Simulations suggest walking with reduced propulsive force would not mitigate the energetic consequences of lower tendon stiffness.

Aging elicits numerous effects that impact both musculoskeletal structure and walking function. Tendon stiffness (kT) and push-off propulsive force (FP) both impact the metabolic cost of walking and are diminished by age, yet their interaction has not been studied. We combined experimental and computational approaches to investigate whether age-related changes in function (adopting smaller FP) may be adopted to mitigate the metabolic consequences arising from changes in structure (reduced kT). We recruited 12 young adults and asked them to walk on a force-sensing treadmill while prompting them to change FP (±20% & ±40% of typical) using targeted biofeedback. In models driven by experimental data from each of those conditions, we altered the kT of personalized musculoskeletal models across a physiological range (2-8% strain) and simulated individual-muscle metabolic costs for each kT and FP combination. We found that kT and FP independently affect walking metabolic cost, increasing with higher kT or as participants deviated from their typical FP. Our results show no evidence for an interaction between kT and FP in younger adults walking at fixed speeds. We also reveal complex individual muscle responses to the kT and FP landscape. For example, although total metabolic cost increased by 5% on average with combined reductions in kT and FP, the triceps surae muscles experienced a 7% local cost reduction on average. Our simulations suggest that reducing FP during walking would not mitigate the metabolic consequences of lower kT. Wearable devices and rehabilitative strategies can focus on either kT or FP to reduce age-related increases in walking metabolic cost.

Quantifying mechanical and metabolic interdependence between speed and propulsive force during walking.

Walking speed is a useful surrogate for health status across the population. Walking speed appears to be governed in part by interlimb coordination between propulsive (FP) and braking (FB) forces generated during step-to-step transitions and is simultaneously optimized to minimize metabolic cost. Of those forces, FP generated during push-off has received significantly more attention as a contributor to walking performance. Our goal was to first establish empirical relations between FP and walking speed and then to quantify their effects on metabolic cost in young adults. To specifically address any link between FP and walking speed, we used a self-paced treadmill controller and real-time biofeedback to independently prescribe walking speed or FP across a range of condition intensities. Walking with larger and smaller FP led to instinctively faster and slower walking speeds, respectively, with ~80% of variance in walking speed explained by FP. We also found that comparable changes in either FP or walking speed elicited predictable and relatively uniform changes in metabolic cost, together explaining ~53% of the variance in net metabolic power and ~14% of the variance in cost of transport. These results provide empirical data in support of an interdependent relation between FP and walking speed, building confidence that interventions designed to increase FP will translate to improved walking speed. Repeating this protocol in other populations may identify other relations that could inform the time course of gait decline due to age and disease.

Muscle metabolic energy costs while modifying propulsive force generation during walking.

We pose that an age-related increase in the metabolic cost of walking arises in part from a redistribution of joint power where muscles spanning the hip compensate for insufficient ankle push-off and smaller peak propulsive forces (FP). Young adults elicit a similar redistribution when walking with smaller FP via biofeedback. We used targeted FP biofeedback and musculoskeletal models to estimate the metabolic costs of operating lower limb muscles in young adults walking across a range of FP. Our simulations support the theory of distal-to-proximal redistribution of joint power as a determinant of increased metabolic cost in older adults during walking.

Imaging and Simulation of Inter-muscular Differences in Triceps Surae Contributions to Forward Propulsion During Walking.

Forward propulsion during the push-off phase of walking is largely governed at the ankle by differential neuromechanical contributions from the biarticular medial (MG) and lateral gastrocnemii (LG) and the uniarticular soleus (SOL). However, the relative contribution of these individual muscles to forward propulsion is equivocal, with important implications for the design and control of wearable assistive devices and for targeted therapeutics. The aim of this study was to evaluate the agreement between empirical and model-predicted triceps surae (i.e., MG, LG, and SOL) contributions to forward propulsion during walking using conditions that systematically manipulated both walking speed and the mechanical demand for forward propulsion at a fixed speed-through the use of aiding and impeding forces. Ten young adults (age: 24.1 ± 3.6 years, 6M/4F) participated. We found that muscle-specific responses derived from experimental measurements (i.e., activation and fascicle behavior) were consistent with those derived from musculoskeletal simulations (i.e., muscle force and positive mechanical work) within the same subjects. In vivo, compared to walking normally, only LG muscle activation was affected by both aiding and impeding forces. Similarly, increased propulsive demand elicited greater relative fascicle shortening in the MG but not the SOL. In silico, only MG and LG force and positive mechanical work increased significantly to meet the increased demands for forward propulsion. By combining electromyography, ultrasound imaging, and musculoskeletal modeling in the same subjects, our cumulative findings suggest that the biarticular gastrocnemius muscles play a more significant role than the uniarticular soleus in governing changes in forward propulsion during the mid to late stance phase of walking.

Heart rate measures from the Apple Watch, Fitbit Charge HR 2, and electrocardiogram across different exercise intensities.

This study compared heart rate (HR) measurements for the Fitbit Charge HR 2 (Fitbit) and the Apple Watch devices with HR measurements for electrocardiogram (ECG). Thirty young adults (15/15 females/males, age 23.5 ± 3.0 years) completed the Bruce Protocol. HR measurements were recorded from the ECG and both devices every minute. Average HR for each participant was calculated for very light, light, moderate, vigorous and very vigorous intensities based on ECG-measured HR. A concordance correlation coefficient (CCC) was calculated to examine the strength of the relationship between ECG measured HR and HR measured by each device. Relative error rates (RER) were also calculated to indicate the difference between each device and ECG. An equivalence test was conducted to examine the equivalence of HRs measured by devices and ECG. The Apple Watch showed lower RER (2.4-5.1%) compared with the Fitbit (3.9-13.5%) for all exercise intensities. For both devices, the strongest relationship with ECG-measured HR was found for very light PA with very high CCC (>.90) and equivalence. The strength of the relationship declined as exercise intensity increased for both devices. These findings indicate that the accuracy of real-time HR monitoring by the Apple Watch and Fitbit Charge HR2 is reduced as exercise intensity increases.

Functional factors that are important correlates to physical activity in people with multiple sclerosis: a pilot study.

PURPOSE: Identify functional factors that are important correlates to physical activity levels among people with multiple sclerosis. METHODS: A total of eight functional tests were conducted and physical activity was objectively measured (Actigraph GT3X accelerometer) for one week in 34 people with multiple sclerosis. A corrected Akaike Information Criterion analysis was performed to identify the strongest correlates with moderate-to-vigorous physical activity, total activity and sedentary time. RESULTS: The multiple regression analysis converged on a model for moderate-to-vigorous physical activity (R2 = 0.31, F = 6.97, p= 0.003) that included total strength of the less-affected leg (partial r = 0.46, p = 0.007) and average peg test performance (partial r = -0.30, p = 0.087). The model for total activity (R2 = 0.40, F = 10.51, p < 0.001) included five times sit-to-stand performance (partial r= -0.44, p = 0.010) and total strength of the less-affected leg (partial r = 0.31, p = 0.077). The model for sedentary time (R2=0.22, F = 9.23, p = 0.005) only included total strength of the more affected leg (r= -0.47, p = 0.005). CONCLUSION: These results suggest that leg strength, manual dexterity and the ability to perform functional tasks may be important correlates with physical activity levels in people with multiple sclerosis. The findings of this pilot study can inform future investigations aiming to increase physical activity levels or develop improved rehabilitation protocols for people with multiple sclerosis. Implications for Rehabilitation Physical activity is an effective means of improving the symptoms associated with multiple sclerosis. Participation in physical activity by people with multiple sclerosis may be affected by functional factors such as leg strength, manual dexterity and the ability to rise from a seated position. Bilateral leg strength differences should be assessed and addressed in people with multiple sclerosis.

Differential Vulnerability to Early-Life Parental Death: The Moderating Effects of Family Suicide History on Risks for Major Depression and Substance Abuse in Later Life.

Only a portion of those individuals exposed to parental death in early life (PDE) develop behavioral health disorders. We utilized demographic pedigree data from the Utah Population Database to test for differential vulnerability to PDE by creating a risk score of familial susceptibility to suicide (FS) at the population level. Using logistic panel regression models, we tested for multiplicative interactions between PDE and FS on the risks of major depressive disorder (MDD) and substance abuse (SA), measured using Medicare claims, after age 65. The final sample included 155,983 individuals (born 1886-1944), yielding 1,431,060 person-years at risk (1992-2009). Net of several potential confounders, including probability of survival to age 65, we found an FS × PDE interaction for females, in which PDE and FS as main effects had no impact but jointly increased MDD risk. No statistically significant main or interactive effects were found for SA among females or for either phenotype among males. Our findings are consistent with a differential vulnerability model for MDD in females, in which early-life stress increases the risk for poor behavioral health only among the vulnerable. Furthermore, we demonstrate how demographic and pedigree data might serve as tools for investigating differential vulnerability hypotheses.

Familial Risk in Patients With Carcinoma of Unknown Primary.

IMPORTANCE: Carcinoma of unknown primary (CUP) accounts for 3% to 5% of all cancers and is associated with poor prognosis. Familial clustering of different cancer sites with CUP is unknown and may provide information regarding etiology, as well as elevated cancer risks in relatives. OBJECTIVE: To quantify the risk of cancer by site in first- and second-degree relatives and first cousins of individuals with CUP. DESIGN, SETTING, AND PARTICIPANTS: Nested case-control study of patients who received a diagnosis of CUP between 1980 and 2010 identified from the Utah Cancer Registry. Population controls with no CUP diagnosis were sex and age matched 10:1 to patients with CUP. Data about relatives were drawn from the Utah Population Database. MAIN OUTCOMES AND MEASURES: Familial aggregation of cancer risk in relatives of cases compared with controls using Cox regression analysis. RESULTS: For the 4160 index patients (median [interquartile range] age, 72 [62-81] years; 47.6% male) who had received a diagnosis of CUP, first-degree relatives were at an elevated risk of CUP themselves (hazard ratio [HR], 1.35 [95% CI, 1.07-1.70]), as well as lung (HR, 1.37 [95% CI, 1.22-1.54]), pancreatic (HR, 1.28 [95% CI, 1.06-1.54]), myeloma (HR, 1.28 [95% CI, 1.01-1.62]), and non-Hodgkin lymphoma (HR, 1.16 [95% CI, >1.00-1.35]) cancers compared with controls without CUP. When the analysis was restricted to relatives of cancer-free controls, additional increased risks for colon (HR, 1.19 [95% CI, 1.06-1.33]) and bladder (HR, 1.18 [95% CI, >1.00-1.38]) cancers were observed. Second-degree relatives of patients with CUP were at a slight increased risk of lung (HR, 1.14 [95% CI, 1.03-1.26]), pancreatic (HR, 1.17 [95% CI, 1.01-1.37]), breast (HR, 1.09 [95% CI, 1.02-1.16]), melanoma (HR, 1.09 [95% CI, >1.00-1.19]), and ovarian (HR, 1.19 [95% CI, 1.02-1.39]) cancers. CONCLUSIONS AND RELEVANCE: Relatives of patients with CUP are at increased risk of CUP and several other malignant neoplasms, including lung, pancreatic, and colon cancer. The present data may suggest sites of origin for CUP and provide cancer risk information for relatives of patients with CUP that can lead to effective intervention. Relatives of patients with CUP should be aware of the elevated risks for lung, pancreatic, and colon cancer and encouraged to modify risk factors and adhere to site-specific population cancer screening.

Increased Risk of Colorectal Cancer Among Family Members of All Ages, Regardless of Age of Index Case at Diagnosis.

BACKGROUND & AIMS: It is not clear whether familial risk of colorectal cancer (CRC) varies with age of index CRC patients or their relatives. We quantified the risk of CRC in first-degree relatives (FDRs), second-degree relatives, and first-cousin relatives of individuals with CRC, stratified by ages and sexes of index patients and ages of relatives. METHODS: CRCs diagnosed between 1980 and 2010 were identified from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Age- and sex-matched CRC-free individuals were selected to form the comparison group. CRC risk in relatives was determined by Cox regression analysis. RESULTS: Of 18,208 index patients diagnosed with CRC, the highest familial risk was observed in FDRs of index CRC patients who were diagnosed at an age younger than 40 years (hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.7-3.79). However, familial risk was increased in FDRs even when the index case was diagnosed with cancer at an advanced age (>80 years; HR, 1.76; 95% CI, 1.59-1.94). Ages of relatives and ages of index cases of CRC each affected familial cancer risk; the highest risk was found in young relatives (<50 years) of individuals with early-onset CRC (<40 years; HR, 7.0; 95% CI, 2.86-17.09). CONCLUSIONS: All relatives of individuals with CRC are at increased risk for this cancer, regardless of the age of diagnosis of the index patient. Although risk is greatest among young relatives of early-onset CRC cases, relatives of patients diagnosed at advanced ages also have an increased risk.

Parental influence on systemic sclerosis.

OBJECTIVE: To examine parental influence on the development of systemic sclerosis (SSc; scleroderma). We designed 3 studies: mitochondrial inheritance, birth order (a possible surrogate marker for microchimerism), and paternal age at conception (a possible surrogate for telomere erosion) to examine their association with development of SSc. METHODS: SSc was defined by International Classification of Diseases, Ninth and Tenth Revision codes (ICD-9 710.1 and ICD 10 M34.0, M34.1, and M34.9) and identified from statewide discharge data, University of Utah Health Science Center Enterprise Data Warehouse (UUHSC), and death certificates that were linked to the Utah Population Database (UPDB) for analysis. Mitochondrial inheritance was evaluated by conditional logistic regression and population attributable risk using familial standardized incidence ratio as the covariate. Chi-square test and logistic regression were used to evaluate birth order and maternal/paternal age at conception of the SSc proband. RESULTS: We found 1,947 unique SSc patients from UUHSC and UPDB. We selected 5 controls per case (n = 9,115), matched by birth year and sex. Mitochondrial inheritance analysis indicated no evidence to suggest SSc was associated with mitochondrial inheritance. Birth order and maternal/paternal age at conception analysis results show that they also do not significantly affect SSc development. CONCLUSION: Results suggest that although heritable risk of SSc is observed, mitochondrial inheritance, birth order, and parental age are not likely responsible for pathogenesis.

Increased risk of colorectal neoplasia among family members of patients with colorectal cancer: a population-based study in Utah.

BACKGROUND & AIMS: Colorectal cancer (CRC) frequently develops in multiple members of the same families, but more data are needed to prepare effective screening guidelines. We quantified the risk of CRC and adenomas in first-degree relatives (FDRs) and second-degree relatives and first cousins of individuals with CRC, and stratified risk based on age at cancer diagnosis. METHODS: We performed a case-control study of Utah residents, 50-80 years old, who underwent colonoscopy from 1995 through 2009. Index cases (exposed to colonoscopy) were colonoscopy patients with a CRC diagnosis. Age- and sex-matched individuals, unexposed to colonoscopy (controls) were selected to form the comparison groups for determining risk in relatives. Colonoscopy results were linked to cancer and pedigree information from the Utah Population Database to investigate familial aggregation of colorectal neoplasia using Cox regression analysis. RESULTS: Of 126,936 patients who underwent a colonoscopy, 3804 were diagnosed with CRC and defined the index cases. FDRs had an increased risk of CRC (hazard rate ratio [HRR], 1.79; 95% confidence interval [CI],1.59-2.03), as did second-degree relatives (HRR, 1.32; 95% CI, 1.19-1.47) and first cousins (HRR, 1.15; 95% CI, 1.07-1.25), compared with relatives of controls. This risk was greater for FDRs when index patients developed CRC at younger than age 60 years (HRR, 2.11; 95% CI, 1.70-2.63), compared with older than age 60 years (HRR, 1.77; 95% CI, 1.58-1.99). The risk of adenomas (HRR, 1.82; 95% CI, 1.66-2.00) and adenomas with villous histology (HRR, 2.43; 95% CI, 1.96-3.01) also were increased in FDRs. Three percent of CRCs in FDRs would have been missed if the current guidelines, which stratify screening recommendations by the age of the proband, were strictly followed. CONCLUSIONS: FDRs, second-degree relatives, and first cousins of patients who undergo colonoscopy and are found to have CRC have a significant increase in the risk of colorectal neoplasia. These data should be considered when establishing CRC screening guidelines for individuals and families.

Epidemiology and familial risk of synchronous and metachronous colorectal cancer: a population-based study in Utah.

BACKGROUND & AIMS: Patients diagnosed with colorectal cancer (CRC) are at risk for synchronous and metachronous lesions at the time of diagnosis or during follow-up evaluation. We performed a population-based study to evaluate the rate, predictors, and familial risk for synchronous and metachronous CRC in Utah. METHODS: All newly diagnosed cases of CRC between 1980 and 2010 were obtained from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. RESULTS: Of the 18,782 patients diagnosed with CRC, 134 were diagnosed with synchronous CRC (0.71%) and 300 were diagnosed with metachronous CRC (1.60%). The risk for synchronous CRC was significantly higher in men (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.02-2.06) and in patients aged 65 years or older (OR, 1.50; 95% CI, 1.02-2.21). Synchronous CRCs were located more often in the proximal colon (OR, 1.70; 95% CI, 1.20-2.41). First-degree relatives of cases with synchronous (OR, 1.86; 95% CI, 1.37-2.53), metachronous (OR, 2.34; 95% CI, 1.62-3.36), or solitary CRC (OR, 1.75; 95% CI, 1.63-1.88) were at increased risk for developing CRC, compared with relatives of CRC-free individuals. Four percent of first-degree relatives of patients with synchronous or metachronous cancer developed CRC at younger ages than the age recommended for initiating CRC screening (based on familial risk), and therefore would not have been screened. CONCLUSIONS: Of patients diagnosed with CRC, 2.3% are found to have synchronous lesions or develop metachronous CRC during follow-up evaluation. Relatives of these patients have a greater risk of CRC than those without a family history of CRC. These results highlight the importance of obtaining a thorough family history and adhering strictly to surveillance guidelines during management of high-risk patients.

Characteristics of missed or interval colorectal cancer and patient survival: a population-based study.

BACKGROUND & AIMS: Colorectal cancers (CRCs) diagnosed within a few years after an index colonoscopy can arise from missed lesions or the development of a new tumor. We investigated the proportion, characteristics, and factors that predict interval CRCs that develop within 6-60 months of colonoscopy. METHODS: We performed a population-based cohort study of Utah residents who underwent colonoscopy examinations from 1995 through 2009 at Intermountain Healthcare or the University of Utah Health System, which provide care to more than 85% of state residents. Colonoscopy results were linked with cancer histories from the Utah Population Database to identify patients who underwent colonoscopy 6-60 months before a diagnosis of CRC (interval cancer). Logistic regression was performed to identify risk factors associated with interval cancers. RESULTS: Of 126,851 patients who underwent colonoscopies, 2659 were diagnosed with CRC; 6% of these CRCs (159 of 2659) developed within 6 to 60 months of a colonoscopy. Sex and age were not associated with interval CRCs. A higher percentage of patients with interval CRC were found to have adenomas at their index colonoscopy (57.2%), compared with patients found to have CRC detected at colonoscopy (36%) or patients who did not develop cancer (26%) (P < .001). Interval CRCs tended to be earlier-stage tumors than those detected at index colonoscopy, and to be proximally located (odds ratio, 2.24; P < .001). Patients with interval CRC were more likely to have a family history of CRC (odds ratio, 2.27; P = .008) and had a lower risk of death than patients found to have CRC at their index colonoscopy (hazard ratio, 0.63; P < .001). CONCLUSIONS: In a population-based study in Utah, 6% of all patients with CRC had interval cancers (cancer that developed within 6 to 60 months of a colonoscopy). Interval CRCs were associated with the proximal colon, earlier-stage cancer, lower risk of death, higher rate of adenoma, and family history of CRC. These findings indicate that interval colorectal tumors may arise as the result of distinct biologic features and/or suboptimal management of polyps at colonoscopy.

Risk of colorectal cancer and adenomas in the families of patients with adenomas: a population-based study in Utah.

BACKGROUND: Guidelines recommend that individuals with a first-degree relative (FDR) diagnosed with colorectal cancer (CRC) or advanced adenoma before age 60 years should undergo colonoscopy starting at age 40 years. The authors quantified the risk of adenomas and CRC in FDRs, second-degree relatives (SDRs), and third-degree relatives (TDRs) of patients diagnosed with adenomas and advanced adenomas. METHODS: A population-based, retrospective, case-control study was performed of residents of the state of Utah aged 50 years to 80 years who underwent colonoscopy between 1995 and 2009 at Intermountain Healthcare or the University of Utah. Controls were selected from the population of colonoscopy patients who were free of adenomas or CRC and matched to each case based on sex and birth year. Colonoscopy results were linked with cancer and pedigree information from the Utah Population Database to investigate the familial aggregation of adenomas and CRC using Cox regression analysis. The unit of analysis was the relatives of cases and controls. RESULTS: Of 126,936 patients who underwent colonoscopy, 43,189 had adenomas and 5563 had advanced adenomas and defined the case population. An elevated risk of CRC was found in FDRs (relative risk [RR], 1.35; 95% confidence interval [95% CI], 1.25-1.46), SDRs (RR, 1.15; 95% CI, 1.07-1.23) of adenoma cases, and in FDRs of advanced adenoma cases (RR, 1.68; 95% CI, 1.29-2.18) compared with controls. Approximately 10% of CRCs diagnosed in relatives would have been missed if the current screening guidelines were strictly adhered to. CONCLUSIONS: Relatives of colonoscopy patients with adenomas and advanced adenomas appear to have a significantly elevated risk of developing colorectal neoplasia. These data should be considered when establishing CRC screening guidelines for individuals and their families.

Establishing a familial basis for papillary thyroid carcinoma using the Utah Population Database.

IMPORTANCE: Determining if relatives of patients diagnosed as having papillary thyroid carcinoma (PTC) are at increased risk of developing the same cancer--and if so, which relatives and to what degree--would help identify those who require closer clinical attention. This could lead to earlier cancer detection and improved prognoses. OBJECTIVE: To define the familial risk of PTC using a unique population research database. DESIGN, SETTING, PARTICIPANTS: Retrospective review at a tertiary care facility using the Utah Population Database, which is linked to medical records and the Utah Cancer Registry, from 1966 through 2011. The study population comprised 4460 patients diagnosed as having PTC in Utah between 1966 and 2011 and their first- through fifth-degree relatives and spouses. These patients were compared 5:1 with matched, population-based controls. MAIN OUTCOMES AND MEASURES: Statistically significant increased risk of PTC in any first- through fifth-degree relatives or spouses of patients diagnosed as having this cancer. RESULTS: First-, second-, and third-degree relatives of PTC probands had a significant increased risk of developing this cancer compared with population controls. First-degree relatives of probands were at a 5.4-fold increased risk (P < 10(-15)) of being diagnosed as having this cancer themselves. Second- and third-degree relatives had a 2.2-fold (P < 10(-11)) and 1.8-fold increased risk (P < 10(-8)), respectively. Siblings of probands were at highest risk (odd ratio, 6.8; P < 10(-15)). There was no significant increased risk observed in spouses of probands. CONCLUSIONS AND RELEVANCE: In the largest population study to date, a high risk of PTC is confirmed in first-degree relatives. Furthermore, significant increased risk extends to second- and third-degree relatives but not to spouses of probands. Translational studies are needed to better define the genetic predisposition to familial papillary thyroid cancer and for the development and implementation of optimal screening approaches.

Maternal prenatal weight gain and autism spectrum disorders.

BACKGROUND: The rising population of individuals identified with an autism spectrum disorder (ASD) calls for further investigation of its underlying etiology. A disturbance in the fetal steroid hormone environment may be a mechanism in which environmental and genetic risk factors interact. The mother, fetus, and placenta collectively create the fetal steroid environment. Prepregnancy BMI and pregnancy weight gain have served as markers for fetal steroid hormone exposure in other disease states. This study's objective is to determine whether prepregnancy BMI and pregnancy weight gain are associated with increased ASD risk across study designs and cohorts while controlling for important confounding variables. METHODS: A population-based Utah ASD cohort (n = 128) was ascertained in a 3-county surveillance area and gender- and age-matched to 10,920 control subjects. A second, research-based ASD cohort of Utah children (n = 288) and their unaffected siblings (n = 493) were ascertained through participation in an ASD genetics study. Prenatal variables were obtained from birth certificate records. RESULTS: ASD risk was significantly associated with pregnancy weight gain (adjusted odds ratio = 1.10, 95% confidence interval: 1.03 to 1.17; adjusted odds ratio = 1.17, 95% confidence interval: 1.01 to 1.35 for each 5 pounds of weight gained), but not prepregnancy BMI, in population and research-based cohorts, respectively. When analyses were restricted to ASD cases with normal IQ, these associations remained significant. CONCLUSIONS: ASD risk associated with a modest yet consistent increase in pregnancy weight gain suggests that pregnancy weight gain may serve as an important marker for autism's underlying gestational etiology. This justifies an investigation into phenomena that link pregnancy weight gain and ASD independent of prepregnancy BMI.

Familial risk of childhood cancer and tumors in the Li-Fraumeni spectrum in the Utah Population Database: implications for genetic evaluation in pediatric practice.

We used the Utah Population Database to examine risk of cancer in relatives of 4,482 pediatric cancer cases (≤18 years old) diagnosed from 1966 to 2009 compared to matched population controls. We quantified cancer risk in relatives of children with cancer to determine evidence of familial aggregation and to inform risk assessment and counseling for families. Odds ratios that reflect risk were obtained using conditional logistic regression models adjusting for number of biological relatives, their degree of genetic relatedness and their person-years at risk. First-degree relatives (primarily siblings) of pediatric cases faced a twofold increased risk of a cancer diagnosis before age 19, which extended to their second-degree relatives (p < 10(-4), respectively). Furthermore, first-degree relatives of children diagnosed before age 5 had a 3.6-fold increased risk of developing pediatric cancer (p < 10(-7)), second-degree relatives of very young (under age 5) cases were at 2.5-fold risk (p < 10(-4)) and third-degree relatives were at twofold risk (P < 10(-3)) of childhood cancer. Although first-degree relatives of pediatric cases have a slight increased risk of adult tumors, when they do develop cancer they have a 1.7-fold risk of developing a tumor in the Li-Fraumeni spectrum. Our findings support the hypothesis of familial aggregation in pediatric cancer and suggest that a higher percent of childhood cancers may be related to hereditary syndromes than are adult cancers. We encourage the collection of a family medical history that is routinely updated for all pediatric cancer patients, and that families with early-onset adult cancers or clusters of several cancers are referred for genetic counseling.

Excess mortality and causes of death in autism spectrum disorders: a follow up of the 1980s Utah/UCLA autism epidemiologic study.

This study's purpose was to investigate mortality among individuals with autism spectrum disorders (ASD) ascertained during a 1980s statewide autism prevalence study (n = 305) in relation to controls. Twenty-nine of these individuals (9.5 %) died by the time of follow up, representing a hazard rate ratio of 9.9 (95 % CI 5.7-17.2) in relation to population controls. Death certificates identified respiratory, cardiac, and epileptic events as the most common causes of death. The elevated mortality risk associated with ASD in the study cohort appeared related to the presence of comorbid medical conditions and intellectual disability rather than ASD itself suggesting the importance of coordinated medical care for this high risk sub-population of individuals with ASD.

Total hip arthroplasty, hip osteoarthritis, total knee arthroplasty, and knee osteoarthritis in patients with developmental dysplasia of the hip and their family members: a kinship analysis report.

BACKGROUND: Developmental dysplasia of the hip (DDH) is a familial condition with a wide phenotypic expression. Families with high rates of DDH may have individuals with subtle phenotypic expression that can progress to osteoarthritis and require total hip arthroplasty (THA). This study compares the rates of THA in relatives of individuals with DDH with individuals in control families. METHODS: Probands with a diagnosis of DDH were identified using medical records linked to the Utah Population Database. Ten age-matched and sex-matched controls were randomly selected from a pool of unaffected individuals within the Utah Population Database. Diagnostic and procedural codes were used to determine the incidence of hip and knee osteoarthritis (HOA and KOA) and of THA and total knee arthroplasty (TKA) among the cases and controls and their relatives. Relative risks (RR) for HOA and KOA and for THA and TKA were calculated for the probands/controls and their family members. RESULTS: The RR of HOA was significantly increased in probands (RR=82.4; P<2e-16), their parents (R=2.22; P=0.0003), and in their grandparents (RR=1.33; P=0.011). The RR of THA was also significantly increased in probands (RR=1168; P <3e-08) and in their grandparents (RR=2.06; P=0.01). The RR of KOA was significantly increased in probands with a diagnosis of DDH (RR=20.96; P=2.2e-8) but not in their parents or grandparents. The RR of TKA was also increased in probands alone (RR=57.47; P=1.7e-05). CONCLUSIONS: Parents and grandparents of individuals with diagnosed DDH are significantly more likely to be diagnosed with HOA and undergo THA than members of the general population. These first-degree and second-degree relatives were not at higher risk for KOA or TKA. Given the known familial association of DDH, this association with osteoarthritis of the hip suggests a risk of undiagnosed hip dysplasia in individuals whose families have a high rate of DDH. LEVEL OF EVIDENCE: Level III.

Hemangioma is associated with atopic disease.

OBJECTIVE: To determine if atopic disease is associated with infantile hemangioma. STUDY DESIGN: Case control study. SETTING: State of Utah inpatient and outpatient records obtained from the Department of Health, Intermountain Healthcare medical records, and the University of Utah Health Care medical records using the Utah Population Database. SUBJECTS: Patients given an International Classification of Diseases, Ninth Revision diagnosis of hemangioma prior to age 5 years, from 1991 to 2009. METHODS: Allergy, asthma, and eczema rates in the hemangioma cohort compared to randomly matched controls using logistic regression analysis. RESULTS: The authors identified 2063 patients in the hemangioma group. The overall odds ratio of atopic disease in patients diagnosed with hemangioma was 1.67 compared to the control group (P < .0001). In the hemangioma cohort, the authors found a 36% increased risk of allergies (P < .0001), 67% increased risk of asthma (P < 4e-12), and 82% increased risk of eczema (P < 2e-16). CONCLUSION: This study indicates that allergy, asthma, and eczema are positively associated with hemangioma. Eczema was most strongly associated with hemangioma, with a nearly 2-fold increased risk. Understanding the relationship between atopic disease and infantile hemangioma may elucidate the pathophysiology of each and ultimately lead to better treatment options.