Edited by: Stephan Weidinger
Determinants of eczema: population-based cross-sectional study in Germany
Article first published online: 30 AUG 2010
© 2010 John Wiley & Sons A/S
Volume 66, Issue 2, pages 206–213, February 2011
How to Cite
Apfelbacher, C. J., Diepgen, T. L. and Schmitt, J. (2011), Determinants of eczema: population-based cross-sectional study in Germany. Allergy, 66: 206–213. doi: 10.1111/j.1398-9995.2010.02464.x
- Issue published online: 5 JAN 2011
- Article first published online: 30 AUG 2010
- Accepted for publication 8 July 2010
- allergic sensitization;
To cite this article: Apfelbacher CJ, Diepgen TL, Schmitt J. Determinants of eczema: population-based cross-sectional study in Germany. Allergy 2011; 66: 206–213.
Background: Eczema is a chronic inflammatory skin disease and is among the most frequent chronic conditions in childhood and adolescence. It is the aim of this study to investigate determinants of eczema in German children and adolescents.
Methods: Data were drawn from the public use files of the German Interview and Examination Survey for Children and Adolescents (KIGGS), a nationwide cross-sectional representative survey conducted between 2003 and 2006, including 17 641 children aged 0–17 (response rate: 66.6%). We investigated the association of a broad set of environmental and lifestyle exposures with ever physician-diagnosed eczema by means of univariable analyses and multivariable logistic regression modelling.
Results: The weighted prevalence of ever physician-diagnosed eczema was 13.2% [95% confidence interval (CI) 12.5–13.9%]. In multivariable analysis, significant positive associations of parental allergies (OR 1.94, 95% CI 1.72–2.19), parent-reported infection after birth (OR 1.45, 95% CI 1.05–2.00) and parent-reported jaundice after birth (OR 1.27, 95% CI 1.04–1.54) were revealed. Being a migrant (OR 0.63, 95% CI 0.49–0.80) and keeping a dog (OR 0.78, 95% CI 0.64–0.96) showed significant inverse associations with eczema. Other lifestyle (alcohol consumption during pregnancy) and environmental factors (mould on the walls, pets, origin from East/West Germany) were not significantly related to eczema.
Conclusions: This study suggests that a family history of allergies is the strongest determinant of eczema. Perinatal health problems were associated with eczema, pointing to the importance of early life factors in the manifestation of eczema.
Eczema is a chronic inflammatory skin disease, characterized by intense itching and typical skin lesions (1). The itchy lesions represent not only a medical problem entailing considerable cost to society, but may also cause substantial psychosocial distress for both the affected individual and the respective family (2, 3).
Eczema is the most frequent chronic condition in infancy in many countries, but it shows wide variation around the globe. Updated data from the International Study of Asthma and Allergies in Childhood (ISAAC) showed the prevalence of eczema (itchy flexural rash in the past 12 months) to vary from 0.9% to 22.5% in 6- and 7- year-old children and from 0.2% to 24.6% in the age group 13–14 years (4).
The role of atopy in eczema has been a subject of debate for decades. It must be noted that in the general population, up to two-thirds of people with eczema might not show allergic sensitization (5). Data from the ISAAC study suggest that the association between atopy and eczema is weak and more variable than previously believed (6). However, in those children with concomitant allergic sensitization, the itchy lesions often represent the beginning of the atopic march (7). Approximately every third child with eczema will also develop asthma or allergic rhinitis (5, 8). Recent studies extend the evidence regarding comorbidities and have found a significant comorbidity of eczema and attention-deficit/hyperactivity disorder (ADHD) (9, 10).
In aetiological terms, eczema is likely to be a complex disease resulting from the interplay of several genetic, environmental, lifestyle and social factors Besides allergic sensitization, a large number of factors potentially involved in the aetiology of eczema such as pet exposure, breastfeeding (11), tobacco smoke (12) as well as gene polymorphisms (13) have been investigated. However, overall, the aetiology of eczema is still unclear (8) and high-quality, population-based, generalizable evidence is scarce.
In 2007, nationally representative data on the prevalence of allergic diseases have been reported for the first time in Germany, using data obtained in the German Interview and Examination Survey (German acronym: KiGGS) (14).
It is the aim of this paper to analyse determinants of eczema occurring in childhood and adolescence in multivariable analysis, using the public use file made available from the KiGGS study in 2008 (15).
Material and methods
Design and study population
The KiGGS study is a representative survey of children and adolescents aged 0–17 , which was conducted from May 2003 to May 2006 (16). The study was approved by the Federal Office for Data Protection and by the ethics committee of Charité Berlin. Prior to the study, a pretest had been carried out on 1630 children and adolescents, by which all instruments were tested, and all procedures were optimized for the main survey (16).
The sample for the main study was drawn in two steps (two-stage sampling). First, 167 communities (primary sampling units) were chosen, stratified by federal state and community size. Participants were randomly selected within primary sampling units from the local population registries with stratification in 1-year age bands. 17 641 children and adolescents participated (response rate: 66.6%).
Data were collected by means of an age-adapted standardized self-administered questionnaire to be completed by parents/caregivers, parallel questionnaires for children and adolescents from age 11, physical examinations and tests as well as a computer-assisted personal interview (CAPI) with parents/caregivers. The CAPI was conducted by physicians who were specifically trained for the purposes of the study and assessed history of selected physician-diagnosed conditions, vaccination status and medication use within past 7 days (16).
If parents gave their consent, a blood sample was taken. Using the system IMMUNOCAP (Phadia, Uppsala, Sweden), specific IgE was determined in those children aged 3–17 for the following antibodies: Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat dander, horse epithelium, dog dander, egg white, peanut, soy bean, milk protein, carrot, potatoes, wheat flour, green apple, rice, rye pollen, timothy grass pollen, Cladosporium herbarum, Aspergillus fumigatus, birch pollen and mugwort pollen (14).
The choice of exposure variables was based on documented or potential associations with eczema. Data on gender, age, socio-economic status (SES), migrant status, geographical living area, number of older siblings, breastfeeding, maternal smoking during pregnancy, maternal alcohol consumption during pregnancy, maternal smoking during lactation, smoking in the living place, perinatal problems (after birth), moulds on the wall, pets and parental allergies were taken from the self-administered questionnaires. Age was categorized into three groups (0–2 years, 3–6 years and 7–17 years). Information on parental income, occupational status and education was used to quantify SES (17), which was categorized into low, medium and high. Migrant status was assigned if the child or adolescent immigrated from another country and if at least one parent was not born in Germany, or if both parents immigrated or had a non-German nationality. Children and adolescents who were born in Germany with only one parent having immigrated and/or of non-German nationality were not assigned migrant status.
Perinatal problems (after birth) encompass breathing difficulties/adjustment disturbances, infection, jaundice and underweight/preterm delivery.
Data on ever physician-diagnosed hay fever/allergic conjunctivitis, asthma and ADHD were obtained from the CAPI. Allergic sensitization was assumed if the child was sensitized to at least one of the above mentioned allergens.
Data on the dependent variable (‘ever physician-diagnosed eczema’) were obtained from the CAPI. The respective question was phrased as follows: ‘Has a physician ever diagnosed eczema (atopic dermatitis, endogenous eczema)?’
All analyses were performed using sas 9.2 for Windows (SAS Institute Inc., Cary, NC, USA). Prevalence of ever physician-diagnosed eczema according to the above listed exposure variables was computed. A design-adjusted version of the Pearson chi-square test, the Rao-Scott chi-square test, was applied to test differences between groups in univariate analyses (18). Only children with a definite ‘yes’ or ‘no’ to the question on ever physician-diagnosed eczema were included for the main univariable analyses (N = 17 270).
Multivariable predictive modelling was performed. A binary logistic regression model was fitted with ‘ever physician-diagnosed eczema’ as dependent variable. All variables that were associated with ever physician-diagnosed eczema in univariate analysis were entered into this model, together with age group and gender. The estimates obtained from this model are thus mutually adjusted estimates. Only children with a definite ‘yes’ or ‘no’ to the questions on ever physician-diagnosed eczema, asthma and hay fever as well as parental allergies were included in this analysis.
Additionally, we performed sensitivity analyses and computed eczema prevalence in relation to different types of breastfeeding, different types of pets and different atopic diseases in parents. To further investigate the role of parental atopy, multivariable models were fitted with the respective parental atopic disease as main explanatory variable, adjusting for age group, gender, SES and migrant status.
Except for the detailed breastfeeding analysis, all analyses applied weights and took the cluster structure of the two-stage sample into account, using PROC SURVEYFREQ and PROC SURVEYLOGISTIC in sas.
As previously reported, 13.4% (n = 2317) of the participants had a physician-diagnosed eczema, yielding a weighted prevalence of 13.2% (95% CI 12.5–13.9%) (14). Among these, onset within the first 2 years of life was reported in 1647 cases (71.1%), onset between third and sixth year of life in 473 cases (20.4%) and onset between seventh and seventeenth year of life in 197 (8.5%) cases. Of the 1845 participants with a physician-diagnosed eczema and information on allergic sensitization, 57.6% (n = 1063) had truly atopic eczema, i.e. eczema with concomitant sensitization to at least one allergen (previously called ‘extrinsic atopic eczema’).
The weighted prevalences of eczema according to potentially associated factors are displayed in Table 1. Age group was significantly associated with eczema prevalence with those children at school age showing the highest prevalence. Eczema prevalence increased with social status and was significantly lower in migrants compared to non-migrants. Having more than one older sibling was associated with a significantly lower prevalence of eczema. The prevalence of eczema was higher in those children who were ever fully breastfed and was highest in those children whose mothers did not smoke during pregnancy and during lactation. It was also highest where no smoking in the living place was reported. There was a significant association with maternal alcohol consumption during pregnancy. Prevalence was approximately twice as high in those children whose parents reported allergies. Gender, residing in East/West Germany, size of the living area, mould on the walls, pets and gestational diabetes were unrelated to the prevalence of eczema. However, when looking at the different kinds of pets in more detail, eczema prevalence was significantly lower in those reporting dog keeping and significantly higher in those reporting keeping small furry pets. No associations were found for cat or bird. We also stratified the analysis of the prevalence of eczema in the age groups according to gender and found that it was significantly higher in boys compared to girls in 0- to 2-year-olds (10.4%, N = 1379 vs 6.9%, N = 1352, P = 0.001), tended to be lower in the 7- to 17-year-olds (13.5%, N = 5500 vs 14.8%, N = 5244, P = 0.07) but was unrelated to gender in the 3- to 6-year-olds (13.2%, N = 1907 vs 13.5%, N = 1888, P = 0.86).
|N (unweighted)||(Weighted) Prevalence of eczema||P-value|
|Infant age (0–2 years)||2731||8.7||<0.0001|
|Kindergarten age (3–6 years)||3795||13.3|
|School age (7–17 years)||10 744||14.1|
|>1 Older sibling||2022||11.6||0.008|
|One or no older sibling||10 328||13.8|
|Ever (fully) breastfed||10 586||14.5||0.0008|
|Not ever (fully) breastfed||4973||12.2|
|Maternal smoking during pregnancy|
|No, never||13 875||13.9|
|Maternal smoking during lactation|
|Did not breastfeed||3477||12.2|
|Smoking in the living place|
|Less than daily||2710||12.7|
|Maternal alcohol consumption during pregnancy|
|Mould on the walls||883||13.3||0.98|
|No mould on the walls||16 035||13.4|
|No cat||13 835||13.5%|
|No dog||14 364||13.7%|
|Small furry pets||2214||15.5%||0.01|
|No small furry pets||14 731||13.1%|
|No birds||15 547||13.4%|
|No gestational diabetes||14 589||13.9|
|No parental allergy||9297||9.5|
When looking at perinatal health problems in more detail (Table 2), we found the prevalence of eczema to be significantly higher in children with infection or jaundice after birth. Breathing/adjustment problems and preterm delivery/underweight were not significantly related to eczema.
|N||Eczema prevalence (%)||P-value|
|Breathing problems/adjustment problems||634||14.9||0.35|
|No breathing problems/adjustment problems||16 177||13.4|
|No infection||16 371||13.2|
|No jaundice||14 742||13.1|
|Underweight/preterm delivery||16 065||13.5|
Table 3 displays results from multivariable logistic regression modelling. Significant positive associations of parental allergies (OR 1.94, 95% CI 1.72–2.19), infection after birth (OR 1.45, 95% CI 1.05–2.00) and jaundice after birth (OR 1.27, 95% CI 1.04–1.54) were revealed in the mutually adjusted model. Being a migrant (OR 0.63, 95% CI 0.49–0.80) and keeping a dog showed significant inverse associations (OR 0.78, 95% CI 0.64–0.96) with eczema.
|Exposure||OR (95% CI)*||OR (95% CI)† [N = 10 833]|
|SES (high vs low)||1.68 (1.44–1.95) [N = 16 853]||1.20 (0.96–1.50)|
|SES (medium vs low)||1.37 (1.18–1.58) [N = 16 853]||1.04 (0.85–1.27)|
|Migrant||0.52 (0.44–0.61) [N = 17 190]||0.63 (0.49–0.80)|
|More than one older sibling||0.85 (0.74–0.99) [N = 12 350]||1.01 (0.86–1.18)|
|Ever fully breastfed||1.26 (1.12–1.42) [N = 15 559]||1.08 (0.93–1.25)|
|Maternal smoking during pregnancy (rarely vs never)||0.81 (0.70–0.95) [N = 16 729]||0.97 (0.77–1.22)|
|Maternal smoking during pregnancy (regularly vs never)||0.62 (0.46–0.85) [N = 16 729]||0.68 (0.46–1.01)|
|Maternal alcohol consumption during pregnancy||1.19 (1.03–1.37) [N = 16 785]||1.03 (0.85–1.24)|
|Smoking in the living place (daily vs never)||0.65 (0.55–0.78) [N = 16 812]||0.83 (0.65–1.06)|
|Smoking in the living place (less than daily vs never)||0.85 (0.75–0.96) [N = 16 812]||0.94 (0.77–1.14)|
|Dog||0.77 (0.66–0.91) [N = 16 945]||0.78 (0.64–0.96)|
|Furry pet||1.16 (0.99–1.36) [N = 16 945]||1.10 (0.91–1.33)|
|Infection||1.65 (1.25–2.17) [N = 16 811]||1.45 (1.05–2.00)|
|Jaundice||1.25 (1.08–1.45) [N = 16 811]||1.27 (1.04–1.54)|
|Parental allergy||2.11 (1.92–2.32) [N = 16 546]||1.94 (1.72–2.19)|
In a more detailed analysis looking at different levels of breastfeeding, we found evidence showing that the prevalence of eczema increased with increasing breastfeeding duration and intensity (Table 4). In a further analysis looking at different types of atopic diseases and their relationship with eczema in the child, we found that all types of atopic diseases in either mother or father were significantly associated with eczema in the offspring (Table 5). Strong associations were seen for eczema in the father (OR 3.33, 95% CI 2.65–4.19) and eczema in the mother (OR 3.27, 95% CI 2.77–3.86), and the strongest association was seen when both father and mother reported eczema (OR 4.70, 95% CI 2.64–8.37).
|N||Prevalence of eczema (%)|
|Fully breastfed until month six||3751||15.8|
|Fully breastfed until month four||3052||15.3|
|Ever fully breastfed (but not until month four)||3689||13.8|
|Ever breastfed (full breastfeeding not specified)||1130||10.2|
|Ever breastfed (but not fully)||1346||12.0|
|N||Prevalence of eczema (%)||P-value||ORs for eczema in child*|
|Mother hay fever||3155||17.6||<0.0001||1.46 (1.28–1.65)|
|Mother no hay fever||13 391||12.3|
|Mother allergic asthma||880||20.3||<0.0001||1.67 (1.36–2.04)|
|Mother no allergic asthma||15 666||13.0|
|Mother eczema||1006||31.6||<0.0001||3.27 (2.77–3.86)|
|Mother no eczema||15 540||12.2|
|Father hay fever||2482||17.4||<0.0001||1.38 (1.21–1.57)|
|Father no hay fever||14 064||12.6|
|Father eczema||456||33.5||<0.0001||3.33 (2.65–4.19)|
|Father no eczema||16 090||12.8|
|Father allergic asthma||613||21.5||<0.0001||1.77 (1.41–2.23)|
|Father no allergic asthma||15 933||13.0|
|Both parents eczema||59||39.8||<0.0001||4.70 (2.64–8.37)|
|Not both parents eczema||16 487||13.3|
Table 6 shows data on comorbidity. The prevalence of eczema was significantly higher in those children who concomitantly suffered from either hayfever/allergic conjunctivitis, asthma or ADHD. The prevalence of eczema was approximately twice as high in those children who were sensitized to at least one allergen.
|Hay fever, allergic conjunctivitis||1689||28.1||<0.0001|
|No hay fever, allergic conjunctivitis||15 513||11.4|
|No asthma||16 474||12.2|
|No ADHD||12 576||14.2|
|Sensitized to at least one allergen||5074*||20.0||<0.0001|
|Not sensitized to at least one allergen||7673*||9.8|
In this cross-sectional study investigating determinants of eczema in German children and adolescents, positive associations of a family history of allergy, infection and jaundice after birth as well as inverse associations of being a migrant and keeping a dog with eczema were found. Gender, number of older siblings and other lifestyle (alcohol consumption and smoking) and environmental factors (mould on the walls, keeping pets other than a dog, origin from East/West Germany) were not found to be significantly related to eczema in multivariable analysis. Univariable analyses suggest that duration and intensity of breastfeeding are positively related to eczema prevalence. Parental eczema shows the strongest association among the three different types of atopic diseases (asthma, eczema and hay fever).
Strengths and weaknesses of the study
The strength of the study is that data were drawn from the only representative study on children’s and the adolescents’ health in Germany. Weights were applied, and the two-stage sampling was taking into account in statistical analysis, lending credibility to the external validity of the findings, i.e. to the generalizability of the results to the totality of all German children and adolescents. A further strength is the comprehensive assessment of a broad range of family, lifestyle and environmental factors which have been implicated in the pathogenesis of eczema. A nonresponse analysis suggested a slight middle-class bias, but hardly any differences between responders and nonresponders with respect to health-related variables (16).
The study is limited by its cross-sectional design which does not allow to disentangle cause and effect because the temporal dimension cannot be analysed in a cross-sectional study. Also, many variables used in the analysis such as parental allergies/allergic diseases stem from self-reports and are notoriously prone to information bias. In particular, the primary outcome used for all the analyses is a parental report of ever physician-diagnosed eczema. Characteristics of proxy respondents such as their age and gender may influence responses in health surveys which involve children (19).
We acknowledge that carrying out many tests on the same data set as was performed in the present analysis (multiple testing) increases the likelihood of significant findings.
Because we adjusted for many variables, overadjustment introduced by controlling for intermediate variables (variables on the causal pathway) may be an issue (20). Overadjustment usually introduces bias towards the null so weak effects may potentially be obscured in the multivariable model. However, our aim was not to quantify the total impact of a given exposure on eczema, but to perform predictive analyses. Further, although exploratory in nature, the analysis was informed by substantive knowledge.
Discussion of results, in relation to literature
The finding of a significant difference in the prevalence of eczema in infant age only with a higher prevalence in boys is in line with a review article which found that eczema shows an insignificant gender difference or a male preponderance in preschool children (21).
The association between eczema and migrant status has rarely been investigated. A study in London found black Carribean children to be more likely to suffer from eczema when compared with white children (22). The association of the prevalence of eczema with a high social class has been reported in various studies (23) and is corroborated by our data, although it does not reach significance in multivariable analysis. An Italian cross-sectional study in children found gender, breastfeeding and pets to be unrelated to eczema (24). This study also found a family history of asthma, hay fever or eczema to double to odds of eczema, a finding that we were able to replicate. In addition, we were also able to dissect the effects of different types of parental atopy, showing that all types of atopic diseases in the parents were related to eczema in the offspring. Parental eczema, however, clearly showed the strongest association with eczema in the offspring: eczema in either mother or father increased the odds of eczema in the offspring more than threefold and eczema in both parents almost increased the odds of eczema in the offspring fivefold. The previously mentioned Italian study, however, differs from the study presented here because it was confined to preschool children.
Data from the German MAS study also show parental eczema to be the strongest risk factor for eczema (25). In this study, each month of breastfeeding increased the risk of eczema. This finding is consistent with our results, showing that eczema prevalence increased with increasing breastfeeding duration and intensity. One large review on breastfeeding, a US Agency of Healthcare Research and Quality (AHRQ) review, suggests a possible protective effect of breastfeeding but also cautions the reader on the observational nature of the included studies (26). Those who breastfeed may be influenced by the disease rather than breastfeeding preceding the disease. In our sample, having ever fully breastfed was significantly higher in parents reporting allergies (P < 0.0001) and associated with SES (P < 0.0001). This may explain why the positive association with eczema was lost in multivariable analysis.
Many studies have been conducted to date looking at the effects of keeping pets on the development of allergic diseases. Our finding of a nonsignificantly increased prevalence of eczema in those reporting pet keeping is in line with a systematic review of cohort, case–control and cross-sectional studies (27). This review did not find evidence to support an increased risk of eczema when keeping furry pets. In contrast, the review even found some evidence of a protective effect, consistent with our finding of reduced prevalences of eczema in those who reported keeping a dog. In must be noted, however, that cross-sectional studies looking at the association of pet-keeping and allergic diseases are prone to a form of selection bias called ‘healthy pet-keeping effect’. This bias occurs because parents with atopic diseases tend to avoid keeping pets or getting rid of pets after the birth of a child (28). The protective effect of keeping furry pets was lost in the only cohort study included in the previously mentioned review which adjusted for avoidance behaviour.
No evidence for an association of moulds and eczema was found in the present study which is in contrast to findings from the Lübeck allergy and environment study (KLAUS) (29). In this study, a significant positive association of visible moulds with eczema was found in multivariable analysis.
The univariable results regarding maternal smoking during pregnancy are bewildering at first sight. We are not aware of any study which found an inverse association of smoking, whether current, during pregnancy or during lactation. In the Osaka Maternal and Child Health Study, no significant association between perinatal tobacco smoke exposure and eczema was observed (30). Assessment of tobacco exposure by questionnaire is however problematic. In a study on the association of environmental tobacco smoke and eczema in German school beginners, exposure assessment was based on urinary cotinine, a nicotine metabolite, allowing a more objective measurement of tobacco exposure (12). This study found a positive significant association of urinary cotinine and eczema. One explanation of our results might thus be misclassification as it might be undesirable for mothers to report having smoked during pregnancy or lactation (social desirability bias). Also, selection bias may have occurred because families with an atopic predisposition may have a higher sensitivity towards potentially harmful behaviours and thus be less likely to smoke, which is confirmed in our data. The prevalence of maternal smoking during pregnancy was significantly lower in those families who reported parental allergies (P < 0.0001) and was also inversely related to SES. In multivariable analysis, the inverse associations of both maternal smoking during pregnancy and smoking in the living place with eczema became nonsignificant.
The relationship of prenatal alcohol consumption has not been investigated much. Evidence from the Danish National Cohort suggests that alcohol during pregnancy was associated with a significantly increased risk of eczema in early infancy (31). Our results point in the same direction, but we did not find a significant relationship in multivariable analysis.
Our finding of an increased odds of eczema in those children who had infection after birth is corroborating the findings of a systematic review published in 2005 (32). All nine studies investigating infection and eczema that were identified in this review indicate a positive association between past infections and eczema. The identified studies included two carefully conducted birth cohort studies (33, 34). However, one recent cohort study using a German administrative health-care and prescription database did not find evidence that infections per se alter the likelihood of subsequent eczema (35). In this study, the relationship of infections and eczema was modified by antibiotic treatment. Interestingly, data from the PARSIFAL study suggest that the role of infection in eczema may depend on the eczema phenotype: severe lower respiratory tract infections in the first 2 years of life were positively related to eczema with asthma or wheeze but inversely related to eczema without asthma or wheeze (36).
Unanswered questions and future research
In summary, this large study suggests that environmental and lifestyle factors that have been implicated in the aetiology of eczema may be less important than previously assumed and may potentially be overridden by the effect of an atopic constitution. However, future research needs to further focus on longitudinal studies with frequent measures of both exposures and eczema symptoms. Further, gene–environment interactions will be crucial to shed more light on the complex aetiology of eczema.
We are indebted to the Robert-Koch-Institut, Berlin, for making the data available as a public use file. We thank all the children/adolescents and their parents for having taken part in this study.
- 15Public-Use-File KiGGS. Kinder und Jugendgesundheitssurvey 2003–2006. Berlin; 2008..
- 17Der Sozialschichtindex im Bundes-Gesundheitssurvey. Gesundheitswesen 1999;61:S178–S183., .
- 26Breastfeeding and maternal and infant health outcomes in developed countries. Evid Rep Technol Assess (Full Rep) 2007;153:1–186., , , , , et al.