Dear Editor,

I am very grateful to Ken Uchino for amplifying and clarifying the detail of some of the points I was trying to make within the word limits of a 'Perspectives' paper. I suggest there are four key elements:

1. The epidemiology is indeed complex and I am neither an academic nor an epidemiologist. However, it would appear that we can agree that there is indeed a difference between 'younger old' (i.e. 65-75) and 'older old' (i.e. 80+), both in relative and absolute risk - albeit in opposite directions. The key point here is not the strength of the associations with age, but the magnitude of impact of treating the risk factor at any given age. This is where interventional trials come in.

2. As I pointed out in my paper, the data about treating hypertension in 80+ year olds accumulated prior to HYVET were very suggestive of benefit; they predicted HYVET would give a definitive answer. HYVET - by far the largest trial looking at patients aged 80+ - failed to live up to this promise. Sadly, the premature termination of the trial (because of excess mortality in the placebo group) arguably raised more questions about the clinical applicability of its results, than the trial answered.

3. The PROSPER trial examined the use of statins in European patients initially aged 70-82 (mean 75), and followed up for an average of 3.2 years. Nearly 20% of patients entered into the 4-week single-blind placebo lead-in period failed to proceed to the randomised period (either for using <75% or more than 120% of placebo, or because they refused to participate). This raises questions as to generalisability. Whilst reducing cardiovascular events, the intervention failed to show a reduction in stroke. I fully accept that absence of evidence is not necessarily evidence of absence, but this must surely raise questions as to the magnitude of any true effect.

4. None of these trials looked into the patients' preferences and priorities re outcomes. I argue that these change significantly with advancing frailty and incapacity (which in turn increase disproportionately with, but are not confined to, increasing age).

If we cannot even be certain of the ostensibly simple quantitative aspect of the decision (the certainty of the magnitude of the treatment effects), how can we properly weigh that up against the much more difficult to define qualitative aspects (the beliefs, values, and priorities of my patient)?

My central point is that without robust evidence applicable to the patient in front of me - usually over 80, and often very frail - how can I help the patient to reach truly informed consent? I may well have some of the estimates of magnitude wrong, but the principle still stands. A treatment decision is only as strong as its weakest link. I suggest that there are so many weak links in this particular evidence chain that it is almost impossible to reach a decision that all doctors would support. Suggesting that a simple 'one size fits all' (i.e. algorithmic guideline- based) solution would be appropriate is simplistic. Without more data we cannot be sure.

For all these reasons I strongly urge that we undertake randomised trials of withdrawals of treatment in real life elderly patients (both frail and robust). This has the potential to find out how much impact these interventions have in clinical practice, as opposed to in the rarefied environment of scientific clinical trials.

In the UK NHS we arguably should have a real opportunity to use 'big data' in real life in this way to find out if there are any signals there amongst the noise. A simple pragmatic trial involving tens of thousands of people would surely have a good chance of giving us the information we need? If the NHS funded this with the money currently earmarked for hitting treatment targets in those over 80, it would not take long to answer this question.

Conflict of Interest:

None declared

Dear Editor,

We are very grateful for the positive comments from Dr Basaria about our meta-analysis of randomized controlled trials (RCTs) showing that testosterone therapy among men increases the risk of a cardiovascular -related event (1;2). As per the Preferred Reporting Items for Systematic Reviews and meta-Analysis (PRISMA) guidelines (item 25) (3), we also highlighted the limitations of our review. We are surprised that a comment on compliance with the PRISMA guidelines is followed by the sentence "Therefore, firm conclusions regarding the association between testosterone therapy and CVD cannot be drawn from this study" (1). This line of reasoning would preclude firm conclusions being drawn from all well-conducted meta-analyses of RCTs, which inevitably each have limitations as well as strengths. In a recent update of the Competing Interests statement associated with his commentary, Dr Basaria, and the editor, have clarified a number of potential conflicts of interest including connections with pharmaceutical companies selling or developing testosterone therapy, which may affect readers' interpretation of the commentary. A separate report describes the way pharmaceutical companies have subtly promoted testosterone therapy (4) despite growing evidence of its harmful effects.

References

(1) Basaria S. Need for standardising adverse event reporting in testosterone trials. Evid Based Med 2013.

(2) Xu L, Freeman G, Cowling BJ, et al. Testosterone and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med 2013;11(1):108.

(3) Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6(7):e1000097.

(4) Braun SR. Promoting "Low T": A Medical Writer's Perspective. JAMA Intern Med 2013;173(15):1458-1460.

Conflict of Interest:

None declared

Dear Editor,

We would like to thank DeFrank and Brewer for their interest in our recently published paper: Long-Term Psychosocial Consequences of False- Positive Screening Mammography.(1)

In the Methods section DeFrank and Brewer write: "Brodersen and colleagues conducted a study of 454 adult women in Denmark screened in the same time period who had normal mammography screening results, false- positives or breast cancer diagnoses." We (Brodersen & Siersma) included 454 adult women in Denmark who had abnormal mammography screening results (false-positives or breast cancer diagnoses) and 864 women with normal screening results - all 1318 screened in the same time period.

In the Methods section DeFrank and Brewer also state that the questionnaire we used: the Consequences Of Screening in Breast Cancer (COS -BC), is a revised version of the question: the Psychosocial Consequences Questionnaire (PCQ). This is not the case. Together with the developer of the original Australian version of the PCQ - deceased Professor Jill Cockburn - we published a systematic reviewed on "The adequacy of measurement of short and long-term consequences of false-positive screening mammography".(2) Part of our conclusion was: "The PCQ is an adequate questionnaire for measuring short-term consequences, and the PCQ is preferable to other measures because of its higher sensitivity. However, there is little evidence that the PCQ is able to adequately detect all long-term consequences of screening mammography. Given the inadequacy of the measurement instruments used, any current conclusions about the long-term consequences of false-positive results of screening mammography must remain tentative". In a qualitative study including six focus interviews with women having false-positive screening mammography we found that the PCQ includes ambiguous items, does not cover all psychosocial consequences of false- positive screening mammography and three items from the PCQ were deleted because they were judged by interviewees to be irrelevant.(3) We also found that the women's experiences in the critical period from abnormal screening mammography until final false-positive diagnosis differed entirely from their experiences after the final diagnosis.(3) Therefore, fifteen new items were generated to cover the negative psychosocial consequences of abnormal and false-positive screening mammography comprehensively.(3) Five new items were produced that concerned the consequences of screening mammography during the period after being declared ''free from'' suspicion of cancer.(3) Response options for the positive items were changed to allow responses in both positive and negative directions. Our conclusion was: "Because of the major changes to both parts of the PCQ the measure derived from this study should be regarded as a new questionnaire with two parts: Consequences Of Screening in Breast Cancer (COS-BC). Part II focuses on the long-term consequences of a false-positive screening mammography".(3) Because we had developed a new questionnaire (based on Jill Cockburn's work) we conducted two psychometric studies using the Item Response Theory Partial Credit Rasch model for polytomous items plus Classical Test Theory to validate the COS-BC.(4;5) Therefore, it is slightly confusing that DeFrank and Brewer calls COS-BC for PCQr when it actually is a new measure. Due to this extensive qualitative and statistical psychometrical work we have provided robust high quality evidence that the subscales of the COS- BC measure each distinct constructs that are unidimensional. It is therefore wrong when DeFrank and Brewer in the Commentary section write that some "subscales mix multiple constructs". Furthermore, we have revealed that the PCQ lacks content validity and encompass ambiguous items. Because the COS-BC has high content validity and adequate psychometric properties we can conclude that the COS-BC and the PCQ do not measure the same thing. It is therefore not appropriate that DeFrank and Brewer compare the scores of the PCQ with the scores of the COS-BC. Furthermore, standard methods, like the correlation coefficients are different from our linear regression methods, and do not adjust for the differential dropout. As stated in our method section: "We used generalized estimating equations methods to account for repeated measurement on the same individual. To adjust for possible bias resulting from differential dropout from the study, the scores available at each follow-up time point were weighted by the inverse of an estimate of the probability of this score being observed at that time point".(1) Those people that are worse off have the tendency to drop out in surveys. In our case, women diagnosed with breast cancer and the women that are most affected by the false-positive screening result could have a higher tendency to drop out; analysing only the subjects that did not drop out will then artificially decrease effects. By using inverse probability weighing and correcting the confidence intervals accordingly using generalized estimating equations we have adjusted for this differential drop out. The relatively small effect sizes found and commented on by DeFrank and Brewer using our data may well be an artefact of not adjusting for dropout.

In the Commentary section DeFrank and Brewer also write that the COS -BC "has a subscale for breast self-examination, a behaviour that many guidelines now recommended against". However, the subscale has not anything to do with breast self-examination recommendations. In our qualitative study we found that women with false-positive screening mammography examined their breasts with their hands and examined their breasts in a mirror as a psychosocial consequence of the false-positive results and not because of any recommendation.

In the Commentary section DeFrank and Brewer also write: "The second half of the PCQr assesses how patients...". Most of these women are not patients. The main part of the women in our survey had a normal or a false -positive screening result and besides that they were healthy. In the same sentence DeFrank and Brewer continue:"....think the testing affected them and uses an uncommon scoring system." We do not find the scoring system as a limitation since the response categories and scoring system for part 2 of the COS-BC were developed during the previous mentioned focus group interviews.(3) Furthermore, part2 of the COS-BC was validated using the empirical knowledge from these interviews,(3) the theory of cognitive dissonance, the theory of sense of coherence, and as mentioned above Item Response Theory Partial Credit Rasch model for polytomous items. (4;6)

In the Commentary section DeFrank and Brewer lastly write: "Finally, the absence of analyses that demonstrate whether changes over time differed by test results, the internal consistency of measures and their reliability over time. Study findings would be strengthened by the inclusion of outcomes assessed before screening or learning of test results." Test for interaction between time and the three screening groups could have been added to the tables, but such test may not have been very informative because of the large differences between the trajectories in the start of follow-up: most tests for interaction were highly significant. Where items are shown to fit a Rasch model the measure can be shown to posses criterion-related construct validity,(7) to be objective (invariant),(8) sufficient(9) and, therefore, also reliable.(10) Furthermore, we have provided evidence that the items in the subscales do not posses differential item functioning in relation to time.

References

(1) Brodersen J, Siersma VD. Long-Term Psychosocial Consequences of False-Positive Screening Mammography. The Annals of Family Medicine 2013;11(2):106-15.

(2) Brodersen J, Thorsen H, Cockburn J. The adequacy of measurement of short and long-term consequences of false-positive screening mammography. J Med Screen 2004 Mar 1;11(1):39-44.

(3) Brodersen J, Thorsen H. Consequences Of Screening in Breast Cancer (COS-BC): development of a questionnaire. Scand J Prim Health Care 20081;26(4):251-6.

(4) Brodersen J. Measuring psychosocial consequences of false- positive screening results - breast cancer as an example. Department of General Practice, Institute of Public Health, Faculty of Health Sciences, University of Copenhagen: M?nedsskrift for Praktisk L?gegerning, Copenhagen. ISBN: 87-88638-36-7; 2006.

(5) Brodersen J, Thorsen H, Kreiner S. Validation of a condition- specific measure for women having an abnormal screening mammography. Value in Health 2007;10(4):294-304.

(6) Brodersen J, Thorsen H, Kreiner S. Consequences Of Screening in Lung Cancer: Development and Dimensionality of a Questionnaire. Value in Health 2010;13(5):601-12.

(7) Rosenbaum PR. Criterion-related construct validity. Psychometrika 1989 ;54(4):625-33.

(8) Rasch G. An Informal Report on a Theory of Objectivity in Comparisons. In: Van der Kamp LJTh, Vlek CAJ, editors. Psychological Measurement Theory.Leyden: University of Leyden; 1967:1-19.

(9) Andersen EB. Sufficient Statistics and Latent Trait Models. Psychometrika 1977;42:69-81.

(10) Bartholomew DJ. The Statistical Approach to Social measurement. San Diego: Academic Press; 1996.

Conflict of Interest:

None declared

Dear Editor,

We thank Beverly Winikoff and Jill Durocher for their thoughtful commentary.(1) Winikoff and Durocher note that the incidence of PPH in our study's (2) oxytocin group was higher than expected. This deviance can occur, particularly in studies with relatively small samples such as ours. Regardless, the randomization produced study groups with similar characteristics to each other,(2) although this particular sample of women had higher risk of postpartum hemorrhage than the general population, something that might be expected in the study hospital, a referral center.

Our results were also consistent with a previously published study comparing sublingual administration of 400 mg tablet misoprostol with oxytocin, one among various criteria upon which causal associations are judged to exist that our study met.(3) We agree and question the pragmatism of a powdered formulation in the article.(2) The potential to reduce drug costs by 33% remains substantial for a medication that is widely recommended for PPH prevention.(4)

We think there is little basis to question the drug potency in our study. The drug manufacturer, Astra-Zeneca provided us with the study medication directly, and we assume the potency was acceptable to the manufacturer upon distribution. Unlike the oxytocin stored under variable field conditions, potentially exposed to sunlight and high temperatures (potentially without refrigeration prior to their purchase in the cited Ghana study),(5) the packaged study medications were stored in a refrigerator maintained at 2 to 8 degrees Celsius within the clinical pharmacy department at our hospital until their use as stated in the manuscript.(2) What is not well known is whether intramuscular administration of oxytocin is less efficacious than oxytocin administered in intravenous solution; the Cochrane Review of uterotonics for PPH prevention typically analyzed IM and IV administration jointly(6) and whether the strong observed effect is attributable to the powdered formulation.

We agree that further investigation of these issues will clarify the questions our article raises about sublingual administration of lower dose misoprostol for PPH prevention.

References

1. Winikoff B, Durocher J. Postpartum bleeding is reduced with sublingual powdered misoprostol when compared with oxytocin injection, but a new formulation of misoprostol is unlikely to revolutionise postpartum haemorrhage care. Evid Based Med. 2012 Nov 2. 10.1136/eb-2012-100966.

2. Bellad M, Tara D, Ganachari M, et al. Prevention of postpartum haemorrhage with sublingual misoprostol or oxytocin: a double-blind randomised controlled trial. BJOG 2012;119:975-86.

3. Rothman KJ. What is Causation?" in Epidemiology: An Introduction. Oxford University Press, New York. 2012;pp 33

4. WHO recommendations for the prevention and treatment of postpartum haemorrhage 2012 http://apps.who.int/iris/bitstream/10665/75411/1/9789241548502_eng.pdf

5. Stanton C, Koski A, Cofie P, et al. Uterotonic drug quality: an assessment of the potency of injectable uterotonic drugs purchased by simulated clients in three districts in Ghana. BMJ Open 2012;2:e000431.

6. Gülmezoglu AM, Forna F, Villar J, Hofmeyr GJ. Prostaglandins for preventing postpartum haemorrhage. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD000494. DOI: 10.1002/14651858.CD000494.pub3.

Conflict of Interest:

None declared