Rapid Responses to:
|
|
Rapid Responses: Rapid Responses published:
-
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Vitamin D & MS
- Peter K Tun (8 December 2004)
-
Dietary link to variation in MS due to birth month
- James L Schinnerer (11 December 2004)
-
Damp climates, oestrogens, nutritional deficiencies and multiple sclerosis.
- Ellen C G Grant (12 December 2004)
-
Re: Damp climates, oestrogens, nutritional deficiencies and multiple sclerosis.
- Aasa Reidak (13 December 2004)
-
Month of birth and risk of multiple sclerosis : new light on past results with Bayesian analysis
- Joëlle Brassard (16 December 2004)
-
relationship
- marvin martin (16 December 2004)
-
Patient with Primary Progressive
- Jennifer Houtler (17 December 2004)
-
Argentinian Data (South Hemisphere)
- Geraldine G Luetic (13 January 2005)
-
Month of birth and degenerative bone diseases
- Vinjar Fonnebo (14 January 2005)
-
Multiple sclerosis, pineal gland and melatonin
- Michel R Odent (16 January 2005)
-
Maybe I missed something here
- Louis B Jacques (21 January 2005)
-
Response to "Timing of birth and risk of multiple sclerosis"
- Thomas Hansen, Esben Meulengracht Flachs, Egon Stenager, Nils Koch Henriksen (15 March 2005)
-
Re: Response to "Timing of birth and risk of multiple sclerosis"
- george c. ebers, Cristen Willer postdoctoral student University of MIchigan (18 March 2005)
-
Re: Argentinian Data (South Hemisphere)
- george ebers (18 March 2005)
-
Author's reply to five other responses
- george ebers (18 March 2005)
-
Taking year-of-birth into account
- Thomas Hansen, Esben Meulengracht Flachs, Egon Stenager, Nils Koch Henriksen (22 March 2005)
-
gestational vitamin D supplement via light
- Rob Swenson (18 February 2007)
|
|
|||
|
Peter K Tun, Associate Specialist Berkshire Neurorehabilitation Service, Royal Berkshire & Battle Hospital, READING, RG30 1AG, UK
Send response to journal:
|
I am very excited to hear the result of your study on my car radio this morning and also on internet news & BMJ first online. Vitamin D modulates the helper T2 lymphocytes to counter balance the activity of helper T1 lymphocytes.Overactive helper T1 lymphocytes are responsible for auto-immune diseases like type 1 diabetes mellitus (40 year followup study of Swedish infants & cod liver oil intake),rheumatoid arthritis, multiple sclerosis and possibly ulcerative collitis. In the American nurses study (n 186,000), followed up for 20 years, 173 developed MS and those who had taken vitamin D supplements 400 IU a day were found to have 40% less chance of developing MS in multivariate analysis (Published in Neurology Journal, 13 Jan 2004). Another study in Austarlia & Tasmania has shown that children between age 5-15 who played in the sun for 1 hour a day on weekends & holidays have 30% less MS that those who did not according to their diaries & actinic skin damage from skin samples. Eskimos & Japanese, living outside 42 degrees latitude, who consume plenty of fish rich in vitamin D (90% of the Japanese vitamin D requirement comes from fish, 3% from eggs & 3% from milk) has MS prevalence of 3/100,000 population whereas in Scotland & Tasmania the prevalence is 250/100,000 population. In Switzerland, those living on top of the mountains where they receive more sunshine have less MS than those living in the valleys where sunshine is blocked by cloud & smoke. Vitamin D absorption from gut is blocked by phytic acid present in wheat, barley, oat & corn.The only cereal that does not contain phytic acid is rice. Serum vitamin D levels of people in equator or sunny climates, where MS prevalence is zero, can be as high as 200 nmol/l without any ill effects. The accepted normal vitamin D level in England is 15-100 nmol/l. Average vitamin D level in America is abour 40 nmol/l. Vitamin D supplements of 1000 IU/day in an adult can increase vitamin D levels to around 60 nmol/l in 3 months. Vitamin D supplements of 4000 IU/day in an adult can increase vitamin D levels to 90 nmol/L in a week. In a German study on around 290 MS patients, frequency & density of MS plaques increases on MRI scan in December and reduces in July with a two months delay from significant seasonal change in intensity of sunshine (vitamin D winter is from October to May in the northern hamisphere). In Cambridge osteoporosis trial the cost of vitamin D supplements sent in post, 3 a times year cost 1 pound sterling. A prospective study is possible in high risk population. Competing interests: None declared |
|||
|
|
|||
|
James L Schinnerer, Researcher 906 Pomona Ave, Albany, CA 94706
Send response to journal:
|
I think it should be considered that diet could be a factor in the results shown in this study, in particular stored food versus fresh food. Even more specifically celiac disease and/or gluten sensitivity has been shown to be a risk factor for MS (Multiple Sclerosis) and could be related to birth month as well. Consider that the populations studied are all northern latitude populations, and it has been well documented that as such they are at much higher risk for celiac disease, in particular those in Scotland. Add to this the fact that the diet of those in the northern hemispheres is more seasonal the farther north you go. This leads to an increased reliance on grains and stored foods during the winter months and more fresh foods during the summer months and this corresponds with the variations in MS seen. That is to say that more grains and less fresh food in winter equals a higher incidence of MS for those born in May and more fresh food and less grains during summer and fall equals a lower incidence of MS in those born in November. So in conclusion it could be the nutritional benefits of fresh food alone, or in conjunction with celiac disease and the tendency of those with celiac disease towards malabsorbtion of nutrients, that are one of the environmental factors contributing to the results seen in this study. Competing interests: None declared |
|||
|
|
|||
|
Ellen C G Grant, physician and medical gynaecologist 20 Coombe Ridings, Kingston-upon-Thames, KT2 7JU, UK
Send response to journal:
|
Damp conditions and nutritional deficiencies are likely to be major causes of multiple sclerosis.1 The late Regina Schoental wrote that man and animals are sporadically exposed to mycotoxins (the secondary metabolites of moulds), which include those produced in damp and cool environment by the almost ubiquitous soil- microfungi, the Fusaria.2 She was concerned that perinatal exposure to the mycotoxins might cause damage to many organs, including the CNS and those which are targets for oestrogenic agents, because of their high fat content. Depending on the levels of the mycotoxins and the time of their action, the effects may manifest themselves as neonatal abnormalities, or as neurological and behavioural anomalies and chronic disorders later in life. Schoental was also concerned about the use of hormones in pregnancy. Grains and milk may also become contaminated with moulds in damp climates. Johnson has described the possible role of gradual accumulation of copper, cadmium, lead and iron and gradual depletion of zinc, magnesium, selenium, vitamins B2, B6, D, and E and essential fatty acids in multiple sclerosis.3 He suggests that supplementation with 100 mg magnesium, 25 mg vitamin B6, 10 mg vitamin B2, 15 mg Zinc and 400 IU vitamin D and E, 100 micrograms Selenium, 180 mg EPA and 120 mg DHA per day between 14 and 16 years of age may prevent MS. However, comprehensive analyses of nutrient levels are available commercially and higher levels of individual supplements are often needed to ensure repletion of deficiencies. Low dose copper supplements (less than a milligram a day) help to avoid low copper stores and low functional SODase activities. Copper deficiency is especially likely in women with artificially high copper levels due to taking contraceptives or menopausal hormones. Antibiotics given for winter infections can cause increases in gut fermentation, with the production of low levels of alcohol in response to food – the “auto-brewery syndrome”.4 Absorption of nutrients is impaired and depressive symptoms and general malaise result. The beneficial effects of anti-fungal medication, low allergy diet (avoiding wheat, milk and yeast) and nutritional supplements can be dramatic. 1 Willer CJ, Dyment DA 2, Dessa Sadovnick D , et al, for the Canadian Collaborative Study Group. Timing of birth and risk of multiple sclerosis: population based study.BMJ, doi: 10.1136/bmj. 38301. 686030.63 (published 7 December 2004) 2 Schoental R. Fusarial mycotoxins and behaviour: possible implications for psychiatric disorder. Br J Psychiatry. 1985 Feb;146:115- 9. 3 Johnson S. The possible role of gradual accumulation of copper, cadmium, lead and iron and gradual depletion of zinc, magnesium, selenium, vitamins B2, B6, D, and E and essential fatty acids in multiple sclerosis. Med Hypotheses. 2000 Sep;55(3):239-41. 4 Eaton KK., McLaren Howard J, Hunnisett A, Harris M. Abnormal Gut Fermentation: Laboratory studies reveal deficiency of B vitamins, zinc, and magnesium. J Nutr Environ Med 2004; 14:115-120. Competing interests: None declared |
|||
|
|
|||
|
Aasa Reidak, elementary teacher Toronto M5B 2H9
Send response to journal:
|
I don't know much about possible causes of MS. On other sites, I have seen mercury in dental amalgams implicated in the development of MS. Nevertheless, I can't easily accept that one's birth month has much to do with the development of MS. If one's birth month does indeed predispose one to developing celiac disease and/or MS later in life, there is relatively easy dietary help available, which could start soon after the child is able to eat solid food or when the signs/symptoms begin to present themselves clinically. Many individuals with various intestinal problems (not only celiac disease) and other disorders (including autism, schizophrenia etc.) have been helped by the specific carbohydrate diet. Elaine Gottschall has been lecturing about the theory behind this diet and more information can be found in her book, entitled "Breaking the Vicious Cycle" and also at her website at www.breakingtheviciouscycle.com . The scd diet is gluten free and mostly casein free (although certain cheeses and homemade yogurt are allowed). I have been following this diet myself, since last July, and am glad to report that the chronic intestinal problems which I have experienced for the last two years, have now cleared up for the most part. As an added bonus, I have lost an unneeded 20 pounds without any calorie counting on my part and am still able to eat most of my favorite vegetables, fruits, and meats. I don't know whether this diet could help one with MS, but if celiac disease could be a prescursor or if mycotoxins are implicated, I believe that this diet may be worth a serious try. It is a bit a of a hassle to follow at first, especially if you still want to eat anything resembling bread or baked goods. However, once one gets accustomed to grinding nuts in a food processor to make nut flour, even this hurdle can be cleared. Competing interests: None declared |
|||
|
|
|||
|
Joëlle Brassard, Research agent Hôpital Cité de la santé, Laval (Québec) Canada
Send response to journal:
|
In their paper, the authors have shown that the babies born in the month of may may have higher risk of developing multiple sclerosis (MS). It is suggested that in familial cases, genes, environmental exposures (vitamin D deficiency in mother’s diet) and climate may interact in the etiologic pathway of MS. According to the authors, these etiologic mechanisms may act during prenatal period or shortly after birth. In 1996, I did a study on the incubation period of the age at onset of MS and the results seem to support the author’s hypothesis. A population of 196 patients (147 females, 49 males) diagnosed between 1990 and 1995 in the MS clinic of Hôpital Notre-Dame of Montréal (Québec). Patients were categorized by type of MS : 1) cyclic form (N=128) and 2) cyclo- progressive and progressive forms (N=68). This strategy was chosen because the MS forms are characterized by different symptoms which may suggest different etiologic causes. For example, the presence of family history is more frequent in patients with an early age at onset (Warren & al. 1991). Also, correlations of the age at onset were observed among monozygotic twins (Bulman & al., 1991; Sadovnick & al., 1990). On the other hand, in progressive form, changes in the endocrine system with age, should have an impact on production of T-cell suppressors. The phenomenon can contribute to an active continuation of the disease associated with progressive forms of MS (Noseworthy & al., 1983). Three models of hazard function were then selected (lognormal, Weibull and logistic) each one corresponding to a dynamic mechanism compatible with a specific etiological hypothesis of MS (major genetic origin (lognormal) or multi-exposures (Weibull) for the cyclic form and endocrine (logistic) for cyclo-progressive and progressive forms). Finally, Bayesian (Hill’s method, 1963) analysis based on the maximum likelihood was performed to looking for a point of origin of the distribution of the age at onset in patients with cyclic MS. With the log normality postulate and in the absence of environmental exposure common to all patients, a point of source in prenatal period should correspond to a genetic origin of MS. The results showed a good fit of the distribution of cyclic form of the disease with the lognormal and Weibull functions. The distribution of cyclo-progressive and progressive forms of MS showed a better fit with the logistic function but not with the lognormal and Weibull. Logistic function is characterized by an asymptote at a given threshold that indicates the end of the process. This function usually suggests an endocrine perturbation associated to the menopause period. Bayesian analysis revealed one point of origin in the prenatal period for the cyclic form. The high probability density region (95%) of the parameter was found between -.5 to -1.5 year and included the prenatal period. On the dynamic point of view, the lognormal fit suggested a process of geometrical progression. This distribution should be the result of the action of a large number of independent factors whose combined effect is multiplicative. So, multiple factors or independent events contribute proportionally to the final effect observed. The cyclic form of disease fits a Weibull function too (this function is part of a set of distributions (called « parallel models ») and this model suggest a system of multi « hits » or multi events for the development of the disease. In light of the prenatal hypothesis, these results obtained in 1996, take on a new meaning. In the absence of a hypothesis of common exposures at the same time for all patients (Horner and Samsa, 1992) I had concluded to genetic like major causal origin in patients with cyclic form of MS. Now, I look at my results with an other lens: first, I think that the Weibull function can represent the real process of development of MS; second, I think that maybe the point of origin should be associated with a prenatal exposure in predisposed persons. Also, I think that the density curve reveals a second mode about five or six years of age. Maybe this mode can be associated with an environmental exposure (bacteria, virus or a vaccine)? The modelisation of the incubation period of disease seems to me, a measure too coherent than others biological attributes. References Warren S, Codkerill R, Warren KG (1991). Risk factors by onset age in multiple sclerosis. Neuroepidemiology, 10 :9-17. Bulman DE, Sadovnick AD, Ebers GC (1991). Age of onset in sibblings concordant for multiple sclerosis. Brain, 114 :937-950. Sadovnick AD, Hashimoto LL, Hashimoto SA (1990). Heterogeneity in multiple sclerosis comparison of clinical manifestations in relatives. Canadian Journal of Neurologic Sciences, 17 :387-439. Noseworthy J, Paty D, Wonnacott T, Feasby T & Ebers G (1983). Multiple sclerosis after age 50. Neurology, 35 :435-38. Hill BM (1963). The three-parameter lognormal distribution and bayesian analysis of a point-source epidemic. American Statistical Association Journal, 58 :72-83. Horner RD, Samsa G (1992). Criteria for use of Sartwell’s incubation period model to study chronic diseases with uncertain etiology. Journal of Clinical epidemiology, 45(10) :1071-80. Parameter’s estimates of a posteriori density () 2 () ln L**() 12 11 10 9 8 7 6 5 4 3 2 1 .5 -.5 -1 -1.5 -2 2.51 2.60 2.68 2.76 2.83 2.89 2.95 3.01 3.05 3.10 3.15 3.19 3.21 3.25 3.27 3.29 3.31 .41 .31 .25 .21 .18 .16 .14 .12 .11 .10 .09 .08 .08 .07 .07 .06 .06 -263.86 -258.47 -255.38 -253.75 -252.57 -253.03 -251.92 -249.02 -250.01 -250.12 -249.95 -249.78 -250.02 -246.70 -244.64 -241.85 -249.40 : ages postulated to find the point of origin. ln L**() : maximum likelihood for each value of . Competing interests: None declared |
|||
|
|
|||
|
marvin martin, retired 29407
Send response to journal:
|
This article regarding MS was interesting. As a Guillain Barre survivor, I am interested if a similar predisposition for GBS may be associated. Competing interests: None declared |
|||
|
|
|||
|
Jennifer Houtler, disabled due to MS Mesa, AZ 85207
Send response to journal:
|
I have Primary Progressive and was born in December. I was diagnosed in 2001. I have always wondered if there was a correllation with the fact that at birth I was severly jaundice and needed a blood transfusion to add iron to my blood. My mother and I have opposite blood types. My sister is fine, although she gets the migraine headaches like our dad did since childhood, like he did. I got them for a period of three years, starting with losing the sight in my right eye for only one hour, then when it returned, had the headache. I had migraines for 3 years, then the MS symptoms started. My father died at 45 of a massive heart attack, so unfortunately he is not around to help answer any of this riddle. My sister did just have a baby. Her migraines continue. Have any studies been done with blood typing between mother and baby at birth? I believe my father had blood type O. I would be curious to know this as well as the hormone levels. Competing interests: None declared |
|||
|
|
|||
|
Geraldine G Luetic, Director of MS Department Sanatorio Britanico. Rosario. Argentina Instituto de Neurociencias de Rosario. Rosario (2000)
Send response to journal:
|
First of all, congratulations for the authors on such an extensive and powerful work. Recognizing MS risk factors is a key issue in finding new preventive measures that could lead in the future, to lower this disease incidence. I was very much concerned from 1998 on the observation that most of my patients from Rosario (Santa Fe) Argentina 29ª South Latitude, were born in winter. That's why I made 4 modest, consecutive observational comparative studies, presented in poster format at LACTRIMS Congress I Buenos Aires 2000, LACTRIMS Congress II Monterrey 2002 and ACTRIMS-ECTRIMS Congress Baltimore, Sept 2002. I found a statistically significant difference among Santa Fe's MS patients to be born in winter than in rest of seasons and when compared to a controlled group (their siblings). Although the limitations of this small study, we found in our area a seasonal tendency of birth towards winter and if we analyze monthy distribution of month of birth, the majority of MS patients were born in September (ending of winter).I agree with the authors that any environmental variable (such as sunlight exposition,vitamin D, viral infectious agent)may play a role in the latter development of MS. Unfortunately in our country we lack official statistics information about people date of birth. The total number of MS patients in Argentina according to the few prevalence studies (Melcon M, Cristiano E et al and the Patagonia Project data), is estimated in 6000 patients, so it is very difficult for us to contribute with extensive data. But it is important to highlight that we are making an effort in this area and this is our little contribution. The difference in month of birth aggregation found in North Hemisphere (higher in May) with my work's data (September) could find an explanation in the different climatic characteristics of both hemispheres. It would be interesting to analyze UV radiation, sunlight hours and other factors in North hemisphere during May and see if they match to the values found in the South Hemisphere during September. For the interested reader, the abstract of the poster presentation "Season of birth in Multiple Sclerosis" at ECTRIMS-ACTRIMS 2002, can be found in the journal Multiple Sclerosis (Arnold) Vol 8; Supp 1, 1 Sept 2002. Competing interests: None declared |
|||
|
|
|||
|
Vinjar Fonnebo, Professor National Research in Complementary and Alternative Medicine, N-9037 TROMSO, Norway
Send response to journal:
|
I read this paper with interest. The findings resemble closely what I reported on degenerative bone diseases in North Norway many years ago (1,2). Peak prevalence was found for persons born in April/May and the lowest prevalence was found in persons born in November. There must be some factor acting either in the fetal period or during the first year of life. For people born above the Arctic Circle it is easy to be drawn to a light-driven hypothesis, but others are possible. 1. Fonnebo V. Month of birth and prevalence of musculoskeletal diseases later in life. Lancet 1987;535:739-40. 2. Fonnebo V. Arthrosis of the hip and knee: environmental causes in the first year of life? A study of 1405 cases of arthrosis in north Norway 1984-1989. Arctic Med Res 1995;54:151-4. Competing interests: None declared |
|||
|
|
|||
|
Michel R Odent, Director Primal Health Research Centre. London NW3 2JR.
Send response to journal:
|
By combining the data linking timing of birth and risk of multiple sclerosis (MS) on the one hand(1), and previous findings of associations between higher latitudes and risk of MS on the other hand, the role of exposure to the sun in the pathogenesis of MS seems probable. Any attempt to interpret the effect of the sun should therefore include a reference to the light-dark sensitivity of the pineal gland, and to the wide-ranging interactions with growth factors of melatonin, which is also a mediator of immune functions and an effective free radical scavenger. Interpretations of the hard data provided by Willer et al would benefit from an overview of all studies linking seasonality of birth and a great variety of personality traits and health conditions. The Primal Health Research Data Bank(2) is specialized in studies exploring correlations between what happened during the ‘Primal period’ (from conception until the first birthday) and what will happen later on in life in terms of health and behaviour. Apart from MS, the keyword ‘seasonality of birth’ leads to topics as divers as life expectancy, body height, learning abilities, fecundability, sex ratio, brain tumours, childhood diabetes, coronary heart disease, insulin resistance, dyslipidemia, cerebrovascular diseases, degenerative bone diseases, substance abuse, schizophrenia, and eating disorders. References: 1 – Willer CJ, Dyment DA, Sadovnick AD, et al. Timing of birth and risk of multiple sclerosis: population based study. BMJ 2005; 330: 120-3. 2 – www.birthworks.org/primalhealth Competing interests: None declared |
|||
|
|
|||
|
Louis B Jacques, Physician Baltimore MD 21244
Send response to journal:
|
Interesting work. I may be missing something here though. What about the month of May (in terms of climate, diet, etc) is so different from April and June? Or possibly, if the risk is actually attributable to month of conception rather than birth month, why is February different from January or March? The May spike would be more convincing if June were not low, and followed by a rise in July. Competing interests: None declared |
|||
|
|
|||
|
Thomas Hansen, Statistician National Institute of Public Health, Øster Farimagsgade 5, DK--1399 København K, Denmark, Esben Meulengracht Flachs, Egon Stenager, Nils Koch Henriksen
Send response to journal:
|
Dear Sir. Recently Willer and colleagues(1) published analyses suggesting that risk for MS was associated with month of birth. Willer and colleagues summed the number of births over the years ranging from 1926 to 1970 to obtain a distribution of births in order to estimate an expected number of MS cases born in a particular month. Failing to take year of birth into account may lead to biased conclusion simply because MS cases born in one year are weighted relative to persons with completely different follow-up time. Another approach would be to follow cohorts of persons born in a particular month in a particular year and then compare the incidence of MS in such a cohort with a similar cohort born another month but from the same or an adjacent year. This corresponds to a simplified age-period- cohort model(2,3) including only cohorts and, additionally, birth month as a factor. Thus, we performed month/cohort modeling of births of MS cases based on data from the Danish Multiple Sclerosis Registry(4) and from Statistics Denmark covering cohorts from 1920 through 1960. The analyses were carried out as Poisson regressions of the number of MS cases born per number of live-born children with the effect of year included as natural cubic splines with knots every five year. We found no evidence of a month-of-birth effect on the risk for MS (P=0.142), though it does appear that persons born during certain time periods of a year (in particular during late Autumn and Winter [September through February]) may have lower risk for MS than persons born outside this period. 1) Cristen J Willer, David A Dyment, A Dessa Sadovnick, Peter M Rothwell, T Jock Murray, George C Ebers for the Canadian Collaborative Study Group. Timing of birth and risk of multiple sclerosis: population based study. BMJ 2005; 330: 125--125. 2) D. Clayton and E. Schifflers. Models for temporal variation in cancer rates. I: Age-period and age-cohort models. Statistics in Medicine, 6:449--467, 1987. 3) D. Clayton and E. Schifflers. Models for temporal variation in cancer rates. II: Age-period-cohort models. Statistics in Medicine, 6:469- -481, 1987. 4) Koch-Henriksen N, Rasmussen S, Stenager E, Madsen M. The Danish Multiple Sclerosis Registry. History, data collection and validity. Dan Med Bull 2001;48:91--94. Competing interests: None declared |
|||
|
|
|||
|
george c. ebers, professor department of clinical neurology oxford uk OX3 0DB, Cristen Willer postdoctoral student University of MIchigan
Send response to journal:
|
Dr. Hansen has overlooked several things which are explicitly stated in the publication. Firstly the Canadian controls were weighted by year of birth . Secondly we included a substantial Danish population from the data previously published by Templer and those results are in the published paper as part of the pooled analysis. Thirdly and for the very reason that we wished to avoid an unrecognised population bias , we used the unaffected siblings of the Canadian patients and found an even greater difference than in comparison with the population controls and the sibs were also significantly different than the pop. controls.We also went to the trouble to do the analysis selecting just one sib from each family to avoid another potential bias but this made no difference to the findings.Therefore the theoretical objection of Dr. Hansen was one which concerned us but one we addressed in the paper. Even if we had not, it is also answered by the finding in the sibs .Relevant to this is that we have analysed birth order in more than 20,000 Canadian MS families and there is no effect for family size under 10 (submitted but available from us as a preprint). Finally we are surprised to find Dr. Hansen apparently confusing absence of evidence with evidence of absence.We think he means no statistically significant evidence when he says no evidence. Since he gives no numbers nor sample size effect or confidence intervals it is difficult to reply in more detail but it is possible the results he reports are within the confidence intervals of the much larger sample in our study.The size of effect is not large, and we did not say that it was , but we are not sympathetic to his dismissal of the findings particularly after taking pains to replicate in several samples and with different controls. We note he did not use family-based controls and we think this is the way future studies of this type should be controlled.This was also clearly indicated in the published paper. Competing interests: None declared |
|||
|
|
|||
|
george ebers, prof. Radcliffe Infirmary Woodstock rd. Oxford OX3 0DB
Send response to journal:
|
We thank Dr. Luetic for sharing her S.Hemisphere results with us . Competing interests: None declared |
|||
|
|
|||
|
george ebers, prof. RadcliffeInfirmary Woodstock Rd. OX3 0DB Oxford
Send response to journal:
|
Re: Response to "Timing of birth and risk of multiple sclerosis" We wish to thank Dr. Fonnebo for his interesting comments. Re: Multiple sclerosis, pineal gland and melatonin Dr. Odent makes an excellent point and the role of the pineal has been underinvestigated in chronobiology of disease. One major difficulty is that it may well be that the process at question happened so long ago that it is difficult to recreate the pathophysiological events decades later. Re: Vitamin D & MS There is indeed considerable interest in primary prevention along the lines spelled out. Re: Month of birth and risk of multiple sclerosis : new light on past results with Bayesian analysis We appreciate the comments of Dr. Brassard and indeed we have unpublished data supporting his findings. Re: Patient with Primary Progressive We have examined maternal fetal incompatibility at the major histocompatibility complex in a large sample and the results are available from me as a preprint. I do not see a connection between MS and migraine but there is a difference in this birth order effect between relapsing and remitting patients and primary progressive but there is more similarity of PPMS to RRMS than there is difference. Competing interests: None declared |
|||
|
|
|||
|
Thomas Hansen, Statistician National Institute of Public Health, Øster Farimagsgade 5, DK--1399 København K, Denmark, Esben Meulengracht Flachs, Egon Stenager, Nils Koch Henriksen
Send response to journal:
|
Dear Dr. Ebers: Our response to your paper concluded 1) that we, using data on virtually all Danish MS cases born between 1920 and 1960, are unable to corroborate your findings and 2) failing to take year-of- birth into account may lead to false conclusions. Not more not less. Thus we do not state that your findings are in error. Our concern regarding your analyses concerns only 'the Canadian data' insofar as the Danish and Swedish data you use are unfit for (our) analyses because MS cases are not 'matched' to non-MS cases ('controls') by country, year-of-birth- and month. We furthermore believe that you misunderstand our meaning of 'an effect of year-of-birth' and we know for sure that we do not understand what you mean by "Population control results, weighted to match patients with MS for year of birth, were similar to non-weighted controls (not shown)". We are basically unable to guess what statistical procedure you have employed but we are reasonably confident that you did not estimate 'an effect of year-of-birth' since you do not report any. Obviously, year- of-birth is a significant predictor of risk for MS (much more so than month-of-birth [you agree to that?!]) and, for example, in the Danish data the relative risk for MS decreases by some 40\% during the period from 1920 to 1960 -- some 150\% the effect size of month-of-birth. What is crucial here is that in order to estimate reliably an effect of month-of-birth one needs to model and 'control' the effect of year-of- birth. This can be done in many different ways and our Poisson regression with 'natural cubic splines' is just one. It may very well be that your method, which we do not understand as described, deals adequately with this problem, and accordingly we would like you to elaborate on it: You state that "weighted to match patients with MS for year of birth". Does that imply that older cohorts are weighted heavier than younger cohorts which have more 'remaining lifetime risk for MS' compared to older cohorts and if so how are the weights actually estimated? However these things may be, we still fell that there are some aspects of your treatment of the year-of-birth problem that we do not fully understand. In order to model the risk for MS according to year-of- birth one obviously needs to know which proportion of cases born in a particular year one has sampled (or assume that this proportion remain constant across all sampled years). In the Danish context this problem has a fairly straightforward solution since our registry is (thought to be) complete for birth cohorts 1920 through 1960. However, if for example one is able to identify only 80\% of the MS cases born in say 1920 (but assume these cases constitute all cases) while, due to generally increased survival and technology, one samples close to 100\% in the birth cohort 1960, obviously the relative risk between 1920 and 1960 is biased. Now, the 17,874 Canadian MS cases obviously comprises several birth cohorts (years) -- some of which may be considered completely 'sampled' and some of which are without question less than completely sampled. For example, assume --for the sake of argument-- that the youngest MS case among the 17,874 Canadian MS cases is born in 1970. Obviously, 1970 would then be less than completely sampled (35 years from birth to onset and diagnosis is certainly not enough for many patients) . At the other end of the spectrum (the year of birth of the oldest MS cases among the 17,874 persons, say 1905) similar problems arise. Persons with MS born the same year as the oldest MS case may have died before the establishment of the Canadian database and thus not included in the database. Therefore it seems impossible to assume the Canadian database to be complete for all the sampled birth years. Instead, a subset of birth years 'in the middle' of the database may very well comprise completely sampled cohorts and only this subset should be included in the analysis in order to avoid the aforementioned bias. This 'weeding out' of the oldest and the youngest cohorts does not appear to have been exercised. Lastly, you state that "Since he [they, we are four authors] gives no numbers nor sample size effect or confidence intervals it is difficult to reply in more detail but it is possible the results he [they, we are four authors] reports are within the confidence intervals of the much larger sample in our study" Since our overall test for 'month' is not (statistically) significant (which we did in fact report: "we found no evidence of a month-of-birth effect on the risk for MS ($P=0.142$)") reporting CIs and 'effect sizes' makes little sense because of the very interpretation of the $P=0.142$: Any results, any 'effect sizes', are due to randomness rather than any systematic effects. If we, however, disregard that 'month' is not significant our estimated effects of months are rather peculiar. Thus, July, has the same low rate ratio as November and January whereas, indeed, the 'Winter' from October through February appear to constitute 'safe months': Month RR January 1.000 February 0.987 March 1.069 April 1.089 May 1.084 June 1.103 July 0.995 <--- NB ! August 1.098 September 1.024 October 0.982 November 0.996 December 0.998 We find it particularly difficult to fit July into the picture especially considering the RRs for June and August being the two highest! To add up, we maintain that your pooled analyses comprising data from several countries (Table 3) are inappropriate because there is no appropriate match between MS cases and country and year-of-birth specific unaffected births ('controls'). Furthermore, we admit that we do not understand your statistical methods and that our first response might have implied that we believed you to be in error. Yet, all we stated was "Failing to take year of birth into account may lead to biased conclusion simply because MS cases born in one year are weighted relative to persons with completely different follow-up time" which is true! However, we still do not understand your statistical methods and would like you to elaborate on precisely how you took year-of- birth into account. Competing interests: None declared |
|||
|
|
|||
|
Rob Swenson, health care software analyst Cerner Corp, Kansas City - ZIP: 66207
Send response to journal:
|
Have there been any studies of mothers with a family history of MS using a tanning salon during pregnancy, and if so did that additional vitamin D in her blood cause her children to have a reduced risk of MS? Obviously such a study would take a very long time, but possibly worthwhile. Competing interests: None declared |
|||