Utah Population Research Articles

UTILIZING POPULATION DATA TO CHARACTERIZE NURSING HOME DECEDENTS AND THEIR FAMILIES AT THE END OF LIFE

Abstract Over 2/3 of nursing home (NH) residents are eligible for palliative care (PC), but do not receive it. Utilizing the Utah Population Database, we examined EOL characteristics for 39,672 NH residents who died in Utah between 1998-2016. Dementia was the leading cause of death (36.6%), followed by cardiovascular disease (23.9%) and COPD (16.7%). Women were more likely than men to die in a NH (21.0 vs 15%) and more likely to die in a NH with heart disease (20.0% vs. 11.7%) or cerebrovascular disease (25.9% vs. 21.0%), compared to men. Use of PC, hospice, and life-sustaining treatments was low within this NH sample, particularly among persons with dementia. First-degree family characteristics varied at EOL with presence of a spouse exerting the greatest influence on EOL care utilization. Understanding population-based NH resident EOL life characteristics can help inform the development of resident- and caregiver-centered PC interventions and health policies.

HEALTH AND WELL-BEING OF FAMILY CAREGIVERS FOLLOWING HOSPICE USE

Abstract Some patterns of hospice use are potentially disruptive and stressful for both patient and family. Using a decedent sample of 17,320 hospice users from the Utah Population Database, linked to the health records of spouse and first-degree relatives (child, parent, sibling, Mean=3.36 per decedent). Stroke decedents had higher odds of delayed admission (i.e., <7 days of hospice), while those with dementia and COPD had higher odds of extended use (i.e., >6 months of hospice), compared to cancer decedents. Family members, especially spouses, who experienced delayed admission or extended use had higher odds of hospitalization and increased use of antidepressants, both prior to and following the death, compared to those with more normative hospice use (6 months or less, typical of cancer patients). The hospice experience has both immediate and lasting consequences on the family; eligibility criteria for the hospice benefit may need to be modified by admitting diagnosis.

Abdominal aortic aneurysm and exfoliation syndrome in Utah.

A pilot study of electronic medical records (EMR) in Utah was undertaken to investigate exfoliation syndrome and exfoliation glaucoma (XFS/XFG) in abdominal aortic aneurysm (AAA) patients. In a subsequent retrospective cohort study of Utah XFS/XFG patients and population controls, the risk of AAA was examined. EMR of a statewide healthcare population were obtained from the Utah Population Database (UPDB) which links decades of medical records with Utah demographic and vital records data. In a pilot study, 7167 patients ages ≥40 years identified with AAA diagnosed from 1996 to 2015, based on International Classification of Diseases (ICD) version 9/10 codes, were included. A univariable hazards model was used to determine the risk of XFS/XFG in AAA patients. An XFS/XFG outcome based on ICD 9/10 codes in AAA patients and in 5:1 sex- and age-matched non-AAA controls was determined. A retrospective cohort of 3412 XFS/XFG patients ages ≥50 years diagnosed from 1996 to 2020 and 10 227 3:1 sex- and age-matched controls who underwent ≥1 dilated eye examination(s) were recently identified and updated diagnoses of AAA were obtained. Multivariable logistic regression was used to estimate AAA risk in XFS/XFG patients compared with controls. In a subset of XFS/XFG patients, chart reviews were conducted to confirm clinically diagnosed AAA. In the AAA pilot, 20 patients (0.3%) and 118 controls (0.3%) developed XFS/XFG, respectively. We observed no increased risk of XFS/XFG in AAA patients compared with non-AAA-matched controls (HR=0.99, 95% CI 0.6-1.6). Among XFS/XFG study patients and controls, 122 patients (3.6%) and 376 controls (3.7%) had an AAA diagnosis. We likewise observed no increased risk of AAA in XFS/XFG patients (OR=0.97, 95% CI 0.8-1.2). In 14 XFS/XFG patients with an ICD 9/10 diagnosis of AAA who underwent chart review, a clinical diagnosis of AAA was confirmed in 9 patients (64.3%). Our findings do not support an association between AAA and XFS/XFG.

Comorbidity and Cancer Disease Rates among Those at High-Risk for Alzheimer's Disease: A Population Database Analysis.

(1) Importance: Alzheimer's disease (AD) is complex and only partially understood. Analyzing the relationship between other more treatable or preventable diseases and AD may help in the prevention and the eventual development of treatments for AD. Risk estimation in a high-risk population, rather than a population already affected with AD, may reduce some bias in risk estimates. (2) Objective: To examine the rates of various comorbidities and cancers in individuals at high-risk for AD, but without a clinical diagnosis, relative to individuals from the same population with normal AD risk. (3) Design, Setting, and Participants: We conducted a study using data from the Utah Population Database (UPDB). The UPDB contains linked data from the Utah Cancer Registry, Utah death certificates, the Intermountain Health patient population, and the University of Utah Health patient population. Subjects were selected based on the availability of ancestral data, linked health information, and self-reported biometrics. (4) Results: In total, 75,877 participants who were estimated to be at high risk for AD based on family history, but who did not have an active AD diagnosis, were analyzed. A lower incidence of diabetes (RR = 0.95, 95% CI [0.92,0.97], p < 0.001), hypertension (RR = 0.97, 95% CI [0.95,0.99], p < 0.001), and heart disease (RR = 0.95, 95% CI [0.93,0.98], p < 0.001) was found. There was no difference in rates of cerebrovascular disease or other forms of dementia. Of the 15 types of cancer analyzed: breast (RR = 1.23, 95% CI [1.16, 1.30], p < 0.001); colorectal (RR = 1.30, 95% CI [1.21, 1.39], p < 0.001); kidney (RR = 1.49, 95% CI (1.29, 1.72), p < 0.001); lung (RR = 1.25, 95% CI [1.13, 1.37], p < 0.001); non-Hodgkin's Lymphoma (RR = 1.29, 95% CI [1.15, 1.44], p < 0.001); pancreas (RR = 1.34, 95% CI [1.16, 1.55], p < 0.001); stomach (RR = 1.59, 95% CI [1.36, 1.86], p < 0.001); and bladder (RR = 1.40, 95% CI [1.25, 1.56], p < 0.001), cancers were observed in significant excess among individuals at high-risk for AD after correction for multiple testing. (5) Conclusions and Relevance: Since age is the greatest risk factor for the development of AD, individuals who reach more advanced ages are at increased risk of developing AD. Consistent with this, people with fewer comorbidities earlier in life are more likely to reach an age where AD becomes a larger risk. Our findings show that individuals at high risk for AD have a decreased incidence of various other diseases. This is further supported by our finding that our high-risk group was also found to have an increased incidence of various cancers, which also increase in risk with age. There is the possibility that a more meaningful or etiological relationship exists among these various comorbidities. Further research into the etiological relationship between AD and these comorbidities may elucidate these possible interactions.

Sex differences in risk for Alzheimer’s disease with extended maternal and paternal family history and vascular risk factors. The Cache County Study.

AbstractBackgroundAge, family history (FH), APOE status, and vascular factors are known risk factors for Alzheimer’s disease (AD). Sex differences in AD risk have been reported for some but not all of these factors. We examined sex differences in the association between FH and AD risk, studying the role of maternal/paternal lineage, parental longevity, and vascular factors in a population‐based cohort.Methods3677 participants (59% female) of the Cache County Memory Study [mean(SD) age = 75.75(7.11) years] were studied. FH of AD and health information were obtained from self‐report or Medicare claims and death certificates via data linkage through the Utah Population Database. AD cases were determined via clinical examination and Medicare claims and non‐cases via clinical examination or negative cognitive screenings.ResultsMultivariate logistic regression models (covarying age, education, and APOE) found that individuals with a first‐ degree relative with AD was associated with a 58% and 66% increased risk of AD in males and females, respectively. In males, APOE Ɛ4 carriers with a history of exceptional maternal longevity (survival age 87+) had 3‐times the risk of AD than males with neither risk factor (OR = 3.15, p interaction p = .020). Males with both exceptional maternal and paternal longevity (survival age 87+) had an 11% reduced risk of AD (OR = 0.894, interaction p = .041). A history of both maternal and paternal lineages of AD was associated with a 46% lower risk (OR = 0.544) at trend level significance (interaction p = .054). In females, maternal lineage of AD was associated with a 56% increased risk of AD (OR = 1.56; p = .005). Females with a history of congestive heart failure and paternal lineage of AD had twice the AD‐risk (OR = 2.26, interaction p = .013) compared to females with neither risk factor. Parental exceptional longevity was not associated with AD risk in females.ConclusionRisk for AD associated with family history varies by sex, maternal and paternal lineage of AD and exceptional parental longevity. Elucidating mechanisms and modifiable lifestyle factors underlying sex differences may facilitate developing primary AD prevention strategies.

Primary ovarian insufficiency has strong familiality: results of a multigenerational genealogical study

To determine the familiality of primary ovarian insufficiency (POI) at population level through examination of multigenerational genealogical information linked to electronic medical records. Case-control study. Not applicable. Women with POI were identified using International Classification of Disease 9 and 10 codes in electronic medical records (1995-2021) from 2 major health care systems in Utah and reviewed for accuracy. Cases were linked to genealogy information in the Utah Population Database (UPDB). All included POI cases (n = 396) were required to have genealogy information available for at least 3 generations of ancestors. The risk of POI in relatives was compared with population rates for POI matched by age, sex, and birthplace. Not applicable. Relative risk of POI in first-, second-, and third-degree relatives. We identified 396 validated cases of POI with an associated 2,132 first-degree relatives, 5,245 second-degree relatives, and 10,853 third-degree relatives. We found an increased risk of POI among the extended relatives of cases. Specifically, first-degree relatives demonstrated an 18-fold increased risk of POI compared with controls relative risk ([RR],18.52 95% confidence interval [CI], 10.12-31.07), second-degree relatives demonstrated a 4-fold increase (RR, 4.21; CI, 1.15-10.79), and third-degree relatives demonstrated a 2.7-fold increase (RR, 2.65; CI, 1.14-5.21]). This is the first population-based study to assess the familial clustering of POI. The data demonstrate excess familiality, familial clustering of POI in excess compared with matched population rates of disease, among first-, second-, and third-degree relatives. These findings support a genetic contribution to POI.

Young-Onset Breast Cancer Outcomes by Time Since Recent Childbirth in Utah

Breast cancer diagnosed within 5 to 10 years after childbirth, called postpartum breast cancer (PPBC), is associated with increased risk for metastasis and death. Whether a postpartum diagnosis is an independent risk factor or a surrogate marker of cancer features associated with poor outcomes remains understudied. To determine whether diagnostic temporal proximity to childbirth is associated with features of breast cancer associated with poor outcomes, including tumor stage, estrogen receptor (ER) status, and risk for distant metastasis and breast cancer-specific mortality, using a population database from the state of Utah. This population-based cohort study using the Utah Population Database (UPDB) included individuals with stage I to III breast cancer diagnosed at age 45 years or younger between 1996 and 2017, followed-up until February 2020. Participant data were analyzed from November 2019 to August 2022. The primary exposures were no prior childbirth or time between most recent childbirth and breast cancer diagnosis. Patients were grouped by diagnoses within less than 5 years, 5 to less than 10 years, or 10 years or more since recent childbirth. The 2 primary outcomes were distant metastasis-free survival and breast cancer-specific death. Cox proportional hazard models were used to investigate associations between exposures and outcomes adjusting for diagnosis year, patient age, tumor stage, and estrogen receptor (ER) status. Of 2970 individuals with breast cancer diagnosed at age 45 years or younger (mean [SD] age, 39.3 [5.0] years; 12 Black individuals [0.4%], 2679 White individuals [90.2%]), breast cancer diagnosis within 5 years of recent childbirth was independently associated with approximately 1.5-fold elevated risk for metastasis (hazard ratio [HR], 1.5; 95% CI, 1.2-2.0) and breast cancer-specific death (HR, 1.5; 95% CI, 1.1-2.1) compared with nulliparous individuals. For cancers classically considered to have tumor features associated with good outcomes (ie, stage I or II and ER-positive), a postpartum diagnosis was a dominant feature associated with increased risk for metastasis and death (eg, for individuals with ER-positive disease diagnosed within <5 years of childbirth: age-adjusted metastasis HR, 1.5; 95% CI, 1.1-2.1; P = .01; age-adjusted death HR, 1.5; 95% CI, 1.0-2.1; P = .04) compared with nulliparous individuals. Furthermore, liver metastases were specifically increased in the group with diagnosis within 5 years postpartum and with positive ER expression (38 of 83 patients [45.8%]) compared with the nulliparous (28 of 77 patients [36.4%]), although the difference was not statistically significant. Overall, these data implicate parity-associated breast and liver biology in the observed poor outcomes of PPBC. In this cohort study of individuals with breast cancer diagnosed at age 45 years or younger, a postpartum breast cancer diagnosis was a risk factor associated with poor outcomes. Irrespective of ER status, clinical consideration of time between most recent childbirth and breast cancer diagnosis could increase accuracy of prognosis in patients with young-onset breast cancer.

Familial aggregation of stillbirth: A pedigree analysis of a matched case-control study.

To determine whether stillbirth aggregates in families and quantify its familial risk using extended pedigrees. State-wide matched case-control study. Utah, United States. Stillbirth cases (n=9404) and live birth controls (18 808) between 1978 and 2019. Using the Utah Population Database, a population-based genealogical resource linked with state fetal death and birth records, we identified high-risk pedigrees with excess familial aggregation of stillbirth using the Familial Standardised Incidence Ratio (FSIR). Stillbirth odds ratio (OR) for first-degree relatives (FDR), second-degree relatives (SDR) and third-degree relatives (TDR) of parents with a stillbirth (affected) and live birth (unaffected) were estimated using logistic regression models. Familial aggregation estimated using FSIR, and stillbirth OR estimated for FDR, SDR and TDR of affected and unaffected parents using logistic regression models. We identified 390 high-risk pedigrees with evidence for excess familial aggregation (FSIR ≥2.00; P-value <0.05). FDRs, SDRs and TDRs of affected parents had 1.14-fold (95% confidence interval [CI]: 1.04-1.26), 1.22-fold (95% CI 1.11-1.33) and 1.15-fold (95% CI 1.08-1.21) higher stillbirth odds compared with FDRs, SDRs and TDRs of unaffected parents, respectively. Parental sex-specific analyses showed male FDRs, SDRs and TDRs of affected fathers had 1.22-fold (95% CI 1.02-1.47), 1.38-fold (95% CI 1.17-1.62) and 1.17-fold (95% CI 1.05-1.30) higher stillbirth odds compared with those of unaffected fathers, respectively. FDRs, SDRs and TDRs of affected mothers had 1.12-fold (95% CI 0.98-1.28), 1.09-fold (95% CI 0.96-1.24) and 1.15-fold (95% CI 1.06-1.24) higher stillbirth odds compared with those of unaffected mothers, respectively. We provide evidence for familial aggregation of stillbirth. Our findings warrant investigation into genes associated with stillbirth and underscore the need to design large-scale studies to determine the genetic architecture of stillbirth.

Familial Clustering and Genetic Analysis of Severe Thumb Carpometacarpal Joint Osteoarthritis in a Large Statewide Cohort

Our goals were to identify individuals who required surgery for thumb carpometacarpal (CMC) joint osteoarthritis (OA), determine if CMC joint OA clusters in families, define the magnitude of familial risk of CMC joint OA, identify risk factors associated with CMC joint OA, and identify rare genetic variants that segregate with familial CMC joint OA. We searched the Utah Population Database to identify a cohort of CMC joint OA patients who required surgery. Affected individuals were mapped to pedigrees to identify high-risk families with excess clustering of CMC joint OA. Cox regression models were used to calculate familial risk of CMC joint OA in related individuals. Risk factors were evaluated using logistic regression models. Whole exome sequencing was used to identify rare coding variants associated with familial CMC joint OA. We identified 550 pedigrees with excess clustering of severe CMC joint OA. The relative risk of CMC joint OA requiring surgical treatment was elevated significantly in first- and third-degree relatives of affected individuals, and significant associations with advanced age, female sex, obesity, and tobacco use were observed. We discovered candidate genes that dominantly segregate with severe CMC joint OA in 4 independent families, including a rare variant in Chondroitin Sulfate Synthase 3 (CHSY3). Familial clustering of severe CMC joint OA was observed in a statewide population. Our data indicate that genetic and environmental factors contribute to the disease process, further highlighting the multifactorial nature of the disease. Genomic analyses suggest distinct biological processes are involved in CMC joint OA pathogenesis. Awareness of associated comorbidities may guide the diagnosis of CMC joint OA in at-risk populations and help identify individuals who may not do well with nonoperative treatment. Further pursuit of the genes associated with severe CMC joint OA may lead to assays for detection of early stages of disease and have therapeutic potential.

Eosinophilic Gastritis and Enteritis Are Increased in Families With Eosinophilic Esophagitis.

There are limited data on the familial risk of distal eosinophilic gastrointestinal diseases (EGIDs) in patients with eosinophilic esophagitis (EoE). We analyzed the risk of eosinophilic gastritis/gastroenteritis (EG/EGE) and eosinophilic colitis (EC) as forms of distal EGIDs using International Disease Classification-9/10 codes in subjects with EoE and their relatives. The Utah Population Database is a resource that links genealogy information and medical records in Utah. We identified EGIDs in probands and their first-degree (FDRs), second-degree (SDRs), and third-degree (TDRs) relatives in the Utah Population Database. Relative risk and 95% confidence intervals were estimated. All individuals with inflammatory bowel disorder were eliminated to avoid misdiagnosis with EGIDs. We included 8,455 subjects with EoE, 396 with EG/EGE, and 172 with EC. Probands with EoE were at increased risk of EG/EGE and EC. Risks of EG/EGE were increased among FDRs and SDRs of probands with EoE , even without concomitant EoE in the relatives. Increased risk of EG/EGE in FDRs and SDRs was also present for EoE probands without EG/EGE or EC. We observed no isolated familial aggregation of EG/EGE after excluding cases with comorbid EoE. EC probands without EoE were at increased risk of EG/EGE, but no evidence of familial risk of EC was observed. The relative risk of EG/EGE is significant among relatives of patients with EoE, suggesting that shared genetic factors exist among these EGIDs. EG/EGE and EC showed limited familial clustering, although sample sizes were small.

Is There an Inherited Contribution to Risk for Sporadic Unilateral Vestibular Schwannoma? Evidence of Familial Clustering.

Unlike the autosomal dominant inheritance of neurofibromatosis 2, there are no known inherited risk factors for sporadic, unilateral vestibular schwannoma (VS), which comprise most VS cases. The authors tested a hypothesis positing a genetic contribution to predisposition to these lesions by analyzing familial clustering of cases. Familial clustering of individuals with unilateral VS was analyzed in two independent genealogical resources with linked diagnosis data: the Veterans Health Administration Genealogy Resource and the Utah Population Database. Tests for excess relatedness, estimation of relative risks (RRs) in close and distant relatives, and identification of pedigrees with a significant excess of unilateral VS among descendants were performed. The average pairwise relatedness of the Veterans Health Administration Genealogy Resource VS cases significantly exceeded the expected relatedness ( p = 0.016), even when close relationships were ignored ( p = 0.002). RR for third- and fifth-degree relatives developing VS were significantly elevated (RR, 60.83; p = 0.0005; 95% confidence interval [CI], 7.37-219.73) and (RR, 11.88; p = 0.013; 95% CI, 1.44-42.90), respectively. No VS-affected first-, second-, or fourth-degree relatives were observed. In the Utah Population Database population, no first- or second-degree relatives with VS were observed. RR for fifth-degree relatives developing VS was significantly elevated (RR, 2.23; p = 0.009; 95% CI, 1.15-3.90). These results provide strong evidence for an inherited predisposition to sporadic, unilateral VS. This study exhibits the value of genealogical resources with linked medical data for examining hypotheses regarding inherited predisposition. The high-risk unilateral VS pedigrees identified in two independent resources provide a powerful means of pursuing predisposition gene identification.

33906 Dermatology rural outreach clinics are feasible and decrease barriers to care in patients with skin cancer

Rural populations have higher skin cancer incidence and cancer-related deaths, likely due to lack of access to health care, environmental exposures, and lower socioeconomic status. To address the pressing need for specialty care in rural communities, in 2018, faculty from the University of Utah Department of Dermatology established monthly rural outreach clinics in Moab, Utah (population: 5268) and later Rock Springs, Wyoming (population: 23,319). We performed a retrospective chart review to evaluate the impact of the dermatology rural outreach clinics, focusing on patients diagnosed with biopsy-proven skin cancer. Distance to the nearest dermatologist was an average of 122.6 miles (Moab to Grand Junction, CO) and 171.2 miles (Rock Springs to Park City, UT). With the outreach clinics, this was reduced to an average of 14.1 miles (P < .0001) and 18.1 miles (P < .0001), respectively. Skin cancer was diagnosed in 17% (116/682) of all outreach clinic patients (median age 67.7 years, 54.3% male, 100% White, 67.5% Medicare). 58.8% had a personal history of skin cancer. Of the 188 total skin cancers diagnosed, squamous cell carcinoma was most common (52.1%), followed by basal cell carcinoma (41.5%), malignant melanoma (2.7%), and melanoma in situ (3.7%). Forty-two patients (36.2%) received Mohs surgery referrals; 90.5% were completed at the University of Utah. We did not find significant differences between the Moab and Rock Springs clinics. These results highlight the importance and feasibility of outreach clinics in providing access to dermatologic care, specifically in diagnosing and treating skin cancers in rural populations.

Mental health disorders are more common in patients with Hodgkin lymphoma and may negatively impact overall survival.

Long-term mental health outcomes werecharacterized in patients who were diagnosed with Hodgkin lymphoma (HL), and risk factors for the development of mental health disorders were identified. Patients who were diagnosed with HL between 1997 and 2014 were identified in the Utah Cancer Registry. Each patient was matched with up to five individuals from a general population cohort identified within the Utah Population Database, a unique source of linked records that includes patient and demographic data. In total, 795 patients who had HL were matched with 3575 individuals from the general population. Compared with the general population, patients who had HL had a higher risk of any mental health diagnosis (hazard ratio, 1.77; 95% confidence interval, 1.57-2.00). Patients with HL had higher risks of anxiety, depression, substance-related disorders, and suicide and intentional self-inflicted injuries compared with the general population. The main risk factor associated with an increased risk of being diagnosed with mental health disorders was undergoing hematopoietic stem cell transplantation, with a hazard ratio of 2.06 (95% confidence interval, 1.53-2.76). The diagnosis of any mental health disorder among patients with HL was associated with a detrimental impact on overall survival; the 10-year overall survival rate was 70% in patients who had a mental health diagnosis compared with 86% in those patients without a mental health diagnosis (p < .0001). Patients who had HL had an increased risk of various mental health disorders compared with a matched general population. The current data illustrate the importance of attention to mental healthin HL survivorship, particularly for patients who undergo therapy with hematopoietic stem cell transplantation.

Significant familial clustering of Peyronie's disease in close and distant relatives.

Peyronie's disease (PD) has previously been observed to co-aggregate in a small number of first-degree relative pairs (e.g., father-son). However, the familial aggregation of PD in more distant relatives, as well as the aggregation of Dupuytren's disease (DD) in probands and relatives, has not been thoroughly investigated. This study explored the evidence for familial clustering of PD and DD in close and distant relatives. The Utah Population Database, which includes genealogy information linked to electronic medical records (available since 1995), was used to identify men and their relatives with PD and DD based on ICD9/10 codes. All cases were required to have high-quality genealogy data. We estimated relative risk (RR) of PD and DD in first- through fifth-degree relatives compared to matched population rates of disease. We also investigated the average relatedness of cases compared to the average relatedness of sets of matched controls. Outcome measures include estimation of relative risk and excessive relatedness as measured by a Genealogical Index of Familiality (GIF) analysis. We analyzed 307 individuals with PD, and their first- through fifth-degree relatives. Approximately 0.12% of the population had PD, 95% of these were diagnosed over the age of 30 years (age range: 10-92 years), and 1.3% of PD probands had a comorbid diagnosis of DD. RR estimates for PD were significant for first- and fifth-degree relatives. RR estimates for DD were significant only for probands. The average relatedness of cases was significantly greater than matched controls, even after removing first- and second-degree relatives. We also found that 74.9% of identified PD probands belonged to pedigrees with a statistical excess of PD. Despite the low prevalence of PD in our healthcare records, the results provide evidence that support a genetic contribution to at least a subset of PD cases.

Early-Onset Colorectal Cancer Survival Differences and Potential Geographic Determinants Among Men and Women in Utah.

By 2030, early-onset colorectal cancer (EOCRC) is expected to become the leading cancer-related cause of death for people age 20 to 49. To improve understanding of this phenomenon, we analyzed the geographic determinants of EOCRC in Utah by examining county-level incidence and mortality. We linked data from the Utah Population Database to the Utah Cancer Registry to identify residents (age 18-49) diagnosed with EOCRC between 2000 and 2020, and we used spatial empirical Bayes smoothing to determine county-level hotspots. We identified 1,867 EOCRC diagnoses (52.7% in male patients, 69.2% in non-Hispanic White patients). Ten counties (34%) were classified as hotspots, with high EOCRC incidence or mortality. Hotspot status was unrelated to incidence rates, but non-Hispanic ethnic-minority men (incidence rate ratio, 1.49; 95% CI, 1.15-1.91), Hispanic White men and women (incidence rate ratio, 2.24; 95% CI, 2.00-2.51), and Hispanic ethnic-minority men and women (incidence rate ratio, 4.59; 95% CI, 3.50-5.91) were more likely to be diagnosed with EOCRC. After adjustment for income and obesity, adults living in hotspots had a 31% higher hazard for death (HR, 1.31; 95% CI, 1.02-1.69). Survival was poorest for adults with a late-stage diagnosis living in hotspots (chi square (1) = 4.0; p = .045). Adults who were married or who had a life partner had a lower hazard for death than single adults (HR, 0.73; 95% CI, 0.58-0.92). The risk for EOCRC is elevated in 34% of Utah counties, warranting future research and interventions aimed at increasing screening and survival in the population age 18 to 49.

Seasonal variation in semen quality is not associated with fecundity in the Utah Population Database.

We determine whether a suspected seasonal variability in semen quality affect subsequent live birth rates. This is a retrospective, cohort analysis of men who provided semen analyses as part of fertility workup through a large andrology lab between 1996 and 2013 and corresponding birth rates using the Utah Population Database (UPDB). Semen parameters were analysed including total motile count (TMC), total sperm count, sperm concentration and progressive motility. Corresponding live births reflect those born in the state of Utah and were derived from birth certificate data available in the UPDB. Descriptive statistics were reported along with linear regression analysis with mixed effected models to test for an interaction between seasonal variation in semen quality and birth rates, accounting for age at the time of the semen analysis and abstinence time. A total of 11,929 patients and 14,765 semen samples were included. Only 3597 men (39% of men) had one or more values outside the World Health Organization reference range for their semen parameters. Linear regression demonstrated a consistent U-shaped relationship between TMC, total sperm count, and sperm concentration and season, with spring and winter yielding the highest values with a decline in the summer and fall. 7319 of these males had recorded live births for a total of 13,502 live births during the study period after a median follow-up of 7.2 years (IQR: 3.9-11.0). We did not find a significant interaction between specific semen parameters for a specific season and subsequent live births. Semen quality was the highest in the spring and winter, however there was no interaction between seasonal variability in semen quality and subsequent births. This is one of the largest studies describing seasonal variation in semen quality in humans.

Abstract 5912: A postpartum breast cancer diagnosis is an independent risk factor for metastasis

Abstract Introduction: A diagnosis of breast cancer after childbirth increases risk for metastasis and death in patients diagnosed at ≤45 years of age [1]. Data to delineate if a postpartum diagnosis is an independent risk factor for breast cancer metastasis remain limited. Here, we addressed this question using early-onset cases available from the Utah Population Database. Methods: This population-based study includes 2,970 women with stage I-III breast cancer, diagnosed at ≤45 years of age between 1996 and 2017. The primary exposures are nulliparity or time between last childbirth and diagnosis of breast cancer. Primary outcomes are distant metastasis and breast cancer-specific death. The Cox proportional hazard model was used to investigate associations between exposures and outcomes adjusting for diagnosis year, age, tumor stage and estrogen receptor (ER) status. Stratified analyses were conducted. Results: Reproductive histories of the breast cancer patients were grouped as nulliparous (n=860), and parous: diagnosed 0-&amp;lt;5 years (n=614), 5-&amp;lt;10 years (n=615) and ≥10 years (n=881) since last childbirth. Through multivariate analyses, we find a breast cancer diagnosis within 5 years postpartum associates with elevated risk for metastasis [(HR)(95%CI)]=1.5(1.2-2.0)] and breast cancer-specific death [HR(95%CI)=1.5(1.1-2.1)] compared to nulliparous cases. Further, for stage I or II cancers that classically have good prognoses, a postpartum diagnosis (0-&amp;lt;5 years) is a dominant feature of increased risk for metastasis [HR(95% CI)]=[1.9 (1.2-2.8)], particularly liver metastasis, and a 2 fold increase in probability of death [HR(95% CI)]=[2.0 (1.2-3.2)]. For women diagnosed with poor prognostic ER- breast cancer, the probability of dying in 0-&amp;lt;5 yrs postpartum group is also ~2 fold compared to nulliparous cases [HR(95% CI)]=[2.3 (1.3-4.1)]. ER+ cases diagnosed 0-&amp;lt;5 yrs postpartum trended towards poor outcomes with marginal significance. Unexpectedly, the proportion of patients progressing to metastasis was the same for ER+ and ER- disease, at 13.2% and 13.5% respectively, with ~3 fold more deaths in women diagnosed with ER+ breast cancer due to increased incidence. Further, we find increased liver metastasis in ER+ patients diagnosed &amp;lt;5 years postpartum, with a full 46% of women who progressed to metastasis having liver as first site of metastasis. Conclusion: This study shows a postpartum diagnosis as an independent risk factor for breast cancer progression and implicates a birth-interval-associated liver biology in the increased liver metastasis observed in this study. Irrespective of ER status, clinical consideration of time between last completed pregnancy and breast cancer diagnosis will increase accuracy of prognosis in young-onset breast cancer patients. 1.Nichols, H.B., et al., Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies. Ann Intern Med, 2018. Citation Format: Zhenzhen Zhang, Solange Bassale, Sonali Jindal, Emily Guinto, Alison Fraser, Tomi Mori, Ken R. Smith, Pepper Schedin. A postpartum breast cancer diagnosis is an independent risk factor for metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5912.

Abstract 30: A pedigree-based approach to ovarian cancer risk variant discovery in the Utah Population Database

Abstract Introduction: Genetic risk variants are critical to risk prediction for invasive epithelial ovarian cancer (EOC), yet an estimated 50-55% of EOC heritability remains missing. Novel approaches to risk variant discovery are needed to detect variants that have not been uncovered by linkage analysis or genome-wide association studies (GWAS). We approach risk variant discovery using Shared Genomic Segment analysis (SGS), a novel statistical genetics method that enables risk variant discovery in extended high-risk pedigrees. Methods: The Utah Population Database (UPDB) is a population-based resource of over ten million individuals connected to the state of Utah, five million of whom are linked to a minimum of three generations of genealogy data. By linking this genealogy data with cancer data from the Utah Cancer Registry, we identified pedigrees with an excess risk of EOC. We generated germline genotyping data from cases (diagnosed 1983-2018) in a subset of these high-risk pedigrees, focusing on pedigrees well-suited for SGS (i.e., at least 3 cases separated by a total of at least 12 meioses). SGS identifies all runs of consecutive alleles that are shared identical-by-state by cases in a pedigree and determines which of these genomic segments are longer than would be expected by chance. These long segments are likely to be identical-by-descent, inherited from a common founder, and may harbor risk variants. Results: We successfully linked UPDB genealogy data to information from the Utah Cancer Registry to identify approximately 2,000 extended high-risk pedigrees with ≥5 ovarian cancer cases, an average of 7-10 meioses between pairs cases, and a statistically significant excess risk of ovarian cancer (α=0.05). We obtained biospecimens for 141 cases in 36 of the most promising pedigrees (i.e., high familial standardized incidence ratio, p-value&amp;lt;0.005, not attributable to known risk variants in BRCA1 or BRCA2 as observed in first-, second- or third-degree relatives of EOC cases). We genotyped 96 out of the 141 cases in these pedigrees (68%). SGS analyses to identify genomic regions that may harbor risk variants are currently underway. Conclusions: Using pedigrees identified in the UPBD, SGS has identified risk loci and novel risk variants for a number of diseases, including breast and hematologic cancers. We have identified a set of EOC high-risk pedigrees for SGS analysis and will leverage SGS to identify genomic regions that may harbor EOC risk variants. Citation Format: Mollie E. Barnard, Robert Sargent, G. Bryce Christensen, Bonita A. Mahaffey, James Albro, Elke A. Jarboe, Terence Rhodes, Nicola J. Camp, Jennifer A. Doherty. A pedigree-based approach to ovarian cancer risk variant discovery in the Utah Population Database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 30.

Birth Spacing and Health and Socioeconomic Outcomes Across the Life Course: Evidence From the Utah Population Database.

The relationship between birth interval length and child outcomes has received increased attention in recent years, but few studies have examined offspring outcomes across the life course in North America. We use data from the Utah Population Database to examine the relationship between birth intervals and short- and long-term outcomes: preterm birth, low birth weight (LBW), infant mortality, college degree attainment, occupational status, and adult mortality. Using linear regression, linear probability models, and survival analysis, we compare results from models with and without sibling comparisons. Children born after a birth interval of 9-12 months have a higher probability of LBW, preterm birth, and infant mortality both with and without sibling comparisons; longer intervals are associated with a lower probability of these outcomes. Short intervals before the birth of the next youngest sibling are also associated with LBW, preterm birth, and infant mortality both with and without sibling comparisons. This pattern raises concerns that the sibling comparison models do not fully adjust for within-family factors predicting both spacing and perinatal outcomes. In sibling comparison analyses considering long-term outcomes, not even the very shortest birth intervals are negatively associated with educational or occupational outcomes or with long-term mortality. These findings suggest that extremely short birth intervals may increase the probability of poor perinatal outcomes but that any such disadvantages disappear over the extended life course.

Cardiovascular disease risk in long-term breast cancer survivors: A population-based cohort study.

Breast cancer survival is increasing, making late effects such as cardiovascular disease (CVD) more relevant. The purpose of this study was to evaluate incident CVD following breast cancer diagnosis among long-term survivors and to investigate possible risk factors for CVD. A population-based cohort of 6641 breast cancer survivors diagnosed between 1997 and 2009 who survived at least 10years was identified within the Utah Cancer Registry. In addition, 36,612 cancer-free women from the general population, matched by birth year and state, were identified within the Utah Population Database. Cox proportional hazards models were used to calculate CVD hazard ratios (HRs) for >10 to 15 and >15years. Long-term breast cancer survivors had an increased risk of newly diagnosed diseases of the circulatory system (HR, 1.32; 99% confidence interval [CI], 1.00-1.75) from 10 to 15years following cancer diagnosis compared with the general population. No increased CVD risks were observed after 15years. Breast cancer survivors with Charlson Comorbidity Index score ≥2 had a significantly higher risk of diseases of the circulatory system (HR, 2.64; 95% CI, 1.08-6.45) beyond 10years following breast cancer diagnosis. Similarly, older age, obesity, lower education, and family history of CVD and breast cancer were risk factors for heart and circulatory system diseases among long-term breast cancer survivors. Risk of CVD compared to the general population was moderate among this cohort of long-term breast cancer survivors between 10 to 15years since cancer diagnosis. Awareness of CVD risks is important for breast cancer survivors.