Friday, July 27, 2012

Amazing:  A failure reported  -- followed by a last minute save

"Negative" results are so rarely reported that my eyes nearly popped out when I saw the article immediately below.  A big study into  intake  of calcium and vitamin D found that they had no beneficial effect at all!

But my cynicism returned when I saw the article immediately following it.  The "failed" study was led by Alison Avenell and it seems that she was very disappointed by her results.  So she called on a big Danish knight in statistical armour to rescue her.

 The second study below rescues her hypothesis.  But it does so only by rounding up a whole heap of previous studies and amalgamating their data into one big statistical blob comprising 70,528  people.  Only then was he able to squeeze out some  evidence in favour of Alison's hypothesis.  The Abstracts from both studies are given below.

All I can say is that if you have to use 70,000 people to find some effect, it is a pretty weak effect and not one that anybody should bother about.  Quite tiny relationships can be demonstrated as statistically significant on samples of as few as 200 people.

And there are many pitfalls in meta-analyses.  The selection of which datasets to include is notoriously arbitrary, for instance

Long-Term Follow-Up for Mortality and Cancer in a Randomized Placebo-Controlled Trial of Vitamin D3 and/or Calcium (RECORD Trial)

By Alison Avenell et al.


Context: Vitamin D or calcium supplementation may have effects on vascular disease and cancer.

Objective: Our objective was to investigate whether vitamin D or calcium supplementation affects mortality, vascular disease, and cancer in older people.

Design and Setting: The study included long-term follow-up of participants in a two by two factorial, randomized controlled trial from 21 orthopedic centers in the United Kingdom.

Participants: Participants were 5292 people (85% women) aged at least 70 yr with previous low-trauma fracture.

Interventions: Participants were randomly allocated to daily vitamin D3 (800 IU), calcium (1000 mg), both, or placebo for 24–62 months, with a follow-up of 3 yr after intervention.

Main Outcome Measures: All-cause mortality, vascular disease mortality, cancer mortality, and cancer incidence were evaluated.

Results: In intention-to-treat analyses, mortality [hazard ratio (HR) = 0.93; 95% confidence interval (CI) = 0.85–1.02], vascular disease mortality (HR = 0.91; 95% CI = 0.79–1.05), cancer mortality (HR = 0.85; 95% CI = 0.68–1.06), and cancer incidence (HR = 1.07; 95% CI = 0.92–1.25) did not differ significantly between participants allocated vitamin D and those not. All-cause mortality (HR = 1.03; 95% CI = 0.94–1.13), vascular disease mortality (HR = 1.07; 95% CI = 0.92–1.24), cancer mortality (HR = 1.13; 95% CI = 0.91–1.40), and cancer incidence (HR = 1.06; 95% CI = 0.91–1.23) also did not differ significantly between participants allocated calcium and those not. In a post hoc statistical analysis adjusting for compliance, thus with fewer participants, trends for reduced mortality with vitamin D and increased mortality with calcium were accentuated, although all results remain nonsignificant.

Conclusions: Daily vitamin D or calcium supplementation did not affect mortality, vascular disease, cancer mortality, or cancer incidence.


But you can't keep true believers down

Vitamin D with Calcium Reduces Mortality: Patient Level Pooled Analysis of 70,528 Patients from Eight Major Vitamin D Trials

Lars Rejnmark, Alison Avenell, et al.


Introduction: Vitamin D may affect multiple health outcomes. If so, an effect on mortality is to be expected. Using pooled data from randomized controlled trials, we performed individual patient data (IPD) and trial level meta-analyses to assess mortality among participants randomized to either vitamin D alone or vitamin D with calcium.

Subjects and Methods: Through a systematic literature search, we identified 24 randomized controlled trials reporting data on mortality in which vitamin D was given either alone or with calcium. From a total of 13 trials with more than 1000 participants each, eight trials were included in our IPD analysis. Using a stratified Cox regression model, we calculated risk of death during 3 yr of treatment in an intention-to-treat analysis. Also, we performed a trial level meta-analysis including data from all studies.

Results: The IPD analysis yielded data on 70,528 randomized participants (86.8% females) with a median age of 70 (interquartile range, 62–77) yr. Vitamin D with or without calcium reduced mortality by 7% [hazard ratio, 0.93; 95% confidence interval (CI), 0.88–0.99]. However, vitamin D alone did not affect mortality, but risk of death was reduced if vitamin D was given with calcium (hazard ratio, 0.91; 95% CI, 0.84–0.98). The number needed to treat with vitamin D plus calcium for 3 yr to prevent one death was 151. Trial level meta-analysis (24 trials with 88,097 participants) showed similar results, i.e. mortality was reduced with vitamin D plus calcium (odds ratio, 0.94; 95% CI, 0.88–0.99), but not with vitamin D alone (odds ratio, 0.98; 95% CI, 0.91–1.06).

Conclusion: Vitamin D with calcium reduces mortality in the elderly, whereas available data do not support an effect of vitamin D alone.


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