Five-year follow-up of a family-based multidisciplinary program for children with obesity.

OBJECTIVE: This study aimed to determine 5-year outcomes from a 12-month, family-based, multidisciplinary lifestyle intervention program for children. METHODS: This study was the 5-year follow-up of a randomized clinical trial comparing a low-intensity control group (home-based assessments) with a high-intensity intervention group (assessments plus weekly sessions) in New Zealand. Participants were aged 5 to 16 years with BMI ≥ 98th centile or > 91st centile with weight-related comorbidities. The primary outcome was BMI standard deviation score (BMISDS). Secondary outcomes included various health markers. RESULTS: Of the 199 children included in the study at baseline (47% who identified as Maori, 53% who identified as female, 28% in the most deprived quintile, mean age = 10.7 years, mean BMISDS = 3.12), 86 completed a 5-year assessment (43%). BMISDS reduction at 12 months was not retained (control = 0.00 [95% CI: -0.22 to 0.21] and intervention = 0.17 [95% CI: -0.01 to 0.34]; p = 0.221) but was greater in participants aged <10 years versus >10 years at baseline (-0.15 [95% CI: -0.33 to 0.03] vs. 0.21 [95% CI: 0.03 to 0.40]; p = 0.008). BMISDS trajectory favored participants with high attendance (p = 0.013). There were persistent improvements in water intake and health-related quality of life in both groups as well as reduced sweet drink intake in the intervention group. CONCLUSIONS: This intervention, with high engagement from those most affected by obesity, did not achieve long-term efficacy of the primary outcome. Attendance and age remain important considerations for future interventions to achieve long-term BMISDS reduction.

A new approach to assessment of the left ventricle.

Cardiac motion is a continuous process; however most measurements to assess cardiac function are taken at brief moments in the cardiac cycle. Using functional data analysis, repeated measurements of left ventricular volume recorded at each frame of a continuous image measured with cardiac ultrasound (echocardiography) were turned into a function of volume over time. The first derivative of the displacement of volume with respect to time is velocity; the second derivative is acceleration. Plotting volume, velocity, and acceleration against each other in a 3-dimensional plot results in a closed loop. The area within the loop is defined by the kinematics of volume change and so may represent ventricular function. •We have developed an approach to analyzing images of the left ventricle that incorporates information from throughout the cardiac cycle. •Comparing systolic and diastolic areas within a loop defined by volume, velocity, and acceleration of left ventricular volume highlights imbalances in the kinematics of the two phases, potentially indicating early sub-clinical disease.•Substantially more information about left ventricular function may be derived from a non-invasive clinically available tool such as echocardiography.

Food Intolerance: Associations with the rs12212067 Polymorphism of FOXO3 in Crohn's Disease Patients in New Zealand.

BACKGROUND: Diet is known to play a major role in Crohn's disease (CD). It has also been reported that the minor G allele from the rs12212067 polymorphism (T>G) in FOXO3 is associated with milder CD. The aim of this study was to investigate the association between the rs12212067 polymorphism and food intolerances for a total of 253 foods. METHODS: Tolerances and intolerances were recorded on a self-reported dietary questionnaire. Each food was scored on a 5-point ordinal scale: beneficial effects as '+ +' or '+', adverse effects as '- -' or '-', and 'makes no difference' as '='. Dietary and genotype data were available for a total of 283 CD patients. RESULTS: We identified 17 foods with beneficial effects in our study which were significantly associated with the G allele of the FOXO3 rs12212067 polymorphism. Of these, sweet potatoes had the highest reported frequency of beneficial responses. We also identified 4 foods with detrimental effects in more than 25% of our study population. These were mustard, wasabi, and raw and cooked tomatoes, which again were significantly associated with the G allele in FOXO3. CONCLUSIONS: There was strong evidence that adverse effects of mustard, wasabi, and raw and cooked tomatoes were significantly associated with the G allele of FOXO3 and that these foods should be avoided by people carrying this allele.

The development and feasibility of a composite score of echocardiographic indices that may stratify outcome in patients with diabetes mellitus.

BACKGROUND: Early detection of changes in cardiac structure and function associated with type 2 diabetes (T2DM) is important. However when multiple abnormalities are present, combining individual measurements can be subjective. This study sought to create a simple echo score that summarises measurements that may detect early and prognostically important changes in cardiac function. METHODS: Standard echocardiography was performed on 849 people with T2DM (median age 65years, 40% female, median duration of diabetes 5.5years). Principal components analysis was performed on measurements of LV mass, LA volume, E:e', and s', to create an objective summary score. The score was included in two Cox proportional hazard models adjusted for CV risk factors: one estimated the development of heart failure (HF) and the second estimated any CV event. RESULTS: The first two principal components represented 75% of the variation between the four echo measurements. A continuous score that represents the residual difference between these two components was derived that only requires measurement of medial E:e' and s'. The score was significantly associated with the development of HF within four years (hazard ratio 1.34; 95% CI 1.15, 1.56). CONCLUSIONS: We have developed a simple, objective score that enhances the use of echocardiography in the detection of sub-clinical cardiac disease in people with T2DM. Initial findings suggest that it may help identify those at increased risk of developing HF within four years.

A comparison of the effects of indexation on standard echocardiographic measurements of the left heart in a healthy multi-racial population.

Accurate reference ranges for measurements from echocardiography rely on an understanding of the distribution of each measurement in the diverse, multi-racial world population. The aim of this study was to determine the influence of gender, age and ethnicity on common echocardiographic measures of the left heart, and to evaluate the effect of different methods of indexation on measurements from healthy, non-Caucasian populations. Standard echocardiographic measurements of left heart size and left ventricular mass (LVM) were assessed in 341 healthy volunteers. Indexation was performed using height, body surface area, and fat free mass (FFM). Quantile regression was used to derive age-adjusted values at the 5th, 50th and 95th‰ of each measurement, by gender, within Caucasians. The effect of indexation method across ethnic groups could then be compared. Indexation of m-mode dimensions may overcompensate for body size, resulting in people of smaller build (women and those of South or East Asian descent) developing higher indexed values than those of larger build (men and people of Maori or Pacific descent). Indexation of 2D volumes by any method improves the integration of values across ethnic groups, with FFM yielding the greatest integration. LVM increases with age, suggesting that the static reference values currently recommended for this measurement may not be appropriate. There are important differences in the distribution of measurements of left heart size by gender, ethnicity and age.

Effects of supplementation with selenium, as selenized yeast, in a healthy male population from New Zealand.

Selenium (Se) supplementation was tested in a group of healthy men from Auckland, New Zealnd with selenized yeast (Selplex, 200 µg/day) as the supplementation mode. A set of biomarkers, including DNA damage levels and seleno-antioxidant enzyme levels, were evaluated at pre- and postsupplementation time points. Supplementation produced significant increases in serum Se levels, red blood cell (RBC) thioredoxin reductase (TR) activity and peroxide-induced DNA damage, when the mean baseline serum Se level was 110 ng/ml. Those with higher baseline serum Se levels gained less serum Se and showed a significant reduction of RBC glutathione peroxidase (GPx) activity by supplementation. The optimum benefits of supplementation on DNA stability are observed when the serum Se level reaches between >120 and <160 ng/ml. However, the most significant observation was that those with highest baseline DNA damage benefit the most from Se supplementation, whereas those having lower baseline DNA damage are disadvantaged. A dose of 200 µg/day selenized yeast was also shown to be a safer supplementation option compared to a similar dose of selenomethionine (SeMet). This study highlights the requirement for prestratification of a population by standing serum Se level and baseline DNA damage level, before any Se supplementation is carried out.

Serum selenium and single-nucleotide polymorphisms in genes for selenoproteins: relationship to markers of oxidative stress in men from Auckland, New Zealand.

There is controversy as to the recommended daily intake of selenium (Se), and whether current New Zealand diets are adequate in this nutrient. Various functional single-nucleotide polymorphisms (SNPs) polymorphisms may affect the efficacy of Se utilisation. These include the glutathione peroxidases GPx1 rs1050450, GPx4 rs713041, as well as selenoproteins SEPP1 rs3877899, SEL15 rs5845, SELS rs28665122 and SELS rs4965373. This cross-sectional study measured serum Se levels of 503 healthy Caucasian men in Auckland, New Zealand, between ages 20-81. The Se distribution was compared with activities of the antioxidant enzymes glutathione peroxidase and thioredoxin reductase, and DNA damage as measured by the single cell gel electrophoresis assay, both without and with a peroxide-induced oxidative challenge. Serum Se was measured using inductively coupled plasma-dynamic reaction cell-mass spectrometry, while selenoprotein SNPs were estimated using TaqMan(®) SNP genotyping assays. While antioxidant enzyme activities and DNA damage recorded after a peroxide challenge increased with increasing serum selenium, the inherent DNA damage levels in leukocytes showed no statistically significant relationship with serum selenium. However, these relationships and dietary Se requirements at the individual level were modified by several different SNPs in genes for selenoproteins. The GPx1 rs1050450 C allele was significantly associated with GPx activity. Significant correlations between serum Se level and GPX activity were seen with all genotypes except for homozygous minor allele carriers, while the GPx1 rs1050450 CT genotype showed the highest correlation. Several genotypes showed significant correlations between serum Se and TR activity with SEPP1 rs3877899 GG genotype showing the highest correlation. A significant decreasing trend in DNA damage with increasing serum Se was seen among GPx1 rs1050450 CC and GPx4 rs713041 TT genotype carriers up to a serum Se level of 116 and 149 ng/ml, respectively. In the absence of this genetic information, we would recommend a serum Se concentration in the region of 100-150 ng/ml as providing a useful compromise.

Genetic variations in matrix metalloproteinases may be associated with increased risk of ulcerative colitis.

Increased production of matrix metalloproteinases (MMPs) plays an important role in tissue damage in inflammatory bowel disease (IBD). Genetically encoded variation between individuals in MMP production may therefore contribute to disease onset, type, or severity. We undertook an extensive candidate gene single nucleotide polymorphism (SNP) study of MMP-1, -2, -3, -7, -8, -9, -10, -12, -13, and -14 and tissue inhibitor of metalloproteinases (TIMPs)-1, -3, and -4 in ulcerative colitis (UC). We identified tagging SNPs across these genes, and genotyped these SNPs in a Caucasian New Zealand dataset consisting of 419 UC patients and 907 controls. SNPs in a number of MMP genes were associated with UC. After correcting for multiple testing SNPs in MMP-3, MMP-8, MMP-10, and MMP-14 remained significant in their associations with UC. In a second study, using samples from a Dutch cohort, most of the significant findings in the New Zealand cohort were not replicated. However, data from an international meta-analysis provide some support for the initial findings. In conclusion, this study provides preliminary evidence to suggest that genetic variation in the MMPs may play a role in interindividual differences in UC susceptibility and clinical outcome. Further studies are needed in other cohorts to determine the robustness of these observations in different populations.

Prediction of ACC/AHA Stage B heart failure by clinical and neurohormonal profiling among patients in the community.

AIM: N-Terminal pro-B-type natriuretic peptide (NT-proBNP) is a useful test to "rule out" heart failure (HF) in patients presenting with dyspnea in primary care. However, many false positive diagnoses may occur. Early identification of abnormal left ventricular (LV) function would allow early intervention. The aim of this study was to predict LV dysfunction in these patients using a combination of neurohormones and other clinical factors. METHODS AND RESULTS: A total of 190 people with dyspnea and/or peripheral edema were assessed. In those with NT-proBNP <100 pmol/L (n = 125), two models were constructed to predict LV dysfunction and so differentiate stage B HF from stage A and no HF. Model 1 included clinical factors and a range of neurohormones, whereas NT-proBNP was the only neurohormone in model 2. A model containing NT-proBNP, A-type NP, NT C-type NP, adrenomedullin, endothelin, creatinine, age, gender, body surface area, cardiothoracic ratio, and hypertension gave the lowest false negative rate (FNR) of 8.2%. The FNR of the model restricted to NT-proBNP as the only neurohormone was 13.7%. CONCLUSIONS: This study demonstrated that by combining a neurohormonal profile with clinical variables, it is possible to differentiate stage B from stage A or no HF in patients presenting to primary care, enabling early intervention which can reduce the progression to stage C HF.

Dietary factors in chronic inflammation: food tolerances and intolerances of a New Zealand Caucasian Crohn's disease population.

Diet is known to play a major role in the symptoms of the inflammatory bowel disease, Crohn's disease (CD). Although no single diet is appropriate to all individuals, most CD patients are aware of foods that provide adverse or beneficial effects. This study seeks to categorise foods in relation to their effects on symptoms of CD, in a New Zealand Caucasian population. Four hundred and forty-six subjects from two different centres in New Zealand were recruited into the study. An extensive dietary questionnaire (257 food items in 15 groups) recorded self-reported dietary tolerances and intolerances. Across each of the food groups, there were statistically significant differences among responses to foods. A two-dimensional graphical summary enabled stratification of foods according to the probability that they will be either beneficial or detrimental. A small number of foods are frequently considered to be beneficial, including white fish, salmon and tuna, gluten-free products, oatmeal, bananas, boiled potatoes, sweet potatoes (kumara), pumpkin, soya milk, goat's milk and yoghurt. Foods that are typically considered detrimental include grapefruit, chilli or chilli sauce, corn and corn products, peanuts, cream, salami, curried foods, cola drinks, high energy drinks, beer, and red wine. For a number of the food items, the same item that was beneficial for one group of subjects was detrimental to others; in particular soya milk, goat's milk, yoghurt, oatmeal, kiwifruit, prunes, apple, broccoli, cauliflower, linseed, pumpkin seed, sunflower seed, ginger and ginger products, beef, lamb, liver, and oily fish. It was not possible to identify a specific group of food items that should be avoided by all CD patients. The wide range of detrimental items suggests that dietary maintenance of remission is likely to be difficult, and to exclude a substantial number of foods. Personalised diets may be especially important to these individuals.

Mushroom intolerance: a novel diet-gene interaction in Crohn's disease.

Carrying a functional single nucleotide polymorphism (L503F, c. 1672 C>T) in the gene for the Na-dependent organic cation transporter (OCTN1), increases the risk of Crohn's disease (CD) in some, but not all, populations. Case-control data on New Zealand Caucasians show no differences for CD risk between individuals carrying the L503F OCTN1 C-allele when compared with those carrying the variant T-allele. However, more of the New Zealand CD cases report intolerance to maize and mushrooms than those who report beneficial effects or no differences. The OCTN1 gene encodes a transporter for ergothionine, a fungal metabolite at high levels in mushrooms but not widely common in other dietary items. An inability to tolerate mushrooms showed statistically significant associations with the variant OCTN1 genotype. That is, among those individuals reporting adverse effects from mushrooms, there was a higher frequency of the variant T-allele when compared with the general population, or with CD patients overall. We believe that this is a novel gene-diet association, suggesting that individuals carrying the OCTN1 variant single nucleotide polymorphism may have an enhanced risk of adverse symptoms associated with consuming mushrooms. Nutrigenomic approaches to dietary recommendations may be appropriate in this group.

Prenatally undernourished rats show increased preference for wheel running v. lever pressing for food in a choice task.

Maternal nutrition during pregnancy has a significant influence in establishing patterns of metabolism and postnatal behaviours in offspring, and therefore shapes their risk of developing disorders in later life. Although it is well established that a mismatch between food consumption and energy expenditure leads to obesity and metabolic dysregulation, little research has investigated the biological origin of such behaviour. We conducted the present experiments to investigate effects of early-life nutrition on preference between wheel running and lever pressing for food during adult life. To address this issue we employed a well-established experimental approach in the rat which has shown that offspring of mothers undernourished during pregnancy develop obesity and metabolic disorders when kept under standard laboratory conditions. Using this experimental approach, two studies were conducted where offspring of ad libitum-fed dams and dams undernourished throughout pregnancy were given the choice between wheel running and pressing a response lever for food. Across subsequent conditions, the rate at which the response lever provided food was varied from 0.22 to 6.0 (study 1) and 0.19 to 3.0 (study 2) pellets per min. Compared with the control group, offspring from dams undernourished during pregnancy showed a consistently greater preference for running over lever pressing for food throughout both experiments of the study. The results of the present study provide experimental evidence that a mother's nutrition during pregnancy can result in a long-term shift in her offspring's lifestyle choices that are relevant to obesity prevention. Such a shift, if endorsed, will have substantial and wide-ranging health consequences throughout the lifespan.

Relatedness and DNA: are we taking it seriously enough?

In forensic DNA testimony most DNA laboratories report the match probability for an unrelated person from some relevant population. These laboratories typically make available the match probability for relatives when requested. This practice has served well for many years. However, as the discrimination power of our multiplexes has increased the estimated match probabilities for both related and unrelated people have become markedly smaller. Associated with this general reduction in match probabilities have been the observations that the relative balance between the match probabilities of the many unrelated people and the few relatives of a suspect has changed. We suggest that we should now report routinely the match probability for a sibling whenever the suspect has a non-excluded sibling.

Evidence in support of self-declaration as a sampling method for the formation of sub-population DNA databases.

Well constructed sub-population databases are fundamental to the application of DNA-based forensic statistics. The size of such databases can affect the ability to examine adequately statistical or population genetic features, and the integrity of both the DNA profile and associated ethnicity information is also of importance. Use of short tandem repeat (STR) DNA profiling technology and the thoughtful construction of the governing legislation has seen large databases of DNA profiles collated for the four major sub-populations of New Zealand. Examination of the data illustrates the suitability of self-declaration as a means of categorizing samples on the basis of ethnicity.

What is the magnitude of the subpopulation effect?

The effect of population subdivision on estimated match probabilities has been raised [Nature 339 (1989) 501; Am. J. Hum. Genet. 48 (1991) 819; Science 254 (1991) 1921]. Previous work [J. Forensic Sci. 39 (1994) 319; J. Forensic Sci. 39 (1994) 988; Am. J. Hum. Genet. 55 (1994) 533] has compared product rule estimates from differing databases and found that the "subpopulation" error may be of the order of a factor of 10. This approach compares an estimate with an estimate. This paper uses simulation to extend these studies by allowing a comparison to a 'true match probability' and supports the conclusion that subpopulation effects are mild. In addition the performance of recommendations 4.1 and 4.2 of NRC II [National Research Council and C.O.D.F. Science, The Evaluation of Forensic DNA Evidence, National Academy Press, Washington, DC, 1996].

A comparison of adjustment methods to test the robustness of an STR DNA database comprised of 24 European populations.

An aim of the European Network of Forensic Science Institutes (ENFSI) is to produce a DNA database of second generation multiplex (SGM) STR profiles that is representative of the resident cosmopolitan populations. To achieve this, data were collected from 24 different populations. All of the data were combined to form one database of 5700 profiles from which allele proportions were calculated. The robustness of this combined European database was tested by estimating parameter d for every DNA profile, where d=log(10)(Pm(c)/Pm(E)) Pm(c) is the match probability of the profile calculated from its cognate database and Pm(E) is the match probability of the combined European database. Overall there was a small tendency for Pm(c)>Pm(E) primarily because of sampling bias. This bias was removed by the simple expediency of applying an adjustment factor to the calculation of Pm(E). These were selected from the Balding size bias correction, the Balding and Nichols Fst correction, a minimum allele proportion (between 0.01 and 0.02), an upper bound of a 95% confidence interval (CI) and a lower bound on the genotype match probability. It was demonstrated that a single European database is a feasible proposition. A combination of different adjustment methods can be used to ensure that the result is conservative relative to the cognate database, and their effect measured by parameter d.

Does capture-recapture analysis provide more reliable estimates of the incidence and prevalence of leg ulcers in the community?

OBJECTIVE: To determine whether capture-recapture analysis provides more reliable estimates of the cumulative incidence and prevalence of leg ulcers in Auckland, New Zealand. METHODS: A population-based, cross-sectional study was conducted in the Central and North Auckland health districts of New Zealand in 1998. Cases were identified through health professional referral and by self-notification. All ages and ulcer types were investigated. Both traditional and capture-recapture methods of analysis were used to estimate the cumulative incidence and prevalence of leg ulcers in the study population. RESULTS: Four hundred and twenty-six people with current leg ulcers were identified during the 12-month study period. Using traditional methods of analysis, the annual cumulative incidence rate of leg ulcers in Auckland was 32 per 100,000, with a point prevalence of 39 per 100,000 and a period prevalence of 79 per 100,000 per year. Results from capture-recapture analysis, however, suggest an annual cumulative incidence rate of 252 per 100,000, with a point prevalence of 248 per 100,000 and a period prevalence of 530 per 100,000 per year. CONCLUSIONS: The traditional method of calculating cumulative incidence and prevalence clearly under-estimates the frequency of leg ulcers in the Auckland region. Capture-recapture analysis provides a more reliable estimate of disease frequency, since cases that remain unidentified in the population are considered.

Logical implications of applying the principles of population genetics to the interpretation of DNA profiling evidence.

There have been several efforts to codify the approach to interpreting DNA evidence [National Research Council, The Evaluation of Forensic DNA Evidence, National Academy Press, Washington, DC, 1996; I.W. Evett, B.S. Weir, Interpreting DNA Evidence: Statistical Genetics for Forensic Scientists Sinauer, Sunderland, MA, 1998]. Despite these efforts there are still aspects of ad hoc decision making in modern DNA interpretation. This article discusses some of the remaining areas of concern in this respect. Because of the immense discriminating power of DNA evidence it is unlikely that these concerns would contribute to a miscarriage of justice. They are more likely to lead to lengthy and wasteful debate in court, and to potential appeals. We advocate a previously developed approach to DNA evidence [Sci. Justice 39 (4) (1999) 257; B.S. Weir, in: D.J. Balding, C. Cannings, M. Bishop (Eds.), Handbook of Statistical Genetics, Wiley Series in Probability and Statistics, Wiley, New York, ISBN: 0-471-86094-8, 2001; J. R. Stat. Soc. A 158 (1) (1995) 21] that would give a more solid logical foundation and hopefully lead to sounder and less debatable testimony.