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School-aged children have consistently shown a surprising developmental lag when attempting to innovate solutions to tool use tasks, despite being capable of learning to solve these problems from a demonstrator. We suggest that this "innovation gap" arises from tool tasks with more complex spatial relations. Following Fragaszy and Mangalam's new tooling theory, we predicted that innovating a new "sticker slide" task should be more challenging when two tools need to be used at the same time (concurrently) rather than one at a time (sequentially), despite the similarity of the other task elements. In line with previous work, both versions of the task were challenging for all ages of children (4-9 years) that we tested. However, the youngest group showed particularly extreme difficulties, which was marked by not a single child innovating the concurrent version. Although success significantly increased with age, even the oldest group failed to reach 50% success on the concurrent version of the task, whereas the majority of the two older groups could solve the sequential version. Thus, in this first study of concurrent tool use in children, we found support for the prediction that increasing the complexity of spatial relations in tooling exacerbates the innovation gap., (© 2024. The Author(s).)

The use of tool sets constitutes one of the most elaborate examples of animal technology, and reports of it in nature are limited to chimpanzees and Goffin's cockatoos. Although tool set use in Goffin's was only recently discovered, we know that chimpanzees flexibly transport tool sets, depending on their need. Flexible tool set transport can be considered full evidence for identification of a genuine tool set, as the selection of the second tool is not just a response to the outcomes of the use of the first tool but implies recognizing the need for both tools before using any of them (thus, categorizing both tools together as a tool set). In three controlled experiments, we tested captive Goffin's in tasks inspired by the termite fishing of Goualougo Triangle's chimpanzees. Thereby, we show that some Goffin's can innovate the use and flexibly use and transport a new tool set for immediate future use; therefore, their sequential tool use is more than the sum of its parts. VIDEO ABSTRACT., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

In four experiments, we explored the inferences people make when they learn that counterfactual thinking has occurred. Experiment 1 ( N = 40) showed that knowing that a protagonist had engaged in counterfactual thinking (compared to no counterfactual thinking) resulted in participants inferring that the past event was closer in time to the protagonist, but there was no difference in inferring how close the past event was between knowing that a protagonist made many or a single counterfactual statement(s). Experiment 2 ( N = 80) confirmed that participants were not affected by the number of counterfactual statements they read when inferring temporal closeness. Experiment 3 ( N = 49) demonstrated that participants who learned that a protagonist had engaged in counterfactual thinking were more likely to infer that the protagonist experienced the controllable event. Experiment 4 ( N = 120) indicated that participants who learned that a protagonist had engaged in counterfactual thinking were more likely to infer that the protagonist experienced the exceptional event. We concluded that the existence (but not the number) of counterfactual thoughts can lead people to infer that events were close, exceptional, and controllable, which suggests that the relations between closeness/controllability/exceptionality and counterfactual thinking are bidirectional. These results showed that as well as making inferences based on facts about the real world, people also make inferences about the real world based on hypothetical worlds., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xie and Beck.)

Associative Tool Use (ATU) describes the use of two or more tools in combination, with the literature further differentiating between Tool set use, Tool composite use, Sequential tool use and Secondary tool use. Research investigating the cognitive processes underlying ATU has shown that some primate and bird species spontaneously invent Tool set and Sequential tool use. Yet studies with humans are sparse. Whether children are also able to spontaneously invent ATU behaviours and at what age this ability emerges is poorly understood. We addressed this gap in the literature with two experiments involving preschoolers (E1, N = 66, 3 years 6 months to 4 years 9 months; E2, N = 119, 3 years 0 months to 6 years 10 months) who were administered novel tasks measuring Tool set, Metatool and Sequential tool use. Participants needed to solve the tasks individually, without the opportunity for social learning (except for enhancement effects). Children from 3 years of age spontaneously invented all of the types of investigated ATU behaviours. Success rates were low, suggesting that individual invention of ATU in novel tasks is still challenging for preschoolers. We discuss how future studies can use and expand our tasks to deepen our understanding of tool use and problem-solving in humans and non-human animals., (© The Author(s) 2022.)

Composite tool use (using more than one tool simultaneously to achieve an end) has played a significant role in the development of human technology. Typically, it depends on a number of specific and often complex spatial relations and there are thus very few reported cases in non-human animals (e.g., specific nut-cracking techniques in chimpanzees and capuchin monkeys). The innovative strategies underlying the innovation and spread of tool manufacture and associative tool use (using > 1 tools) across tool using animals is an important milestone towards a better understanding of the evolution of human technology. We tested Goffin's cockatoos on a composite tool problem, the 'Golf Club Task', that requires the use of two objects in combination (one used to control the free movement of a second) to get a reward. We demonstrate that these parrots can innovate composite tool use by actively controlling the position of the end effector and movement of both objects involved in a goal directed manner. The consistent use of different techniques by different subjects highlights the innovative nature of the individual solutions. To test whether the solution could be socially transmitted, we conducted a second study, which provided only tentative evidence for emulative learning. To our knowledge, this indicates that the cognitive preconditions for composite tool use have also evolved outside the primate lineage., (© 2022. The Author(s).)

The ratchet effect - the accumulation of beneficial changes in cultural products beyond a level that individuals could reach on their own - is a topic of increasing interest. It is currently debated which social learning mechanisms allow for the generation and transmission of cumulative culture. This study focused on transmission, investigating whether 4- to 6-year-old children were able to copy cumulative technological design and whether they could do so without action information (emulation). We adapted the spaghetti tower task, previously used to test for accumulation of culture in human adults. A baseline condition established that the demonstrated tower design was beyond the innovation skills of individual children this age and so represented a culture-dependent product for them. There were 2 demonstration conditions: a full demonstration (actions plus (end-)results) and an endstate- demonstration (end-results only). Children in both demonstration conditions built taller towers than those in the baseline. Crucially, in both demonstration conditions some children also copied the demonstrated tower. We provide the first evidence that young children learn from, and that some of them even copy, cumulative technological design, and that - in line with some adult studies - action information is not always necessary to transmit culture-dependent traits.

Recent studies of children's tool innovation have revealed that there is variation in children's success in middle-childhood. In two individual differences studies, we sought to identify personal characteristics that might predict success on an innovation task. In Study 1, we found that although measures of divergent thinking were related to each other they did not predict innovation success. In Study 2, we measured executive functioning including: inhibition, working memory, attentional flexibility and ill-structured problem-solving. None of these measures predicted innovation, but, innovation was predicted by children's performance on a receptive vocabulary scale that may function as a proxy for general intelligence. We did not find evidence that children's innovation was predicted by specific personal characteristics., (© 2016 The Authors.)

The variety and complexity of human-made tools are unique in the animal kingdom. Research investigating why human tool use is special has focused on the role of social learning: while non-human great apes acquire tool-use behaviours mostly by individual (re-)inventions, modern humans use imitation and teaching to accumulate innovations over time. However, little is known about tool-use behaviours that humans can invent individually, i.e. without cultural knowledge. We presented 2- to 3.5-year-old children with 12 problem-solving tasks based on tool-use behaviours shown by great apes. Spontaneous tool use was observed in 11 tasks. Additionally, tasks which occurred more frequently in wild great apes were also solved more frequently by human children. Our results demonstrate great similarity in the spontaneous tool-use abilities of human children and great apes, indicating that the physical cognition underlying tool use shows large overlaps across the great ape species. This suggests that humans are neither born with special physical cognition skills, nor that these skills have degraded due to our species' long reliance of social learning in the tool-use domain., (© 2016 The Authors.)

In three studies, we explored the retention and transfer of tool-making knowledge, learnt from an adult demonstration, to other temporal and task contexts. All studies used a variation of a task in which children had to make a hook tool to retrieve a bucket from a tall transparent tube. Children who failed to innovate the hook tool independently saw a demonstration. In Study 1, we tested children aged 4-6 years (N = 53) who had seen the original demonstration 3 months earlier. Performance was excellent at the second time, indicating that children's knowledge was retained over the 3 month period. In Studies 2 and 3 we explored transfer of the new knowledge to other tasks. In Study 2, children were given two variants of the apparatus that differed in surface characteristics (e.g., shape and color). Participants generalized their knowledge to these new apparatuses even though the new pipecleaner also differed in size and color. Five- to 6-year-olds (N = 22) almost always transferred their knowledge to problems where the same tool had to be made. Younger, 3- to 5-year-olds' (N = 46), performance was more variable. In Study 3, 4- to 7-year-olds (N = 146) saw a demonstration of hook making with a pipecleaner, but then had to make a tool by combining pieces of wooden dowel (or vice versa: original training on dowel, transfer to pipecleaner). Children did not transfer their tool-making knowledge to the new material. Children retained tool-making knowledge over time and transferred their knowledge to new situations in which they needed to make a similar tool from similar materials, but not different materials. We concluded that children's ability to use tool-making knowledge in novel situations is likely to depend on memory and analogical reasoning, with the latter continuing to develop during middle childhood.

We know that even young children are proficient tool users, but until recently, little was known about how they make tools. Here, we will explore the concepts underlying tool making, and the kinds of information and putative cognitive abilities required for children to manufacture novel tools. We will review the evidence for novel tool manufacture from the comparative literature and present a growing body of data from children suggesting that innovation of the solution to a problem by making a tool is a much more challenging task than previously thought. Children's difficulty with these kinds of tasks does not seem to be explained by perseveration with unmodified tools, difficulty with switching to alternative strategies, task pragmatics or issues with permission. Rather, making novel tools (without having seen an example of the required tool within the context of the task) appears to be hard, because it is an example of an 'ill-structured problem'. In this type of ill-structured problem, the starting conditions and end goal are known, but the transformations and/or actions required to get from one to the other are not specified. We will discuss the implications of these findings for understanding the development of problem-solving in humans and other animals.

Saying something "almost happened" indicates that one is considering a close counterfactual world. Previous evidence suggested that children start to consider these close counterfactuals at around 2 years of age (P. L. Harris, 1997), substantially earlier than they pass other tests of counterfactual thinking. However, this success appears to result from false positives. In Experiment 1 (N = 41), 3- and 4-year-olds could identify a character who almost completed an action when the comparison did not complete it. However, in Experiments 1 and 2 (N = 98), children performed poorly when the comparison character completed the action. In Experiment 3 (N = 28), 5- and 6-year-olds consistently passed the task, indicating that they made appropriate counterfactual interpretations of the "almost" statements. This understanding of close counterfactuals proved more difficult than standard counterfactuals., (© 2011 The Authors. Child Development © 2011 Society for Research in Child Development, Inc.)

Children more frequently specified possibilities correctly when uncertainty resided in the physical world (physical uncertainty) than in their own perspective of ignorance (epistemic uncertainty). In Experiment 1 (N=61), 4- to 6-year-olds marked both doors from which a block might emerge when the outcome was undetermined, but a single door when they knew the block was hidden behind one door. In Experiments 2 (N=30; 5- to 6-year-olds) and 3 (N=80; 5- to 8-year-olds), children placed food in both possible locations when an imaginary pet was yet to occupy one, but in a single location when the pet was already hidden in one. The results have implications for interpretive theory of mind and "curse of knowledge."

Elevated C-reactive protein (CRP) levels are associated with both prevalent and incident cardiovascular disease. In this study, familial aggregation was estimated, and we tested for association between serum CRP levels and polymorphisms within the CRP and APOE genes in sib-ships with type 2 diabetes mellitus, a population at increased risk for cardiovascular disease. CRP levels were determined in 461 diabetes-affected subjects from 224 sibships from the Diabetes Heart Study (DHS). Heritability estimates of CRP levels were obtained using variance component models. Genetic influence on serum CRP levels by single nucleotide polymorphisms (SNPs) in the CRP and APOE genes was evaluated by association analysis using mixed models. Subjects were Caucasian American (84%) and African-American (16%), 53% female, and had an average age of 62.2 +/- 9.2 years. The median CRP level was 3.3 mg/L (range 0 to 59.3 mg/L), and estimated heritability for CRP was approximately 40%. Estimates of heritability were significantly greater than zero (P < 0.0001) and relatively constant, despite adjustments for important modifiers (age, sex, ethnicity, diabetes duration, statin-use and anti-inflammatory use) of CRP. There was no significant evidence for association of CRP levels with CRP gene SNPs; however, consistent with previous reports, there was significant evidence of association of CRP levels with polymorphisms within the APOE gene. These data indicate CRP levels are significantly influenced by genetic (and/or environmental) factors that are shared within DHS families. While the APOE locus shows evidence of contributing to CRP levels, no evidence of CRP gene polymorphism association with CRP levels was observed.

Two experiments explored whether children's correct answers to counterfactual and future hypothetical questions were based on an understanding of possibilities. Children played a game in which a toy mouse could run down either 1 of 2 slides. Children found it difficult to mark physically both possible outcomes, compared to reporting a single hypothetical future event, "What if next time he goes the other way ..." (Experiment 1: 3-4-year-olds and 4-5-year-olds), or a single counterfactual event, "What if he had gone the other way ...?" (Experiment 2: 3-4-year-olds and 5-6-year-olds). An open counterfactual question, "Could he have gone anywhere else?," which required thinking about the counterfactual as an alternative possibility, was also relatively difficult.

Background: Adhesion molecules, such as P-selectin, play a pivotal role in leukocyte adhesion to the endothelium during inflammation. We investigated the relationship between P-selectin gene polymorphisms and albuminuria in 565 European American siblings (84% with type 2 diabetes) from 227 families participating in the Diabetes Heart Study (DHS)., Methods: Three common missense P-selectin polymorphisms (S290N, N562D, and T715P) were genotyped. Albuminuria was defined as an albumin:creatinine ratio (ACR) > or = 17 mg/g in males, and > or = 25 mg/g in females. Tests of association were based on generalized estimating equations (GEE1) and tests of linkage disequilibrium were based on the quantitative pedigree disequilibrium test (QPDT)., Results: Each copy of the 290Asn (S290N) allele was associated with a 45% absolute increase in ACR (P= 0.007), and a higher risk for the presence of albuminuria [odds ratio (OR), 1.71 for each 290A sn allele] (P= 0.002). Adjustment for other determinants of ACR, including stratification by age, gender, and presence of diabetes, did not alter these results. Haploytpe analyses using both GEE1 and QPDT methods revealed that the N-N-T haplotype, containing asparagine codons at sites S290N and N562D, was associated with an increased risk of albuminuria (OR 1.77) (P= 0.005, for each additional copy of the N-N-T haplotype)., Conclusion: The 290Asn (S290N) variant of P-selectin was associated with a higher prevalence and greater degree of albuminuria in European American siblings of type 2 diabetic families.

Aims/hypothesis: The heritability of fasting serum insulin and glucose concentrations in non-diabetic members of multiplex hypertensive families is unknown., Methods: We calculated the familial aggregation of fasting serum glucose and insulin concentrations and performed a genome-wide scan to assess whether quantitative trait loci contribute to these phenotypes in 2,412 non-diabetic individuals from 1,030 families enrolled in the Hypertension Genetic Epidemiology Network (HyperGEN) in the Family Blood Pressure Program., Results: The heritability (+/-SE) of fasting serum insulin was 0.47+/-0.085 in European Americans and 0.28+/-0.08 in African Americans (p<0.0001 for both), after adjusting for age, sex, and BMI. A genome-wide scan for fasting serum insulin yielded a maximum log of the odds (LOD) score of 2.36 on chromosome 5 at 20 cM (p=0.0004) in European Americans, and an LOD score of 2.28 on chromosome 19 at 11 cM (p=0.0004) in African Americans. The heritability of fasting serum glucose was 0.5109+/-0.08 in the former and 0.29+/-0.09 in the latter (p<0.0003 for both) after adjusting for age, sex and BMI. A genome-wide scan for fasting serum glucose revealed a maximum LOD score of 2.07 on chromosome 5 at 26 cM (p=0.0009) in European Americans., Conclusions/interpretation: These analyses demonstrate the marked heritability of fasting serum insulin and glucose concentrations in families enriched for the presence of members with hypertension. They suggest that genes associated with fasting serum insulin concentration are present on chromosomes 19 and 5, and that genes associated with fasting serum glucose concentration are on chromosome 5, in families enriched for hypertension.

Objectives: To research the lay public's understanding of equipoise and randomisation in randomised controlled trials (RCTs) and to look at why information on this may not be not taken in or remembered, as well as the effects of providing information designed to overcome barriers., Design: Investigations were informed by an update of systematic review on patients' understanding of consent information in clinical trials, and by relevant theory and evidence from experimental psychology. Nine investigations were conducted with nine participants., Setting: Access (return to education), leisure and vocational courses at Further Education Colleges in the Midlands, UK., Participants: Healthy adults with a wide range of educational backgrounds and ages., Investigations: Participants read hypothetical scenarios and wrote brief answers to subsequent questions. Sub-samples of participants were interviewed individually to elaborate on their written answers. Participants' background assumptions concerning equipoise and randomisation were examined and ways of helping participants recognise the scientific benefits of randomisation were explored., Main Outcome Measures: Judgments on allocation methods; treatment preferences; the acceptability of random allocation; whether or not individual doctors could be completely unsure about the best treatment; whether or not doctors should reveal treatment preferences under conditions of collective equipoise; and how sure experts would be about the best treatment following random allocation vs doctor/patient choice. Assessments of understanding hypothetical trial information., Results: Recent literature continues to report trial participants' failure to understand or remember information about randomisation and equipoise, despite the provision of clear and readable trial information leaflets. In current best practice, written trial information describes what will happen without offering accessible explanations. As a consequence, patients may create their own incorrect interpretations and consent or refusal may be inadequately informed. In six investigations, most participants identified which methods of allocation were random, but judged the random allocation methods to be unacceptable in a trial context; the mere description of a treatment as new was insufficient to engender a preference for it over a standard treatment; around half of the participants denied that a doctor could be completely unsure about the best treatment. A majority of participants judged it unacceptable for a doctor to suggest letting chance decide when uncertain of the best treatment, and, in the absence of a justification for random allocation, participants did not recognise scientific benefits of random allocation over normal treatment allocation methods. The pattern of results across three intervention studies suggests that merely supplementing written trial information with an explanation is unlikely to be helpful. However, when people manage to focus on the trial's aim of increasing knowledge (as opposed to making treatment decisions about individuals), and process an explanation actively, they may be helped to understand the scientific reasons for random allocation., Conclusions: This research was not carried out in real healthcare settings. However, participants who could correctly identify random allocation methods, yet judged random allocation unacceptable, doubted the possibility of individual equipoise and saw no scientific benefits of random allocation over doctor/patient choice, are unlikely to draw upon contrasting views if invited to enter a real clinical trial. This suggests that many potential trial participants may have difficulty understanding and remembering trial information that conforms to current best practice in its descriptions of randomisation and equipoise. Given the extent of the disparity between the assumptions underlying trial design and the assumptions held by the lay public, the solution is unlikely to be simple. Nevertheless, the results suggest that including an accessible explanation of the scientific benefits of randomisation may be beneficial provided potential participants are also enabled to reflect on the trial's aim of advancing knowledge, and to think actively about the information presented. Further areas for consideration include: the identification of effective combinations of written and oral information; helping participants to reflect on the aim of advancing knowledge; and an evidence-based approach to leaflet construction.

Objective: To conduct linkage analysis for body mass index (BMI, kg/m2), waist-to-hip ratio (WHR), visceral adipose tissue mass (VAT, cm2) and subcutaneous adipose tissue mass (SAT, cm2) using a whole genome scan., Design: Cross-sectional family study., Study Subjects: African-American families from Los Angeles (AA, n=21 extended pedigrees) and Hispanic-American families (HA) from San Antonio, TX (HA-SA, n=33 extended pedigrees) and San Luis Valley, CO (HA-SLV, n=12 extended pedigrees), totaling 1049 individuals in the Insulin Resistance and Atherosclerosis (IRAS) Family Study., Measurements: VAT and SAT were measured using a computed tomography scan obtained at the fourth and fifth lumbar vertebrae. All phenotypes were adjusted for age, gender, and study center. VAT, SAT, and WHR were analyzed both unadjusted and adjusted for BMI., Results: Significant linkage to BMI was found at D3S2387 (LOD=3.67) in African-Americans, and at D17S1290 in Hispanic-Americans (LOD=2.76). BMI-adjusted WHR was linked to 12q13-21 (D12S297 (LOD=2.67) and D12S1052 (LOD=2.60)) in Hispanic-Americans. The peak LOD score for BMI-adjusted VAT was found at D11S2006 (2.36) in Hispanic families from San Antonio. BMI-adjusted SAT was linked to D5S820 in Hispanic families (LOD=2.64). Evidence supporting linkage of WHR at D11S2006, VAT at D17S1290, and SAT at D1S1609, D3S2387, and D6S1056 was dependent on BMI, such that the LOD scores became nonsignificant after adjustment of these phenotypes for BMI., Conclusions: Our findings both replicate previous linkage regions and suggest novel regions in the genome that may harbor quantitative trait locis contributing to variation in measures of adiposity.

African Americans are at increased risk of type 2 diabetes and many diabetes complications. We have carried out a genome-wide scan for African American type 2 diabetes using 638 affected sibling pairs (ASPs) from 247 families ascertained through impaired renal function to identify type 2 diabetes loci in this high-risk population. Of the 638 ASPs, 210 were concordant for diabetes with impaired renal function. A total of 390 markers, at an average spacing of 9 cM, were genotyped by the Center for Inherited Disease Research (CIDR) as part of the International Type 2 Diabetes Linkage Analysis Consortium. Nonparametric linkage (NPL) analyses conducted using the exponential model implemented in Genehunter Plus provided suggestive evidence for linkage at 6q24-q27 (163.5 cM, logarithm of odds [LOD] 2.26). Multilocus NPL regression analysis identified the 6q locus (D6S1035, LOD 2.67) and two additional regions: 7p (LOD 1.06) and 18q (LOD 0.87) as important in this model. NPL regression-based interaction analyses and ordered subset analyses (OSAs) supported the presence of a locus at chromosome 7p (29-34 cM) in the pedigrees with the earliest mean age of diagnosis of type 2 diabetes (P = 0.009 for interaction, DeltaP = 0.0034 for OSA) and lower mean BMI (P = 0.009 for interaction, DeltaP = 0.070 for OSA). These results provide evidence that genes predisposing African-American individuals to type 2 diabetes are located in the 6q and 7p regions of the genome.

With the availability of longitudinal data, age-specific (stratified) or age-adjusted genetic analyses have the potential to localize different putative trait influencing loci. If age does not influence the locus-specific penetrance function within the range examined, age-stratified analyses will tend to yield comparable results for an individual trait. However, age-stratified results should vary across age strata when the locus-specific penetrance function is age dependent. In this paper, age-stratified and age-adjusted quantitative trait loci (QTL) linkage analyses were contrasted for height, weight, body mass index (BMI), and systolic blood pressure on a subset of the Framingham Heart Study. The strata comprised individuals with data present in each of three age groups: 31-49, 50-60, 61-79. Genome-wide QTL analyses were performed using SOLAR. Over all ages, a linkage signal for height was detected on chromosome 14q11.2 near marker GATA74E02A (LOD for ages 31-49 = 2.38, LOD for ages 50-60 = 1.84, LOD for ages 61-79 = 2.45). Evidence of linkage to BMI in the 31-49 age group was found on chromosome 3q22 (GATA3C02, LOD = 2.89, p = 0.0003) at the same location as the signal for weight (LOD = 3.10, p = 0.0002). Linkage was also supported on chromosome 1p22.1 for BMI (LOD = 2.21, p = 0.0014) and weight (LOD = 2.47, p = 0.0007) in the 31-49 age group. Our age-stratified results suggest that QTL that are expressed over long periods of time and affecting multiple, correlated traits may be identified using genome scan and variance-component methodology to help detect early and/or late gene expression.

The Framingham Heart Study provides a unique source of longitudinal family data related to CVD risk factors. Age-stratified heritability estimates were obtained over three age groups (31-49 years, 50-60 years, and 61-79 years), reflecting the longitudinal nature of the data, for four quantitative traits. Age-adjusted heritability estimates were obtained at a single common time point for the same four quantitative traits. The importance of these groups is that they consist of the same individuals. The highest age-stratified heritability estimate (h2 = 0.88 (+/- 0.06)) was for height in the model adjusting for gender over all three age groups. SBP gave the lowest heritability estimate (h2 = 0.15 (+/- 0.11)) for the 70 age group in the model adjusting for gender, height, BMI, smoker, and drinker. BMI had slightly higher estimates (h2 = 0.64 (+/- 0.11)) in the 40 age group than previously published. The highest age-adjusted heritability estimate (h2 = 0.90 (+/- 0.06)) was for height in the model adjusting for gender. SBP gave the lowest heritability estimate (h2 = 0.38 (+/- 0.09)) for unadjusted model. These results indicate that some common, complex traits may vary little in their genetic architecture over time and suggest that a common set of genes may be contributing to observed variation for these longitudinally collected phenotypes.

Albuminuria increases the risk of cardiovascular events in patients with essential hypertension and diabetic subjects. The heritability (h2) of albuminuria in multiplex hypertensive families is unknown. We calculated the familial aggregation of urine albumin:creatinine ratio (ACR) and performed a genome-wide scan to assess for loci contributing to ACR in participants enrolled in the Hypertension Genetic Epidemiology Network (HyperGEN). To perform the genome scan, we analyzed genotype results from 2589 individuals from 805 families in the Family Blood Pressure Program. ACR and covariates were available in 1727 individuals (mean age, 57.1 years). Estimates of h2 were obtained by using variance component methodology as implemented in the SOLAR software package. Linkage was tested between 387 markers spanning the genome at an average interval of 9.32 cM, using SOLAR multipoint analysis. The h2 of log urine ACR was 0.49 (P<1x10(-7)) after controlling for significant main and interactive effects of age, gender, race, body mass index, blood pressure, and use of ACE inhibitors or angiotensin-2 receptor blockers. The genome-wide scan revealed a maximum LOD score of 2.73 on chromosome 19 (robust corrected LOD, 2.40; P=0.0009) at marker D19S591 and a LOD score of 2.0 on chromosome 12 (robust corrected LOD, 1.75; P=0.005) at marker PAH. These analyses demonstrate the marked heritability of urine ACR in families enriched for the presence of members with essential hypertension. They suggest that a gene(s) associated with urinary ACR may be present on human chromosomes 19 and 12.

A high performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was developed to measure the thymosin alpha 1 (Talpha1) concentration in human serum. Tá1 in human serum was determined by solid phase extraction and reverse phase LC-MS/MS. The high-performance liquid chromatography (HPLC) system interfaced with the MS/MS system with a Turbo Ion spray interface. Positive ion detection and multiple reaction monitoring (MRM) mode were used for this human serum quantitation. Eight different concentration standards were used to establish the detection range. Six quality control (QC) and 2 matrix blanks were checked by calibration curves performed on the same day. The lower quantitation limit was 0.5 ng/mL Talpha1 in human serum. Calibration curves were established between 0.5 to 100 ng/mL by weighted linear regression. The correlation coefficients for different days were 0.9955 or greater. Quantitation of Talpha1 by the LC-MS/MS method is fast, accurate, and precise.