.2%), age 14 had the highest AUC (0.703). ART initiation before 10 years old is strongly associated with vertical HIV acquisition. Therefore, a cut-off age of 10 would remain the recommendation in LMIC regions with similar epidemiology as South Africa for determining MOHA in research and clinic settings.