PEER REVIEW HISTORY

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ARTICLE DETAILS

TITLE (PROVISIONAL) Vitamin D status in recently arrived immigrants from Africa and Asia:
a cross-sectional study from Norway of children, adolescents and
adults.
AUTHORS Eggemoen, Aase Ruth; Knutsen, Kirsten; Dalen, Ingvild; Jenum,
Anne

VERSION 1 - REVIEW

REVIEWER BENER, ABDULBARI BENER

World Health Organization, Medical Statistics & Epidemiology,
REVIEW RETURNED 11-Jun-2013

GENERAL COMMENTS 1. Title: The title is adequate.

2. Abstract: The abstract is adequately addressed.
3. Introduction: The introduction is adequate.
4. Materials and Methods:
The Methods section is grossly deficient.
- Subjects and methodology: This section has some significant
deficiencies; however there are some suggestions for improvement.
a. Setting and Study Population: It would be helpful to the readers if
this were displayed in diagram format, such as subject collection
location or site, showing those excluded and included in the study.
b. The study based on adequate sample size and with different
ethnical proportion, which may not be appropriate to make
comparisons.
c. Are patients subjects randomly?
d. Eligibility criteria: The authors need to explicitly report any
inclusion criteria for the selection of subjects in this study fir the case
and control?
e. Is there any quality control procedure for Vitamin D?
5. Results: The results are clearly presented and adequately
addressed.
6. Discussion: The discussion is well written and adequately
addressed.
7. Contribution to the literature: The authors should provide key
points and the contribution of current study to literature and what
messages are provided with the present study?
8. Limitations: The authors should report some of the limitations of
this study in detailed.
9. .Conclusions: The conclusion is not very conclusive, since based
on a small sample size.

In conclusion, this study is well written and is well designed. It

addresses an important issues concerning Diabetes risk assessment
and public health topic in a very thorough and yet concise manner.
Although, the study does not contribute novel knowledge or add
sufficiently to the current literature, but, it would help local policy
makers, therefore, the manuscript can be considered for the
 publication after major revision in BMJ Open”.

REVIEWER Holvik, Kristin

Norwegian Institute of Public Health
REVIEW RETURNED 11-Jun-2013

GENERAL COMMENTS This descriptive cross-sectional study contributes new knowledge

about the prevalence of vitamin D deficiency in recently arrived
immigrants to Norway, originating from 52 different African and
Asian countries, covering children, adolescents and adults of both
genders.

The manuscript is well written. The purpose, methods and results

are clearly presented. The STROBE checklist of items in reports of
cross-sectional studies has been included.

As this is a descriptive quality study with the sole purpose to

describe 25(OH)D levels according to region of origin, gender, and
age, the inability of the cross-sectional design to make causal
inferences is not of particular concern. On the contrary, this design is
suitable for identifying the risk groups, being the main purpose of the
manuscript.

Potential selection bias, on the other hand, would be of major

concern. The studied sample results from referrals from various
instances, and those referred represent certain categories of
immigrants including asylum seekers, UN refugees, and family
immigrants, but not most working immigrants. Another aspect is to
which degree the health status in general, and vitamin D status in
particular, of those who have arrived would represent that of the
background populations in the regions and countries of origin. The
Authors have discussed in depth the possibility of selection bias.
They have estimated that their study population covered 60% of the
source population. While acknowledging that those referred may be
more ill than those not referred, they argue well for the assumption
that the study sample may be considered fairly representative. It
would be a strength to include a sensitivity analysis (see below).

SPECIFIC POINTS TO BE ADDRESSED:

1. Introduction, page 4: It should perhaps be made clearer that

migration to higher latitudes seems to aggravate vitamin D status,
but that vitamin D status also is highly variable in the countries of
origin before migration (cf. ref. 5) and may be very low despite
abundant sunlight.

2. Introduction, page 4: The statement “Deficiency causes rickets in

children and osteomalacia in adults” seems to be a rather drastic
claim considering the Authors' definition of deficiency as all serum
25(OH)D concentrations below 50 nmol/l. Please rephrase.

3. Materials and methods, page 5: If I understand correctly, the

background population covered by this study is restricted to
immigrants belonging to Oslo municipality (i.e. the capital of Norway,
60°N). This should be clearly stated, along with an estimate of the
 proportion who settle in Oslo, if possible.

4. Materials and methods: A description of the countries or areas

included in the four predefined regions of origin would be helpful to
the reader (i.e. geographic location; latitude). This could be
presented in a figure or information box. If the Authors feel that the
list of 52 countries is too long to include, a solution could be to report
4-5 of the most highly represented countries in each region, or to
include a map with colored/shaded areas.

5. Table 1: More information about age distribution according to

region of origin should preferably be provided, e.g. full age range or
interquartile range.

6. Table 1: The footnotes are difficult to interpret; there seems to be

some editing error.

7. Figures: Figure titles should be more specific. For Figure 1, I

recommend to modify the title into the following: Proportion of
subjects (%) in categories of serum 25(OH)D concentrations in
women and men according to geographic origin. For Figure 2, I
recommend to modify the title into the following: Proportion of
subjects (%) in categories of serum 25(OH)D concentrations in
women and men according to origin from Somalia, Eritrea,
Afghanistan or Iraq.

8. Table 2: Did the Authors examine whether the observed age

differences in 25(OH)D could be confounded by region of origin, or
was this not considered based on the fairly similar age distribution
across regions of origin? Please state in text.

9. Discussion: Did the Authors consider including a sensitivity

analysis for evaluating the plausible effect of selection bias? (See
e.g. Greenland S: Basic methods for sensitivity analysis of biases.
Int J Epidemiol 1996; 25: 1107-16.)

10. Discussion, page 15: Reference 37 may be replaced with the

URL: www.nnr5.org, describing the currently ongoing revision of the
Nordic Nutrition Recommendations.

11. Terminology: Please refer to the exposure variable consistently

as 25(OH)D as defined on page 5, rather than “Vitamin D levels”,
“levels of Vitamin D”, “25(OH)vitamin D values” and other variants
encountered through the manuscript.

12. Terminology: Please use the corresponding terms men and

women (or males and females) consistently, rather than reporting
“men” and “females” in the same sentence (e.g. page 13).

VERSION 1 – AUTHOR RESPONSE

Referee: 1
Reviewer: ABDULBARI BENER BENER
World Health Organization, Medical Statistics & Epidemiology,

1. Title: The title is adequate.

2. Abstract: The abstract is adequately addressed.
3. Introduction: The introduction is adequate.
4. Materials and Methods:
The Methods section is grossly deficient.
- Subjects and methodology: This section has some significant deficiencies; however there are some
suggestions for improvement.

a. Setting and Study Population: It would be helpful to the readers if this were displayed in diagram
format, such as subject collection location or site, showing those excluded and included in the study.
Reply: Thank you for your comment. This is a one-year study sample of all individuals referred to the
Centre of Migrant Health in Oslo in 2010. We have added in the text (page 5, line 138-139):
“Individuals with missing values of 25(OH)D were excluded.” We have also added in the text (page 5,
line 144 and line 146): “(obligatory screening of tuberculosis)” and “UN refugee reception centre”.
Further, we have added in the text (page 6, line 169-172): “A total of 618 had a health check up at the
Centre in 2010, 27 (4%) individuals had no valid 25(OH)D; blood test not ordered in 16 who had
recently drawn blood elsewhere, seven did not take the recommended blood tests and for four the
blood samples were not analyzed”.

We have added in the text (page 7, line 206-209): Individuals were referred to the Centre from
Section for Prevention of Tuberculosis at Oslo University Hospital (n=118), Norwegian courses for
recently settled immigrants (n=105), school nurses (n=101), Child Health Clinics (n=99), asylum
reception centres (n=48) and UN refugee reception centre (n=47).”

See also reply referee 2, point 9.

b. The study based on adequate sample size and with different ethnical proportion, which may not be
appropriate to make comparisons.
Reply: Thank you for your comment. We agree that this is a heterogenic material, and we have taken
into account the sample size within each region by estimating confidence intervals and p-values. We
fully recognize the possibility of selection bias and contacted official authorities to make our best
estimates of the source population while preparing our paper. We have now added more information
about the number of individuals from countries with eight or more individuals in the text (page 6, line
159-162).

See also reply referee 2, point 4 and 9.

c.+ d. Are patients subjects randomly? Eligibility criteria: The authors need to explicitly report any
inclusion criteria for the selection of subjects in this study fir the case and control?
Reply: This is a cross-sectional study of consecutive referrals for a free medical examination,
including individual with or without any symptoms or disease. See 4 a) and b)

e. Is there any quality control procedure for Vitamin D?

Reply: Thank you for your notice. The Hormone Laboratory, Oslo University Hospital, Aker is the
largest Norwegian laboratory for special analysis of hormones. The laboratory is accredited by
Norwegian Accreditation (NS-EN ISO/IEC 17025), and has an extensive internal control system. The
methods for measuring vitamin D is stated in the text (line 152-153). “According to The Hormone
Laboratory, the intra- and inter-assay coefficients of variation CV were 6 and 13-16% respectively”,
which is now included in the text (page 5, line 153-155).

5. Results: The results are clearly presented and adequately addressed.

6. Discussion: The discussion is well written and adequately addressed.
7. Contribution to the literature: The authors should provide key points and the contribution of current
study to literature and what messages are provided with the present study?
Reply: Three key points (page 3, line 70-76) are stated under Key Messages. Additionally, we did our
best to clearly present the contribution of the current study to literature as a strength (page 3, line 79-
80) since there is a limit of three key points under Key Messages.

8. Limitations: The authors should report some of the limitations of this study in detailed.
Reply: We did our best to present the most relevant limitations (page 14, line 273-285).We contacted
official authorities to make our best estimates of the source population (page 6, line 165-176), and we
have added some new information about the source population (line 176-179).

9. Conclusions: The conclusion is not very conclusive, since based on a small sample size.
Reply: As reflected in the paper, we agree that the sample size for some ethnic groups is small, but
on the other hand, for some of these countries we identified none or very few published studies. We
therefore think the paper may give an important and appropriate contribution to prior literature
regarding vitamin D status in recently arrived immigrants from Africa and Asia to Europe.

In conclusion, this study is well written and is well designed. It addresses an important issues
concerning Diabetes risk assessment and public health topic in a very thorough and yet concise
manner. Although, the study does not contribute novel knowledge or add sufficiently to the current
literature, but, it would help local policy makers, therefore, the manuscript can be considered for the
publication after major revision in BMJ Open”.
Reply: We thank you for this positive overall view of the paper.

Referee: 2
Reviewer: Kristin Holvik
Researcher, Ph.D.
Norwegian Institute of Public Health
Norway

I declare that I have no competing interests.

This descriptive cross-sectional study contributes new knowledge about the prevalence of vitamin D
deficiency in recently arrived immigrants to Norway, originating from 52 different African and Asian
countries, covering children, adolescents and adults of both genders.

The manuscript is well written. The purpose, methods and results are clearly presented. The
STROBE checklist of items in reports of cross-sectional studies has been included.

As this is a descriptive quality study with the sole purpose to describe 25(OH)D levels according to
region of origin, gender, and age, the inability of the cross-sectional design to make causal inferences
is not of particular concern. On the contrary, this design is suitable for identifying the risk groups,
being the main purpose of the manuscript.

Potential selection bias, on the other hand, would be of major concern. The studied sample results
from referrals from various instances, and those referred represent certain categories of immigrants
including asylum seekers, UN refugees, and family immigrants, but not most working immigrants.
Another aspect is to which degree the health status in general, and vitamin D status in particular, of
those who have arrived would represent that of the background populations in the regions and
countries of origin. The Authors have discussed in depth the possibility of selection bias. They have
estimated that their study population covered 60% of the source population. While acknowledging that
those referred may be more ill than those not referred, they argue well for the assumption that the
study sample may be considered fairly representative. It would be a strength to include a sensitivity
analysis (see below).

SPECIFIC POINTS TO BE ADDRESSED:

1. Introduction, page 4: It should perhaps be made clearer that migration to higher latitudes seems to
aggravate vitamin D status, but that vitamin D status also is highly variable in the countries of origin
before migration (cf. ref. 5) and may be very low despite abundant sunlight.

Reply: Thank you for your comment. We agree and have now included the sentence (page 4, line
102-104): “Migration to higher latitudes seems to aggravate vitamin D deficiency, but vitamin D status
also differs in the countries of origin and may be very low despite abundant sunlight.”

2. Introduction, page 4: The statement “Deficiency causes rickets in children and osteomalacia in
adults” seems to be a rather drastic claim considering the Authors' definition of deficiency as all serum
25(OH)D concentrations below 50 nmol/l. Please rephrase.
Reply: Thank you for noticing. We have added ”Severe” before deficiency (line 115).

3. Materials and methods, page 5: If I understand correctly, the background population covered by
this study is restricted to immigrants belonging to Oslo municipality (i.e. the capital of Norway, 60°N).
This should be clearly stated, along with an estimate of the proportion who settle in Oslo, if possible.
Reply: Thank you for your comment. We have included the requested information in the sentence
(page 5, line 137-138): “This is a cross-sectional study of all new immigrants referred to Centre of
Migrant Health, Health Agency, Oslo municipality, the capital of Norway, situated at 60°N, in 2010.”
We have added the sentence (page 5, line 139-140): “The background population covered by this
study is restricted to immigrants in the municipality of Oslo.”
The proportion settling in Oslo, is estimated on page 6, line 165-169. We have also corrected the
number of countries from 52 to 51 (line 202), and we apologize for this error.

4. Materials and methods: A description of the countries or areas included in the four predefined
regions of origin would be helpful to the reader (i.e. geographic location; latitude). This could be
presented in a figure or information box. If the Authors feel that the list of 52 countries is too long to
include, a solution could be to report 4-5 of the most highly represented countries in each region, or to
include a map with colored/shaded areas.

Reply: Thank you for your suggestions. To make it easy for the reader to find the information of the
countries, we have added information of the countries with an immigrant number of eight or more in
Table 1:
“Countries with ≥eight or more individuals are listed:
249 immigrants from South Sahara Africa, primarily from Somalia (n=130), Eritrea (n=46), Ethiopia
(n=27), Ghana (n=10) and Kenya (n=8).
188 immigrants from Middle East/North Africa, primarily from Afghanistan (n=82), Iraq (n=43),
Palestine (n=17), Iran (n=13), Morocco (n=12), and Chechnya (n=9).
60 immigrants from South Asia, primarily from Pakistan (n=34), Sri Lanka (n=16) and Nepal (n=9).
54 immigrants from East Asia, primarily from Philippines (n=16), Thailand (n=15) and Myanmar
(n=15).”
We have also now presented the countries with the largest number of participants within each region
in page 6, line 159-162.

5. Table 1: More information about age distribution according to region of origin should preferably be
provided, e.g. full age range or inter-quartile range.
Reply: Thank you for your kind suggestions, see reply to point 6.

6. Table 1: The footnotes are difficult to interpret; there seems to be some editing error.
Reply: Thank you for noticing. We have added the full age range and inter-quartile range for all
regions. We have revised the footnotes, and all information of countries with eight or more immigrants
are now included in the table. The % sign is deleted within the table, and the footnote * and ** are
deleted (unimportant information).

7. Figures: Figure titles should be more specific. For Figure 1, I recommend to modify the title into the
following: Proportion of subjects (%) in categories of serum 25(OH)D concentrations in women and
men according to geographic origin. For Figure 2, I recommend to modify the title into the following:
Proportion of subjects (%) in categories of serum 25(OH)D concentrations in women and men
according to origin from Somalia, Eritrea, Afghanistan or Iraq.
Reply: Thank you for your kind suggestions. We have revised the titles of figure 1 and 2 accordingly.

8. Table 2: Did the Authors examine whether the observed age differences in 25(OH)D could be
confounded by region of origin, or was this not considered based on the fairly similar age distribution
across regions of origin? Please state in text.
Reply: Table 2 presents unadjusted geometric mean levels of 25(OH)D, for which potential
confounding is not considered. In Table 3, however, adjusted results presents age differences within
each region of origin, and reflects that there are larger differences for some groups than for others,
hence, the age differences in Table 2 may to some extent be confounded by region of origin (as well
as by other factors). However, we prefer not to comment on this specifically, as it pertains to all the
results in Table 2.

9. Discussion: Did the Authors consider including a sensitivity analysis for evaluating the plausible
effect of selection bias? (See e.g. Greenland S: Basic methods for sensitivity analysis of biases. Int J
Epidemiol 1996; 25:1107-16.)
Reply: Thank you for referring to this important paper on Sensitivity Analysis of Bias, which is and
important issue, not least for most epidemiological research. We agree that we could clarify better the
referrals and the status of our patients.

First, based on clinical practice with this group over several years, the great majority referred are
mostly healthy individuals (added in the text line 258) referred for a routinely health examination from
Child Health Clinics, school nurses and Section for Prevention of Tuberculosis at Oslo University
Hospital, etc. Second, working immigrants are not a target group for the Centre of Migrant Health and
therefore normally not referred to the centre. Third, the largest groups of working immigrants to
Norway are from other countries than the family immigrants. Family immigrants in our study are
primarily from countries of political instability and even war and conflict.
Nevertheless, we fully recognize the possibility of bias, and have tried to perform a sensitivity
analysis.

We have previously estimated that the study population covers about 60% of the source population.
However, we have now collected supplementary information from the Norwegian Directorate of
Immigration about family immigrants from different countries of all continents to Oslo in 2010.
We have added to the text (page 6, line 177-179): “Detailed information from The Norwegian
Directorate of Immigration about family immigrants from to Oslo in 2010, indicates that our sample
covers about 85% of family immigrants from Somalia, Ethiopia and Eritrea, and 68% from Iraq, Iran,
Morocco and Afghanistan.”

We have also performed a sensitivity analysis as suggested and have added to the text (page 13, line
265-273): “We have performed a sensitivity analysis for the groups from South Sahara Africa and
Middle East under the assumption that the proportion with 25(OH)D <50nmol among the 40% not
referred was 25% lower than we reported. If so, the true prevalence in the total South Sahara Africa
group would be 66%, not 73% as reported. Similarly, the true prevalence in the Middle Eastern group
would be 73%, not 81%. However, 25(OH)D < 50nmol/l would still be very prevalent. Data from the
Norwegian Directorate of Immigration indicates that our sample covers about 85% of family
immigrants from Somalia, Ethiopia and Eritrea, and 68% from Iraq, Iran, Morocco and Afghanistan.
This lends support to the notion that the study population, especially the groups from South Sahara
Africa and Middle East can be considered as representative for recently arrived immigrants from
these regions.”

See also reply referee 1, point 4 a) and b).

10. Discussion, page 15: Reference 37 may be replaced with the URL: www.nnr5.org, describing the
currently ongoing revision of the Nordic Nutrition Recommendations.
Reply: Thank you for your kind suggestions. We have revised the reference accordingly.

11. Terminology: Please refer to the exposure variable consistently as 25(OH)D as defined on page 5,
rather than “Vitamin D levels”, “levels of Vitamin D”, “25(OH)vitamin D values” and other variants
encountered through the manuscript.
Reply: Thank you for noticing. We now refer to [25(OH)D] consistently throughout the manuscript
except the introduction (this change is not highlighted).

12. Terminology: Please use the corresponding terms men and women (or males and females)
consistently, rather than reporting “men” and “females” in the same sentence (e.g. page 13).
Reply: Thank you for noticing. We have revised the terminology and use males and females
consistently throughout the manuscript.