Chris Frost

By how much does dietary salt reduction lower blood pressure? I--Analysis of observational data among populations.

OBJECTIVE--To estimate the quantitative relation between blood pressure and sodium intake. DESIGN--Data were analysed from published reports of blood pressure and sodium intake for 24 different communities (47 000 people) throughout the world. MAIN OUTCOME MEASURE--Difference in blood pressure for a 100 mmol/24 h difference in sodium intake. Allowance was made for differences in blood pressure between economically developed and undeveloped communities to minimise overestimation of the association through confounding with other determinants of blood pressure. RESULTS--Blood pressure was higher on average in the developed communities, but the association with sodium intake was similar in both types of community. A difference in sodium intake of 100 mmol/24 h was associated with an average difference in systolic blood pressure that ranged from 5 mm Hg at age 15-19 years to 10 mm Hg at age 60-69. The differences in diastolic blood pressure were about half as great. The standard deviation of blood pressure increased with sodium intake implying that the association of blood pressure with sodium intake in individuals was related to the initial blood pressure--the higher the blood pressure the greater the expected reduction in blood pressure for the same reduction in sodium intake. For example, at age 60-69 the estimated systolic blood pressure reduction in response to a 100 mmol/24 h reduction in sodium intake was on average 10 mm Hg but varied from 6 mm Hg for those on the fifth blood pressure centile to 15 mm Hg for those on the 95th centile. CONCLUSIONS--The association of blood pressure with sodium intake is substantially larger than is generally appreciated and increases with age and initial blood pressure.

By how much does dietary salt reduction lower blood pressure? III--Analysis of data from trials of salt reduction.

OBJECTIVE--To determine whether the reduction in blood pressure achieved in trials of dietary salt reduction is quantitatively consistent with estimates derived from blood pressure and sodium intake in different populations, and, if so, to estimate the impact of reducing dietary salt on mortality from stroke and ischaemic heart disease. DESIGN--Analysis of the results of 68 crossover trials and 10 randomised controlled trials of dietary salt reduction. MAIN OUTCOME MEASURE--Comparison of observed reductions in systolic blood pressure for each trial with predicted values calculated from between population analysis. RESULTS--In the 45 trials in which salt reduction lasted four weeks or less the observed reductions in blood pressure were less than those predicted, with the difference between observed and predicted reductions being greatest in the trials of shortest duration. In the 33 trials lasting five weeks or longer the predicted reductions in individual trials closely matched a wide range of observed reductions. This applied for all age groups and for people with both high and normal levels of blood pressure. In people aged 50-59 years a reduction in daily sodium intake of 50 mmol (about 3 g of salt), attainable by moderate dietary salt reduction would, after a few weeks, lower systolic blood pressure by an average of 5 mm Hg, and by 7 mm Hg in those with high blood pressure (170 mm Hg); diastolic blood pressure would be lowered by about half as much. It is estimated that such a reduction in salt intake by a whole Western population would reduce the incidence of stroke by 22% and of ischaemic heart disease by 16% [corrected]. CONCLUSIONS--The results from the trials support the estimates from the observational data in the accompanying two papers. The effect of universal moderate dietary salt reduction on mortality from stroke and ischaemic heart disease would be substantial--larger, indeed, than could be achieved by fully implementing recommended policy for treating high blood pressure with drugs. However, reduction also in the amount of salt added to processed foods would lower blood pressure by at least twice as much and prevent some 75,000 [corrected] deaths a year in Britain as well as much disability.

Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis

BACKGROUND TRACK-HD is a prospective observational study of Huntingtons disease (HD) that examines disease progression in premanifest individuals carrying the mutant HTT gene and those with early stage disease. We report 12-month longitudinal changes, building on baseline findings. METHODS we did a 12-month follow-up of patients recruited from the four TRACK-HD study sites in Canada, France, the Netherlands, and the UK. Participants were premanifest individuals (preHD) carrying the mutant HTT gene, patients with early HD, and controls matched by age and sex with the combined preHD and early HD groups. Data were collected by use of 3T MRI and clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric measures. Statistical analysis assessed annualised change with the use of linear regression models to estimate differences between groups. FINDINGS 116 preHD individuals, 114 early HD patients, and 115 people in the control group completed follow-up. Four preHD individuals, nine early HD patients, and eight people in the control group did not complete the follow-up. A further nine participants, who completed follow-up assessments, were unable to undergo MRI. After adjustment for demographics, annualised rates of generalised and regional brain atrophy were higher in preHD and early HD groups than in controls. Whole-brain atrophy rates were 0·20% (95% CI 0·05-0·34; p=0·0071) per year higher in preHD participants and 0·60% (0·44-0·76; p<0·0001) in early HD patients, and caudate atrophy rates were 1·37% (0·99-1·75; p<0·0001) per year higher in preHD and 2·86% (2·34-3·39; p<0·0001) in early HD. Voxel-based morphometry revealed grey-matter and white-matter atrophy, even in subjects furthest from predicted disease onset. Quantitative imaging showed statistically significant associations with disease burden, an indicator of disease pathology, and total functional capacity, a widely-used clinical measure of disease severity. Relative to controls, decline in cognition and quantitative motor function was detectable in both pre- and early HD, as was deterioration in oculomotor function in early HD. INTERPRETATION quantitative imaging showed the greatest differentiation across the spectrum of disease and functional measures of decline were sensitive in early HD, with cognitive and quantitative motor impairment also detectable in preHD. We show longitudinal change over 12 months in generalised and regional brain volume, cognition, and quantitative motor tasks in individuals many years from predicted disease onset and show the feasibility of obtaining quantifiable endpoints for future trials.

Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data

BACKGROUND TRACK-HD is a multinational prospective observational study of Huntingtons disease (HD) that examines clinical and biological findings of disease progression in individuals with premanifest HD (preHD) and early-stage HD. We aimed to describe phenotypic changes in these participants over 36 months and identify baseline predictors of progression. METHODS Individuals without HD but carrying the mutant huntingtin gene (classed as preHD-A if ≥10·8 years and preHD-B if <10·8 years from predicted onset), participants with early HD (classed as HD1 if they had a total functional capacity score of 11-13 and HD2 if they had a score of 7-10), and healthy control individuals were assessed at four study sites in the Netherlands, the UK, France, and Canada. We measured 36-month change for 3T MRI, clinical, cognitive, quantitative motor, and neuropsychiatric assessments and examined their prognostic value. We also assessed the relation between disease progression and the combined effect of CAG repeat length and age. All participants were analysed according to their baseline subgroups. Longitudinal results were analysed using a combination of repeated-measure weighted least squares models and, when examining risk of new diagnosis, survival analysis. FINDINGS At baseline, 366 participants were enrolled between Jan 17, and Aug 26, 2008, and of these 298 completed 36-month follow-up: 97 controls, 58 participants with preHD-A, 46 with preHD-B, 66 with HD1, and 31 with HD2. In the preHD-B group, several quantitative motor and cognitive tasks showed significantly increased rates of decline at 36 months, compared with controls, whereas few had at 24 months. Of the cognitive measures, the symbol digit modality test was especially sensitive (adjusted mean loss 4·11 points [95% CI 1·49-6·73] greater than controls; p=0·003). Among psychiatric indicators, apathy ratings specifically showed significant increases (0·34 points [95% CI 0·02-0·66] greater than controls; p=0·038). There was little evidence of reliable change in non-imaging measures in the preHD-A group, with the exception of the speeded tapping inter-tap interval (0·01 s [95% CI 0·01-0·02] longer than controls; p=0·0001). Several baseline imaging, quantitative motor, and cognitive measures had prognostic value, independent of age and CAG repeat length, for predicting subsequent clinical diagnosis in preHD. Of these, grey-matter volume and inter-tap interval were particularly sensitive (p=0·013 and 0·002, respectively). Longitudinal change in these two measures was also greater in participants with preHD who received a diagnosis of HD during the study compared with those who did not, after controlling for CAG repeat length and age-related risk (p=0·006 and 0·0003, respectively). In early HD, imaging, quantitative motor, and cognitive measures were predictive of decline in total functional capacity and tracked longitudinal change; also, neuropsychiatric changes consistent with frontostriatal pathological abnormalities were associated with this loss of functional capacity (problem behaviours assessment composite behaviour score p<0·0001). Age and CAG repeat length explained variance in longitudinal change of multimodal measures, with the effect more prominent in preHD. INTERPRETATION We have shown changes in several outcome measures in individuals with preHD over 36 months. These findings further our understanding of HD progression and have implications for clinical trial design. FUNDING CHDI Foundation.

Reliability, repeatability and reproducibility: analysis of measurement errors in continuous variables

Clinical practice involves measuring quantities for a variety of purposes, such as aiding diagnosis, predicting future patient outcomes, and serving as endpoints in studies or randomized trials. Measurements are almost always prone to various sorts of errors, which cause the measured value to differ from the true value; accordingly, studies investigating measurement error frequently appear in this and other journals. The importance of measurement error depends upon the context in which the measurements in question are to be used. For example, a certain degree of measurement error may be acceptable if measurements are to be used as an outcome in a comparative study such as a clinical trial, but the same measurement errors may be unacceptably large to make measurements usable in individual patient management, such as screening or risk prediction. In the past 20 years many papers have been published advocating how studies of measurement error should be analyzed, with a paper by Bland and Altman1 being one of the most cited and well known examples. There has been much controversy concerning the choice of parameter to be estimated and reported, and consequently confusion surrounding the meaning and interpretation of results from studies investigating measurement error. In this paper we first distinguish between the general concepts of agreement and reliability to aid researchers in considering which are relevant for their particular application. We then review the statistical methods that can be used to investigate and quantify agreement and reliability, dealing separately with the different types of measurement error study, while emphasizing the largely common techniques that should be used for data analysis. We reiterate that the judgment of whether agreement or reliability are acceptable must be related to the clinical application, and cannot be proven by a statistical test. We highlight the fact that reliability depends on the population in which measurements are made, and not just on the measurement errors of the measurement method. We discuss the advantages of method comparison studies making at least two measurements with each measurement method on each subject. A key advantage is that the cause of a correlation between paired differences and means in the so-called Bland–Altman plot can be determined, in contrast to when only a single measurement is made with each method. Throughout the paper, we try to emphasize that calculated values of agreement and reliability from measurement error studies are estimates of parameters, and as such we should report such estimates with CIs to indicate the uncertainty with which they have been estimated. We restrict our attention to measurements of a continuous quantity; alternative methods are required for categorical data2.

Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data.

BACKGROUND TRACK-HD is a prospective observational biomarker study in premanifest and early Huntingtons disease (HD). In this report we define a battery of potential outcome measures for therapeutic trials. METHODS We assessed longitudinal data collected at baseline, 12 months, and 24 months at sites in Leiden (Netherlands), London (UK), Paris (France), and Vancouver (Canada). Participants were individuals without HD but carrying the mutant HTT gene (ie, premanifest HD), patients with early HD, and healthy control individuals matched by age and sex to the combined HD groups. Data were collected with 3T MRI, clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric assessments. We estimated adjusted, between-group differences in rates of change in these measures and concomitant longitudinal effect sizes. FINDINGS Longitudinal data were available for 116 control individuals, 117 premanifest gene carriers, and 116 participants with early HD. Significantly greater progressive grey-matter, white-matter, whole-brain, and regional atrophy was recorded in the premanifest and early HD groups than in the control group. Effect sizes for atrophy rates between participants with early HD and controls were largest in the caudate (2·04, 95% CI 1·68 to 2·48) and white matter (1·70, 1·40 to 2·08). Functional, quantitative motor, and cognitive measures deteriorated to a greater extent in the early HD group than in controls, with the largest effect size in the symbol digit modality test (1·00, 0·67 to 1·27). In the early HD group, changes in structural imaging and various cognitive and quantitative motor scores were associated with worsening total motor score (TMS) and total functional capacity (TFC). In the premanifest group, despite significant declines in regional and overall brain volumes, few functional variables showed significant 24 month change compared with controls; TMS, emotion recognition, and speeded tapping were exceptions. Premanifest individuals with progression, predefined as an increase in TMS score of 5 points or more, any TFC decline, or a new diagnostic confidence score of 4, exhibited higher rates of brain atrophy and deterioration on some quantitative motor tasks compared with other premanifest participants. INTERPRETATION On the basis of longitudinal effect size, we recommend several objective outcome measures for clinical trials in participants with early HD. Hypothetical treatment effects defined by slower longitudinal changes in these measures would be detectable over a realistic timescale with practical sample sizes. The restricted 24 month cognitive or motor decline in the premanifest sample illustrates the greater challenge in trial design for this group. FUNDING CHDI/HighQ Foundation Inc.

Infant feeding patterns and risks of death and hospitalization in the first half of infancy: multicentre cohort study

OBJECTIVE To determine the association of different feeding patterns for infants (exclusive breastfeeding, predominant breastfeeding, partial breastfeeding and no breastfeeding) with mortality and hospital admissions during the first half of infancy. METHODS This paper is based on a secondary analysis of data from a multicentre randomized controlled trial on immunization-linked vitamin A supplementation. Altogether, 9424 infants and their mothers (2919 in Ghana, 4000 in India and 2505 in Peru) were enrolled when infants were 18-42 days old in two urban slums in New Delhi, India, a periurban shanty town in Lima, Peru, and 37 villages in the Kintampo district of Ghana. Mother-infant pairs were visited at home every 4 weeks from the time the infant received the first dose of oral polio vaccine and diphtheria-pertussis-tetanus at the age of 6 weeks in Ghana and India and at the age of 10 weeks in Peru. At each visit, mothers were queried about what they had offered their infant to eat or drink during the past week. Information was also collected on hospital admissions and deaths occurring between the ages of 6 weeks and 6 months. The main outcome measures were all-cause mortality, diarrhoea-specific mortality, mortality caused by acute lower respiratory infections, and hospital admissions. FINDINGS There was no significant difference in the risk of death between children who were exclusively breastfed and those who were predominantly breastfed (adjusted hazard ratio (HR) = 1.46; 95% confidence interval (CI) = 0.75-2.86). Non-breastfed infants had a higher risk of dying when compared with those who had been predominantly breastfed (HR = 10.5; 95% CI = 5.0-22.0; P < 0.001) as did partially breastfed infants (HR = 2.46; 95% CI = 1.44-4.18; P = 0.001). CONCLUSION There are two major implications of these findings. First, the extremely high risks of infant mortality associated with not being breastfed need to be taken into account when informing HIV-infected mothers about options for feeding their infants. Second, our finding that the risks of death are similar for infants who are predominantly breastfed and those who are exclusively breastfed suggests that in settings where rates of predominant breastfeeding are already high, promotion efforts should focus on sustaining these high rates rather than on attempting to achieve a shift from predominant breastfeeding to exclusive breastfeeding.

Prevalence of Angina in Women Versus Men A Systematic Review and Meta-Analysis of International Variations Across 31 Countries

Background— In the absence of previous international comparisons, we sought to systematically evaluate, across time and participant age, the sex ratio in angina prevalence in countries that differ widely in the rate of mortality due to myocardial infarction. Methods and Results— We searched MEDLINE and EMBASE until February 2006 for healthy population studies published in any language that reported the prevalence of angina (Rose questionnaire) in women and men. We obtained myocardial infarction mortality rates from the World Health Organization. A total of 74 reports of 13 331 angina cases in women and 11 511 cases in men from 31 countries were included. Angina prevalence varied widely across populations, from 0.73% to 14.4% (population weighted mean 6.7%) in women and from 0.76% to 15.1% (population weighted mean 5.7%) in men, and was strongly correlated within populations between the sexes (r=0.80, P<0.0001). Angina prevalence showed a small female excess with a pooled random-effects sex ratio of 1.20 (95% CI 1.14 to 1.28, P<0.0001). This female excess was found across countries with widely differing myocardial infarction mortality rates in women (interquartile range 12.7 to 126.5 per 100 000), was particularly high in the American studies (1.40, 95% CI 1.28 to 1.52), and was higher among nonwhite ethnic groups than among whites. This sex ratio did not differ significantly by participant’s age, the year the survey began, or the sex ratio for mortality due to myocardial infarction. Conclusions— Over time and at different ages, independent of diagnostic and treatment practices, women have a similar or slightly higher prevalence of angina than men across countries with widely differing myocardial infarction mortality rates.

A meta-analysis of hippocampal atrophy rates in Alzheimer's disease

Hippocampal atrophy rates are useful in both diagnosing and tracking Alzheimers disease (AD). However, cohorts and methods used to determine such rates are heterogeneous, leading to differences in reported annualised rates. We performed a meta-analysis of hippocampal atrophy rates in AD patients and matched controls from studies reported in the peer-reviewed literature. Studies reporting longitudinal volume change in hippocampi in AD subjects together with controls were systematically identified and appraised. All authors were contacted either to confirm the results or to provide missing data. Meta-analysis and meta-regression were then performed on this data. Nine studies were included from seven centres, with data from a total of 595 AD and 212 matched controls. Mean (95% CIs) annualised hippocampal atrophy rates were found to be 4.66% (95% CI 3.92, 5.40) for AD subjects and 1.41% (0.52, 2.30) for controls. The difference between AD and control subject in this rate was 3.33% (1.73, 4.94).

Correcting for regression dilution bias: comparison of methods for a single predictor variable

In an epidemiological study the regression slope between a response and predictor variable is underestimated when the predictor variable is measured imprecisely. Repeat measurements of the predictor in individuals in a subset of the study or in a separate study can be used to estimate a multiplicative factor to correct for this ‘regression dilution bias’. In applied statistics publications various methods have been used to estimate this correction factor. Here we compare six different estimation methods and explain how they fall into two categories, namely regression and correlation‐based methods. We provide new asymptotic variance formulae for the optimal correction factors in each category, when these are estimated from the repeat measurements subset alone, and show analytically and by simulation that the correlation method of choice gives uniformly lower variance. The simulations also show that, when the correction factor is not much greater than 1, this correlation method gives a correction factor which is closer to the true value than that from the best regression method on up to 80% of occasions. We also provide a variance formula for a modified correlation method which uses the standard deviation of the predictor variable in the main study; this shows further improved performance provided that the correction factor is not too extreme. A confidence interval for a corrected regression slope in an epidemiological study should reflect the imprecision of both the uncorrected slope and the estimated correction factor. We provide formulae for this and show that, particularly when the correction factor is large and the size of the subset of repeat measures is small, the effect of allowing for imprecision in the estimated correction factor can be substantial.