Cardiopulmonary Resuscitation in Adults and Children With Mechanical Circulatory Support: A Scientific Statement From the American Heart Association.

Cardiac arrest in patients on mechanical support is a new phenomenon brought about by the increased use of this therapy in patients with end-stage heart failure. This American Heart Association scientific statement highlights the recognition and treatment of cardiovascular collapse or cardiopulmonary arrest in an adult or pediatric patient who has a ventricular assist device or total artificial heart. Specific, expert consensus recommendations are provided for the role of external chest compressions in such patients.

Sleep-disordered breathing is associated with higher carboxymethyllysine level in elderly women but not elderly men in the cardiovascular health study.

CONTEXT: Carboxymethyl-lysine (CML) results from oxidative stress and has been linked to cardiovascular disease. OBJECTIVE: The objective of this study is to investigate the association between sleep-disordered breathing (SDB) - a source of oxidative stress - and CML. MATERIALS AND METHODS: About 1002 participants in the Cardiovascular Health Study (CHS) were studied. RESULTS: Women with SDB had significantly higher CML concentration compared with those without SDB (OR = 1.63, 95%CI = 1.03-2.58, p = 0.04). The association was not significant among men. DISCUSSION: SDB was associated with CML concentration among elderly women but not men in the Cardiovascular Health Study. CONCLUSION: Accumulation of CML may be an adverse health consequence of SDB.

Empirically derived subtypes of serious emotional disturbance in a large adolescent sample.

PURPOSE: The heterogeneity of serious emotional disturbance has been thoroughly documented among adolescents with nationally representative data derived from structured interviews, although use of these interviews may not be feasible within the context of brief and self-administered school surveys. This study seeks to identify distinct subtypes of serious emotional disturbance in a large school-based sample. METHODS: A total of 108,736 students fully completed the K6 scale that was included on the 2012 Kentucky Incentives for Prevention Survey. Latent class analysis was used to derive subtypes of serious emotional disturbance among students receiving a positive screen (n = 15,147). To determine significant predictors of class membership, adjusted rate ratios and 95 % confidence intervals were calculated using multinomial logistic regression. RESULTS: A four-class model was the most parsimonious, with four distinct subtypes emerging that varied by both symptom type and severity: comorbid moderate severity, comorbid high severity, anxious moderate severity, and depressed high severity. Age, gender, race/ethnicity, family structure, substance use, antisocial behavior, role impairments, and peer victimization were significant predictors of class membership, although the magnitude of these effects was stronger for the two high severity groups. CONCLUSIONS: Our results suggest heterogeneity of serious emotional disturbance by both symptom type and severity. Prevention programs may benefit by shifting focus from specific disorders to the core features of serious emotional disturbance, including psychological distress, high comorbidity, and role impairments.

Mitochondrial genomic variation associated with higher mitochondrial copy number: the Cache County Study on Memory Health and Aging.

BACKGROUND: The mitochondria are essential organelles and are the location of cellular respiration, which is responsible for the majority of ATP production. Each cell contains multiple mitochondria, and each mitochondrion contains multiple copies of its own circular genome. The ratio of mitochondrial genomes to nuclear genomes is referred to as mitochondrial copy number. Decreases in mitochondrial copy number are known to occur in many tissues as people age, and in certain diseases. The regulation of mitochondrial copy number by nuclear genes has been studied extensively. While mitochondrial variation has been associated with longevity and some of the diseases known to have reduced mitochondrial copy number, the role that the mitochondrial genome itself has in regulating mitochondrial copy number remains poorly understood. RESULTS: We analyzed the complete mitochondrial genomes from 1007 individuals randomly selected from the Cache County Study on Memory Health and Aging utilizing the inferred evolutionary history of the mitochondrial haplotypes present in our dataset to identify sequence variation and mitochondrial haplotypes associated with changes in mitochondrial copy number. Three variants belonging to mitochondrial haplogroups U5A1 and T2 were significantly associated with higher mitochondrial copy number in our dataset. CONCLUSIONS: We identified three variants associated with higher mitochondrial copy number and suggest several hypotheses for how these variants influence mitochondrial copy number by interacting with known regulators of mitochondrial copy number. Our results are the first to report sequence variation in the mitochondrial genome that causes changes in mitochondrial copy number. The identification of these variants that increase mtDNA copy number has important implications in understanding the pathological processes that underlie these phenotypes.

Associations between genetic variants in the TGF-ß signaling pathway and breast cancer risk among Hispanic and non-Hispanic white women.

The TGF-ß signaling pathway has a significant role in breast cancer initiation and promotion by regulating various cellular processes. We evaluated whether genetic variation in eight genes (TGF-ß1, TGF-ß2, TGF-ßR1, TGF-ßR2, TGF-ßR3, RUNX1, RUNX2, and RUNX3) is associated with breast cancer risk in women from the Breast Cancer Health Disparities Study. A total of 3,524 cases (1,431 non-Hispanic whites (NHW); 2,093 Hispanics/Native Americans(NA)) and 4,209 population-based controls (1,599 NHWs; 2,610 Hispanics/NAs) were included in analyses. Genotypes for 47 single nucleotide polymorphisms (SNPs) were determined. Additionally, 104 ancestral informative markers estimated proportion of NA ancestry. Associations with breast cancer risk overall, by menopausal status, NA ancestry, and estrogen receptor (ER)/progesterone receptor tumor phenotype were evaluated. After adjustment for multiple comparisons, two SNPs were significantly associated with breast cancer risk: RUNX3 (rs906296 ORCG/GG = 1.15 95 % CI 1.04-1.26) and TGF-ß1 (rs4803455 ORCA/AA = 0.89 95 % CI 0.81-0.98). RUNX3 (rs906296) and TGF-ßR2 (rs3773644) were associated with risk in pre-menopausal women (p adj = 0.002 and 0.02, respectively) and in those with intermediate to high NA ancestry (p adj = 0.04 and 0.01, respectively). Self-reported race was strongly correlated with NA ancestry (r = 0.86). There was a significant interaction between NA ancestry and RUNX1 (rs7279383, p adj = 0.04). Four RUNX SNPs were associated with increased risk of ER- tumors. Results provide evidence that genetic variation in TGF-ß and RUNX genes are associated with breast cancer risk. This is the first report of significant associations between genetic variants in TGF-ß and RUNX genes and breast cancer risk among women of NA ancestry.

Associations between TCF7L2 polymorphisms and risk of breast cancer among Hispanic and non-Hispanic white women: the Breast Cancer Health Disparities Study.

The transcription factor 7-like 2 (TCF7L2) gene is part of the Wnt/ß-catenin signaling pathway and plays a critical role in cell development and growth regulation. TCF7L2 variants rs12255372 and rs7903146 have been associated with risk of Type 2 diabetes. Few epidemiological studies have examined the association between TCF7L2 and breast cancer risk. We investigated the associations between 25 TCF7L2 single nucleotide polymorphisms (SNPs) and breast cancer in Hispanic and non-Hispanic white (NHW) women from the 4-Corner's Breast Cancer Study, the San Francisco Bay Area Breast Cancer Study, and the Mexico Breast Cancer Study. A total of 4,703 Hispanic (2,093 cases, 2,610 controls) and 3,031 NHW (1,431 cases, 1,600 controls) women were included. Odds ratios (OR) and 95 % confidence intervals (CI) were calculated using logistic regression to estimate the association between the TCF7L2 SNPs and breast cancer risk. We also examined effect modification by self-reported ethnicity, genetic admixture, and diabetes history. After adjusting for multiple comparisons, four TCF7L2 SNPs were significantly associated with breast cancer overall: rs7903146 (OR(TT) 1.24; 95 % CI 1.03-1.49), rs3750805 (OR(AT/TT) 1.15; 95 % CI 1.03-1.28), rs7900150 (OR(AA) 1.23; 95 % 1.07-1.42), and rs1225404 (OR(CC) 0.82; 95 % 0.70-0.94). Among women with a history of diabetes, the TT genotype of rs3750804 increased breast cancer risk (OR, 2.46; 95 % CI 1.28-4.73). However, there was no association among women without a diabetes history (OR, 1.06; 95 % CI 0.85-1.32). We did not find significant interactions by ethnicity or by genetic admixture. Findings support an association between TCF7L2 and breast cancer and history of diabetes modifies this association for specific variants.

ADRB2 G-G haplotype associated with breast cancer risk among Hispanic and non-Hispanic white women: interaction with type 2 diabetes and obesity.

INTRODUCTION: Polymorphisms in the beta-2-adrenergic receptor (ADRB2) gene have been studied in relation to risk of type 2 diabetes and obesity, risk factors that have received increased attention in relation to breast cancer. We evaluated the hypothesis that ADRB2 variants (rs1042713, rs1042714) are associated with breast cancer risk in non-Hispanic white (NHW) and Hispanic (H) women using data from a population-based case-control study conducted in the southwestern United States. METHODS: Data on lifestyle and medical history, and blood samples, were collected during in-person interviews for incident primary breast cancer cases (1,244 NHW, 606 H) and controls (1,330 NHW, 728 H). ADRB2 genotypes for rs1042713(G/A) and rs1042714(G/C) were determined using TaqMan assays. The associations of each variant and corresponding haplotypes with breast cancer were estimated using multivariable logistic regression. RESULTS: Two copies compared to one or zero copies of the ADRB2 G-G haplotype were associated with increased breast cancer risk for NHW women [odds ratio (OR), 1.95; 95 % confidence interval (95 % CI), 1.26-3.01], but with reduced risk for H women [OR, 0.74; 95 % CI, 0.50-1.09]. Effect estimates were strengthened for women with a body mass index (BMI) ≥25 kg/m(2) [H: OR, 0.50; 95 % CI, 0.31-0.82; NHW: OR, 3.85; 95 % CI, 1.88-7.88] and for H women with a history of diabetes [H: OR, 0.32; 95 % CI, 0.12-0.89]. CONCLUSIONS: These data suggest that ethnicity modifies the association between the ADRB2 G-G haplotype and breast cancer risk, and being overweight or obese enhances the divergence of risk between H and NHW women.

Part 6: electrical therapies: automated external defibrillators, defibrillation, cardioversion, and pacing: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

The recommendations for electrical therapies described in this section are designed to improve survival from SCA and life-threatening arrhythmias. Whenever defibrillation is attempted, rescuers must coordinate high-quality CPR with defibrillation to minimize interruptions in chest compressions and to ensure immediate resumption of chest compressions after shock delivery. The high first-shock efficacy of newer biphasic defibrillators led to the recommendation of single shocks plus immediate CPR instead of 3-shock sequences that were recommended prior to 2005 to treat VF. Further data are needed to refine recommendations for energy levels for defibrillation and cardioversion using biphasic waveforms.

Therapeutic Hypothermia: What's Hot about Cold.

Reducing body temperature to 33 °C in patients who have been resuscitated from cardiac arrest but who remain comatose can ameliorate anoxic encephalopathy and improve recovery. Experimental animal studies have suggested that cooling to 33 °C also aids the resuscitative process itself, facilitating the resumption of spontaneous circulation (ROSC). The mechanism of cooling benefit is probably the reduction of metabolic demand of most organs, and reduced production of toxic metabolites and reactive oxygen species. External cooling by application of ice or pads through which cold water circulates is effective but requires up to 8 hours to achieve the target temperature of 33 °C. Our goal was to develop a faster method of cooling that could be initiated during cardiopulmonary resuscitation. In anesthetized swine, we induced ventricular fibrillation by passing alternating current down an electrode catheter in the right ventricle. We then ventilated the animals' lungs with liquid perfluorocarbons (PFCs), a technique known as total liquid ventilation (TLV). Perfluorocarbons are oxygen-carrying modules; we pre-oxygenated the PFCs by bubbling 100% O(2) through the solution for 2 minutes before use, and pre-cooled the PFCs to -15 °C. The cold oxygenated PFCs reduced pulmonary artery temperature (a surrogate for myocardial temperature) to 33 °C in about 6 minutes. Using this technique we achieved ROSC in 8 of 11 (82%) animals given TLV versus 3 of 11 (27%) control animals receiving conventional CPR without PFCs (P<0.05). We also compared the cold TLV technique with the administration of intravenous iced saline to achieve hypothermia. Both the cold TLV and cold saline techniques produced rapid hypothermia, but we could achieve ROSC in only 2 of 8 (25%) animals given cold saline versus 7 of 8 (88%) given cold TLV. This result is likely due to the rise in right atrial pressure and corresponding reduction in coronary perfusion pressure caused by volume loading with IV saline, in addition to the higher pO(2) associated with pre-oxygenated PFCs. Cold TLV is a promising technique for achieving rapid intra-arrest and post-resuscitation hypothermia in patients experiencing cardiac arrest.

Colorectal adenomas and cancer link to chromosome 13q22.1-13q31.3 in a large family with excess colorectal cancer.

BACKGROUND: Colorectal cancer is the fourth most common type of cancer and the second most common cause of cancer death. Fewer than 5% of colon cancers arise in the presence of a clear hereditary cancer condition; however, current estimates suggest that an additional 15-25% of colorectal cancers arise on the basis of unknown inherited factors. AIM: To identify additional genetic factors responsible for colon cancer. METHODS: A large kindred with excess colorectal cancer was identified through the Utah Population Database and evaluated clinically and genetically for inherited susceptibility. RESULTS: A major genetic locus segregating with colonic polyps and cancer in this kindred was identified on chromosome 13q with a non-parametric linkage score of 24 (LOD score of 2.99 and p=0.001). The genetic region spans 21 Mbp and contains 27 RefSeq genes. Sequencing of all candidate genes in this region failed to identify a clearly deleterious mutation; however, polymorphisms segregating with the phenotype were identified. Chromosome 13q is commonly gained and overexpressed in colon cancers and correlates with metastasis, suggesting the presence of an important cancer progression gene. Evaluation of tumours from the kindred revealed a gain of 13q as well. CONCLUSIONS: This identified region may contain a novel gene responsible for colon cancer progression in a significant proportion of sporadic cancers. Identification of the precise gene and causative genetic change in the kindred will be an important next step to understanding cancer progression and metastasis.

Extending the Fellegi-Sunter probabilistic record linkage method for approximate field comparators.

Probabilistic record linkage is a method commonly used to determine whether demographic records refer to the same person. The Fellegi-Sunter method is a probabilistic approach that uses field weights based on log likelihood ratios to determine record similarity. This paper introduces an extension of the Fellegi-Sunter method that incorporates approximate field comparators in the calculation of field weights. The data warehouse of a large academic medical center was used as a case study. The approximate comparator extension was compared with the Fellegi-Sunter method in its ability to find duplicate records previously identified in the data warehouse using different demographic fields and matching cutoffs. The approximate comparator extension misclassified 25% fewer pairs and had a larger Welch's T statistic than the Fellegi-Sunter method for all field sets and matching cutoffs. The accuracy gain provided by the approximate comparator extension grew as less information was provided and as the matching cutoff increased. Given the ubiquity of linkage in both clinical and research settings, the incremental improvement of the extension has the potential to make a considerable impact.

The impact of a growing minority population on identification of duplicate records in an enterprise data warehouse.

Patient medical records are often fragmented across disparate healthcare databases, potentially resulting in duplicate records that may be detrimental to health care services. These duplicate records can be found through a process called record linkage. This paper describes a set of duplicate records in a medical data warehouse found by linking to an external resource containing family history and vital records. Our objective was to investigate the impact database characteristics and linkage methods have on identifying duplicate records using an external resource. Frequency counts were made for demographic field values and compared between the set of duplicate records, the data warehouse, and the external resource. Considerations for understanding the relationship that records labeled as duplicates have with dataset characteristics and linkage methods were identified. Several noticeable patterns were identified where frequency counts between sets deviated from what was expected including how the growth of a minority population affected which records were identified as duplicates. Record linkage is a complex process where results can be affected by subtleties in data characteristics, changes in data trends, and reliance on external data sources. These changes should be taken into account to ensure any anomalies in results describe real effects and are not artifacts caused by datasets or linkage methods. This paper describes how frequency count analysis can be an effective way to detect and resolve anomalies in linkage results and how external resources that provide additional contextual information can prove useful in discovering duplicate records.

Pharmacological vs Exercise Stress Echocardiography for Detection of Cardiac Allograft Vasculopathy.

OBJECTIVE: To test the hypothesis that exercise and dobutamine would provide levels of cardiac stress that are comparable to those achieved in a general stress test population, and to one another, in heart transplant recipients. PATIENTS AND METHODS: From February 10, 2015, to December 31, 2017, 81 patients underwent exercise stress (N=45) or dobutamine stress (N=36) echocardiography at a mean ± SD of 11±14 years (range, 1-29 years) after heart transplant. Hemodynamic and inotropic responses were compared between groups, and to a prior test, longitudinally. The primary outcome was peak heart rate (HR) × systolic blood pressure (SBP). RESULTS: Peak exercise HR × SBP × 10-3 was a mean ± SD of 24.9±4.9 mm Hg/min for exercise stress vs 21.2±3.4 mm Hg/min during dobutamine stress (P<.001). In 35 patients who underwent a dobutamine stress test followed later by another dobutamine stress test, peak HR × SBP changed by 4.2%±16% (P=.05). In 25 patients who underwent a dobutamine stress test followed later by an exercise stress test, peak HR × SBP increased by 12%±23% (P=.002 vs serial dobutamine stress tests). Peak exercise HR did not correlate with time since heart transplant, patient age, or graft age. Peak dobutamine HR correlated modestly with patient age (r 2 =0.28). Inotropic responses were similar in both groups. Overall, patients preferred exercise stress testing to dobutamine stress tests. Dobutamine stress testing was more expensive than exercise stress tests. CONCLUSION: Exercise induces a level of cardiac stress that is equal to or greater than dobutamine-induced stress, at lower cost, in heart transplant recipients who express preference for exercise stress testing.

Germline mutation rates in young adults predict longevity and reproductive lifespan.

Ageing may be due to mutation accumulation across the lifespan, leading to tissue dysfunction, disease, and death. We tested whether germline autosomal mutation rates in young adults predict their remaining survival, and, for women, their reproductive lifespans. Age-adjusted mutation rates (AAMRs) in 61 women and 61 men from the Utah CEPH (Centre d'Etude du Polymorphisme Humain) families were determined. Age at death, cause of death, all-site cancer incidence, and reproductive histories were provided by the Utah Population Database, Utah Cancer Registry, and Utah Genetic Reference Project. Higher AAMRs were significantly associated with higher all-cause mortality in both sexes combined. Subjects in the top quartile of AAMRs experienced more than twice the mortality of bottom quartile subjects (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.21-3.56; p = 0.008; median survival difference = 4.7 years). Fertility analyses were restricted to women whose age at last birth (ALB) was ≥ 30 years, the age when fertility begins to decline. Women with higher AAMRs had significantly fewer live births and a younger ALB. Adult germline mutation accumulation rates are established in adolescence, and later menarche in women is associated with delayed mutation accumulation. We conclude that germline mutation rates in healthy young adults may provide a measure of both reproductive and systemic ageing. Puberty may induce the establishment of adult mutation accumulation rates, just when DNA repair systems begin their lifelong decline.

Selecting the transthoracic defibrillation shock directional vector based on VF amplitude improves shock success.

INTRODUCTION: Termination of ventricular fibrillation (VF) by a defibrillating shock is more likely to occur when the VF amplitude is larger. We hypothesized that a defibrillation shock would achieve higher success if the shock vector was oriented along the largest of the VF amplitudes measured simultaneously in 3 orthogonal ECG leads, and that this axis could be determined near-instantaneously in real time. METHODS AND RESULTS: In 9 closed-chest anesthetized swine, a new directional defibrillation (DD) device was used to simultaneously measure the VF peak amplitudes displayed by 3 orthogonal pairs of defibrillation electrodes: anterior-posterior, lateral-lateral, and superior-inferior. Four shocks at each of 3 energy levels (30 Joules [J], 50 J, and 100 J) were delivered through the electrode pair measuring the largest (LA) and smallest (SA) VF peak amplitude at the time of the shock. The odds of shock success (VF termination followed by a perfusing rhythm) were 5 times more likely when shocks were delivered from the LA electrodes than the SA electrodes (odds ratio 5.10, 95% CI: 1.39, 18.79). At the intermediate energy level of 50 J, shocks delivered through the LA electrode pairs had an almost 9 times higher odds of shock success than 50 J shocks delivered through the SA electrode pairs (68.3% vs 18.9%, P = 0.002) (odds ratio 8.94, 95% CI: 2.59, 30.82). Transthoracic impedance and current did not differ for shocks delivered in the LA versus SA groups. CONCLUSION: Choosing the defibrillation directional vector based on the largest VF amplitude improved shock success.

A population-based assessment of the familial component of acute kidney allograft rejection.

BACKGROUND: The genetic determinants of acute kidney transplant rejection (AR) are not well studied, and familial aggregation has never been demonstrated. The goal of this retrospective case-control study was to exploit the unique nature of the Utah Population Database (UPDB) to evaluate if AR or rejection-free survival aggregates in families. METHODS: We identified 891 recipients with genealogy data in the UPDB with at least one year of follow-up, of which 145 (16.1%) had AR and 77 recipients had biopsy-proven rejection graded >or=1A. We compared the genealogical index of familiality (GIF) in cases and controls (i.e. recipients with random assignment of rejection status). RESULTS: We did not find evidence for familial clustering of AR in the entire patient population or in the subgroup with early rejection (n = 52). When the subgroup of recipients with rejection grade >or=1A (n = 77) was analysed separately, we observed increased familial clustering (GIF = 3.02) compared to controls (GIF = 1.96), although the p-value did not reach the level of statistical significance (p = 0.17). Furthermore, we observed an increase in familial clustering in recipients who had a rejection-free course (GIF = 2.45) as compared to controls (GIF = 2.08, p = 0.04). When all recipients were compared to non-transplant controls, they demonstrated a much greater degree of familiality (GIF = 2.03 versus GIF 0.63, p < 0.001). CONCLUSIONS: There is a familial component to rejection-free transplant course and trend to familial aggregation in recipients with AR grade 1A or higher. If a genetic association study is performed, there are families in Utah identified in the current study that can be targeted to increase the power of the test.

Intra-arrest hypothermia: both cold liquid ventilation with perfluorocarbons and cold intravenous saline rapidly achieve hypothermia, but only cold liquid ventilation improves resumption of spontaneous circulation.

BACKGROUND: Rapid intra-arrest induction of hypothermia using total liquid ventilation (TLV) with cold perfluorocarbons improves resuscitation outcome from ventricular fibrillation (VF). Cold saline intravenous infusion during cardiopulmonary resuscitation (CPR) is a simpler method of inducing hypothermia. We compared these 2 methods of rapid hypothermia induction for cardiac resuscitation. METHODS: Three groups of swine were studied: cold preoxygenated TLV (TLV, n=8), cold intravenous saline infusion (S, n=8), and control (C, n=8). VF was electrically induced. Beginning at 8 min of VF, TLV and S animals received 3 min of cold TLV or rapid cold saline infusion. After 11 min of VF, all groups received standard air ventilation and closed chest massage. Defibrillation was attempted after 3 min of CPR (14 min of VF). The end point was resumption of spontaneous circulation (ROSC). RESULTS: Pulmonary arterial (PA) temperature decreased after 1 min of CPR from 37.2 degrees C to 32.2 degrees C in S and from 37.1 degrees C to 34.8 degrees C in TLV (S or TLV vs. C p<0.0001). Coronary perfusion pressure (CPP) was higher in TLV than S animals during the initial 3 min of CPR. Arterial pO(2) was higher in the preoxygenated TLV animals. ROSC was achieved in 7 of 8 TLV, 2 of 8 S, and 1 of 8C (TLV vs. C, p=0.03). CONCLUSIONS: Moderate hypothermia was achieved rapidly during VF and CPR using both cold saline infusion and cold TLV, but ROSC was higher than control only in cold TLV animals, probably due to better CPP and pO(2). The method by which hypothermia is achieved influences ROSC.

Left heart decompression by atrial stenting during extracorporeal membrane oxygenation.

Persistent severe left ventricular dysfunction during extracorporeal membrane oxygenation (EcmO) requires left heart decompression. We describe stenting of the atrial septum as an alternative emergency approach for left heart decompression during EcmO in addition to the already published surgical and transcatheter approaches.

Familial predisposition to developmental dysplasia of the hip.

BACKGROUND: Developmental dysplasia of the hip (DDH) is a common birth defect and is thought to have genetic contributions to the phenotype. It is likely that DDH is genetically heterogeneous with environmental modifiers. The Utah Population Database (UPDB) is a computerized integration of pedigrees, vital statistics, and medical records representing over 6 million individuals, and is a unique resource providing the ability to search for familial factors beyond the nuclear family, decreasing the effect of a shared environment. The purpose of this study is to assess the degree of relationship between individuals with DDH. METHODS: Datasets were created from UPDB statewide birth certificates and from the University of Utah Health Sciences Center enterprise data warehouse using records for DDH and linked to the UPDB. Controls for the dataset were selected that matched cases on birth year and sex and 10 controls were selected per case. Statistics computed for each family were the number of descendants, the observed number of affected, the expected number of affected, P value, familial standardize incidence ratio, relative risks (RRs), and standard error. A kinship analysis tool was used to find pedigrees with excess DDH. RESULTS: The combined data resulted in 1649 distinct individuals with DDH. RR was significantly increased in first-degree relatives (RR=12.1; P<0.000001), siblings (RR=11.9; P<0.000001) and first cousins (RR=1.7; P=0.04). A total of 468 families were identified with at least 5 affected individuals in a family. These results were then filtered to only contain families that had a P value of less than 0.01. This resulted in 141 founders with anywhere between 4 and 30 affected living descendants with a P value of less than 0.01 with family sizes ranging from 594 to 44,819 descendants. A total of 28 founders had a familial standardize incidence ratio of greater than 5.0. CONCLUSIONS: These data suggest a genetic contribution to DDH with a 12-fold increase in risk for first-degree relatives. Better phenotypic characterization and classification will be critical for future genetic analyses.

American founder mutation for attenuated familial adenomatous polyposis.

BACKGROUND & AIMS: Specific mutations in the adenomatous polyposis coli (APC) gene can lead to an attenuated form of familial adenomatous polyposis (AFAP). Although AFAP mutation carriers have a 69% risk of colorectal cancer by age 80, clinical recognition remains a challenge in some cases because they present with few colonic adenomas and are difficult to distinguish clinically from patients with sporadic polyps. METHODS: Family relationships were established using family history reports, the Utah Population Database, and the public records of the Mormon Church. Genetic analysis of representative family members was performed using a 10,000 single nucleotide polymorphism array platform. Colonoscopy data were available on 120 individuals with the AFAP mutation. RESULTS: Two large AFAP kindreds with the identical APC disease-causing mutation (c.426_427delAT) were linked to a founding couple who came to America from England around 1630. Genetic analysis showed that the 2 families share a conserved haplotype of 7.17 Mbp surrounding the mutant APC allele. The data show that 36.6% of the mutation-positive family members have fewer than 10 colonic adenomatous polyps, and 3 (6.8%) of these individuals were diagnosed with colorectal cancer. CONCLUSIONS: In view of the apparent age of this mutation, a notable fraction of both multiple-adenoma patients and perhaps even colon cancer cases in the United States could be related to this founder mutation. The colon cancer risk associated with the mutation makes genetic testing of considerable importance in patients with a personal or family history of either colonic polyps or cancer at a young age.