The Association between Migration and Prevalence of Allergic Diseases: A Systematic Review and Meta-Analysis Open Access

The prevalences of allergic diseases (i.e., allergic rhinitis [AR], atopic dermatitis [AD], asthma) have remained in flux for the past two centuries and have grown to the forefront of attention due to their drastic increase [1]. Multiple environmental factors (e.g., microbial exposure, air pollution) and mechanisms of action have been put forward as culprits in the pathogenesis of allergic disease, with varying degrees of evidential support [2]. Indeed, a plethora of epidemiological studies have been published, implicating numerous risk factors both non-modifiable (e.g., genetics, gender) and modifiable (e.g., diet, microbes, pollution) in the manifestation of allergic diseases [3]. Notably, migration has also been demonstrated to be associated with the manifestation of allergic disease. The healthy immigrant effect (HIE) refers to the phenomenon where immigrants exhibit lower prevalences of disease than the native population of the destination country [4]. Epidemiological evidence has been reported for the association of first-generation migrant status with a lowered risk of allergic diseases [5, 6].

We aimed to systematically review the current literature on allergic diseases and migration. Our review investigated three specific allergic diseases – AR, AD, and asthma – and the changes in their prevalence associated with movement across different geographic regions or time spent in the new region following movement, both of which constituted acts of migration. Additionally, we aimed to update a previous systematic review of asthma and migration while expanding upon a previous narrative review of migration and allergic diseases [5, 6]. Finally, we address current hypotheses for the association of migration with allergic diseases and provide direction for future studies.

The current systematic review was conducted under updated guidelines established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement and was neither funded nor registered [7]. Per PRISMA 2020 guidelines, this review was completed against the PRISMA checklist, and the search process was documented with the PRISMA 2020 flow diagram (Fig. 1, online suppl. Tables 1, 2; for all online suppl. material, see https://doi.org/10.1159/000539382). To obtain a comprehensive record of articles examining any of the three allergic diseases – AD, AR, and asthma – and migrant status, we developed a search term that selected for articles wherein the title or abstract fulfilled two criteria: (1) used keywords or terms relevant to any of the three allergic diseases (i.e., AR, AD, asthma); (2) included terms referring to migration. The Web of Science Core Collection database was searched in September 2023 using the following search term: TI = ([migran* OR migrat* OR immigra*] AND [epidemiology OR prevalence] AND [allergic disease OR atopic dermatitis OR allergic dermatitis OR allergic rhinitis OR atopic rhinitis OR asthma]) OR AB = ([migran* OR migrat* OR immigra*] AND [epidemiology OR prevalence] AND [allergic disease OR atopic dermatitis OR allergic dermatitis OR allergic rhinitis OR atopic rhinitis OR asthma]).

The default publication date filter was applied – i.e., articles published between 1900 and 2023 were searched; no other filters were used. To ensure a thorough overview of the published literature, a secondary search was conducted, whereby citations of articles returned by the primary search were screened per our eligibility criteria and included in our review where appropriate. This process was repeated for citations of articles from the secondary search. The citations from secondary search articles were largely already included in our review, indicating that our literature search was sufficiently comprehensive.

Records from our primary search were subjected to screening based on the title and abstract. Articles that addressed any of the three allergic diseases as the outcome and migration as the exposure were included. We defined migration as the movement of individuals from one region to another; hence, articles comparing migrants to natives or comparing migrants based on duration since migration were included. Full-text articles available in English were then retrieved and rescreened according to the eligibility criteria. Excluded records were frequently of irrelevant topics (n = 100) or review articles (n = 27). The screening process was conducted by the first reviewer (Q.Y.A.W.) and reviewed by the second reviewer (F.T.C.). Finally, quality assessments via the JBI critical appraisal tool were performed for studies that fulfilled the eligibility criteria [8].

Information relevant to the study setting, sample size, sample demographics, country of study, and study type were extracted. Additionally, allergic disease outcomes and exposures relating to the movement of individuals were recorded. Due to variations in terminology between studies, outcomes were categorized as either AR (e.g., of terminology: hay fever, rhinoconjunctivitis), AD (e.g., of terminology: eczema), or asthma (e.g., of terminology: wheezing). Finally, where reported, regression model types, the resultant effect size estimates and standard error or confidence intervals (CIs), and confounding factors adjusted for in the model were abstracted. Only adjusted effect sizes were extracted from articles reporting both crude and adjusted effect sizes. For the proceeding meta-analyses, an abbreviated version of our dataset comprising the following information was used: author and publication year, outcome, exposure and reference group, effect size, and CIs (or standard error, where reported).

The risk of bias for included articles we assessed using the checklist for analytical cross-sectional studies from critical appraisal tools for use in JBI systematic reviews [8]. Eight study criteria were examined to assess the study risk of bias: (1) were the criteria for inclusion in the sample clearly defined, (2) were the study subjects and the setting described in detail, (3) was the exposure measured in a valid and reliable way, (4) were objective, standard criteria used for measurement of the condition, (5) were confounding factors identified, (6) were strategies to deal with confounding factors stated, (7) were the outcomes measured in a valid and reliable way, (8) was appropriate statistical analysis used. Each criterion was checked as either “yes” where explicitly fulfilled, “no” where lacking, or “unclear” where ambiguity was involved. The number of “yes” to a given fulfilled criteria was tallied and converted to a percentage denominated against the eight criteria. Studies that scored less than 50% were considered to have a high risk of bias.

Random effects meta-analysis using the DerSimonian-Laird method was conducted for common outcomes where the odds ratios and their accompanying 95% CI or standard error were reported [9]. For studies reporting 95% CIs, the standard error was calculated using the formula: (upper CI−lower CI) ÷ 3.92; the standard error was necessary for computing the pooled odds ratio (pOR) in the meta-analysis. pORs were calculated where appropriate, with consideration taken to ensure that study subjects did not overlap between studies and that exposure and reference categories were comparable. Among studies reporting odds ratios, exposure groups were primarily immigrants while reference groups were nonimmigrants; however, some studies assigned the immigrant group as a reference instead – for our analyses, the comparison was reversed by taking the inverse of the odds ratio. Where relevant, statistical significance was determined using the alpha value of 0.05. Heterogeneity was assessed using the I² index, whereby I² > 50% and an accompanying p value <0.05 was indicative of significant heterogeneity. Finally, for each pOR, publication bias was assessed using Begg’s funnel plots and Egger’s test.

Our search process was documented using the PRISMA 2020 flow diagram (Fig. 1). Searching the Web of Science databases yielded 201 records, of which 13 were excluded before screening due to non-English language of publication or article type. Of the remaining 188 articles, the title and abstract of 57 were deemed not to meet our eligibility criteria, while another 26 were review articles. Full texts of 105 articles were sought for retrieval, of which 4 were inaccessible, 56 were irrelevant, and 1 was a review article. References of the 44 relevant articles were hand searched, yielding a further 6 pertinent original research publications. Overall, a total of 50 articles were included in the current systematic review (online suppl. Table 3). Forty-eight studies fulfilled at least 4 of the criteria and had a score of at least 50% in our risk of bias assessment. The remaining two studies were included upon referring to their citations to verify their methods (online suppl. Table 4).

Articles examined herein were published across the years 1994–2022 and originated from at least 14 distinct countries (Table 1). Moreover, two articles were multicenter studies, including a European Community Respiratory Health Survey (ECRHS) publication analyzing data from Europe, the USA, Australia, and New Zealand, and an International Study of Asthma and Allergies in Childhood (ISAAC) publication spanning 48 countries [10, 11]. Studies were preponderantly of the cross-sectional nature (n = 43), with the remaining studies being prospective cohort studies (n = 2), longitudinal studies (n = 4), and one retrospective cohort study. Overall, an estimated total of 3,755,248 individuals were included in 48 studies, barring two studies that did not report their sample size [12, 13]. Asthma was the most extensively studied of the three allergic diseases, with 46 articles investigating a variety of asthma-related outcomes including wheezing and chronic cough (online suppl. Table 5). Notwithstanding, 16 articles relevant to AR and 14 articles relevant to AD were retrieved. Allergic disease outcomes were frequently classified using questionnaires (n = 41), with notable standardized examples including the ISAAC and ECRHS questionnaires. The minority of studies involved the examination of medical records (n = 6), collected data via telephone interviews (n = 2), or conducted an interview accompanied by physical examination in a mobile health unit (n = 1). A summary of study details can be found in Table 1.

Forty articles studied the movement of individuals across regions, with 39 evaluating cross-border movement between countries and 1 assessing the movement of individuals between affluent and deprived areas within the UK (online suppl. Table 6). Twelve articles assessed the relationship between duration of residence in the destination country with allergic disease among immigrants, 9 recorded the age at immigration, while 2 assessed acculturation which could be interpreted as a proxy measure of duration of residence. Most studies were conducted from the standpoint of an affluent region, wherein immigration entailed the movement of individuals from less affluent or equally affluent regions to an affluent region. Only 1 study analyzed the migration of individuals to a less affluent area [14]. Furthermore, while the destination of migration was often defined, the countries of origin were not usually reported with immigrants possibly originating from a variety of countries. Among studies that specified the country of origin, Mexican migrants to the USA (n = 5) and Chinese migrants (n = 5) were the most well represented, Ethiopians and migrants from the former Soviet Union (i.e., Russia, Ukraine, Georgia, Kazakhstan) were reported by two studies each, while Albanians, Malaysians, and Turkish were reported by one study each.

Despite the heterogeneity between studies with respect to migrant ethnicities, countries of origin, individuals categorized into the immigrant group, and country of destination, several unifying conclusions could be achieved. First, immigrants to regions variously referred to as affluent, high-income, or developed generally exhibited lower prevalences of AR, AD, and asthma as compared to the native population. This observation was consistent regardless of whether the migration event occurred between countries or within countries. A single noteworthy study compared migrants to deprived areas against those remaining in affluent areas and found that there was an increased likelihood of asthma among the migrant group (adjusted odds ratio = 1.71, 95% CI = 1.25–2.35). Second, as the duration of residence in the destination country increased, the prevalence of allergic diseases among the immigrant group increased – in most studies where the host country population exhibited a higher prevalence of allergic diseases than the immigrant population, the prevalence of allergic diseases among immigrant population approached that of the host region and stabilized. Third, the earlier the age of immigration to a country wherein the prevalence of allergic diseases was comparatively higher, the lower the magnitude of difference between the prevalence among immigrants and that of the host population. However, this finding could have been confounded by the possibility that at the time of data collection, individuals who immigrated at a younger age would have resided for a longer duration in the host region than those who immigrated later. Findings from the various studies are summarized in Table 1.

pORs were calculated for comparable outcomes and exposure-reference group pairs. Migration was not significantly associated with AD prevalence (pOR = 0.68, 95% CI = 0.31, 1.49, I² = 89.95%; Fig. 2a). A lower odds of AR was observed among immigrants when compared to nonmigrants (pOR = 0.58, 95% CI = 0.45, 0.74, I² = 73.36%; Fig. 2b), but residing at least 10 years in the destination country among immigrants compared to a residence duration of less than 10 years was associated with an increased likelihood of AR (pOR = 8.36, 95% CI = 4.15, 16.81, I² = 0.00%; Fig. 2c). Being a migrant also significantly decreased one’s odds of asthma (pOR = 0.56, 95% CI = 0.44, 0.72, I² = 86.07%; Fig. 3a), but residing in the host country for at least 10 years significantly associated with an increase in asthma among immigrants (pOR = 1.85, 95% CI = 1.25, 2.73, I² = 0.00%; Fig. 3b). Immigrating aged 5 and below compared to immigrating after the age of 5 was not a significant risk factor (pOR = 1.01, 95% CI = 0.68, 1.50, I² = 82.62%; Fig. 3c). Of note, there was significant heterogeneity in almost all the pORs calculated herein, except for the associations of 10 years of residence in the host country with AR and AD, respectively. While there appeared to be publication bias for AD and AR studies, funnel plots and Egger’s test p value indicated nonsignificant publication bias for asthma studies (online suppl. Fig. 1).

Results from our meta-analysis showed that immigrants, when compared to natives from their destination country, have a significantly lowered odds of AR (pOR = 0.58) and asthma (pOR = 0.56). These findings are reminiscent of the putative HIE, alternatively referred to as the healthy migrant hypothesis, which postulates that migrants exhibit better health than nonmigrants [15]. This trend has been observed in among migrants to Australia, Canada, the UK, and the USA – chronic diseases (comprising cancer, cardiac disease, diabetes, ulcers, arthritis, hypertension, bronchitis or emphysema, and asthma) were less prevalent among immigrants as compared to natives [16]. Additionally, the HIE has been found to be stronger for migrants from developing countries than those from developed countries [16].

The HIE has popularly been attributed to possible selection biases such as the salmon-bias or reverse-migration hypothesis where migrants with poorer health are more likely to return home, or a disparity in access to healthcare resulting from language barriers and low socioeconomic status [17‒19]. The former speculation has been dispelled more than once [18, 20]. Furthermore, studies included in this review found an increase in the prevalence of AR and asthma among immigrants who had resided in their host countries for at least 10 years. On the latter count, a study of undocumented immigrants to the USA who are frequently of lower socioeconomic status and lack access to healthcare showed the persistence of the HIE [21]. Thus, while healthcare access and sociocultural factors may modify the effects of immigrant status on health, they do not fully account for the HIE [18].

The human microbiome refers to the genetic material of microbiota which includes bacteria, fungi, and viruses [22]. While most of the human microbiota lives in the gut, various body sites such as the nasal cavity, skin, respiratory tract, and lungs are also hosts to microbes [22, 23]. Within their local sites, resident microbes have been implicated in various disorders – for example, the skin microbiota comprises Propionibacterium acnes which is associated with acne, while the fungi species Malassezia spp. has been implicated in seborrheic dermatitis [24]. Further examples of local disorders associated with their resident microbiota include inflammatory bowel disease, which may be exacerbated due to contact of bacterial antigens with immune cells as a result of a defective mucosal barrier [25]. Regardless of the site of colonization, the human microbiota also appears to be able to exert systematic effects on the human body [26]. Increasingly, evidence supporting the essential role of the microbiota on human health is being revealed, such as the regulation of the immune system by commensal intestinal bacteria [27]. Additionally, the gut microbiome has also been implicated in the immune response and allergic disease, where children suffering from allergic diseases had fewer microaerophilic bacteria and increased aerobic microorganisms among their intestinal microflora [28].

Indeed, there has been an emergence of evidence associating the microbiome with allergic diseases [29]. Asthmatic individuals exhibited increased proteobacteria such as Haemophilus spp. in the bronchi as compared to non-asthmatics, notwithstanding a dearth of causal evidence [30]. Further studies established that bacterial diversity, community composition, and relative abundance of specific phylotypes are associated with the degree of bronchial hyperresponsiveness among asthmatics, suggesting a possible role for microbes in asthma severity [31]. With AD, disease states were characterized by changes in microbial diversity and composition of Staphylococcus spp., where untreated flares were associated with reduced bacterial diversity and high Staphylococcus proportions [32]. Additionally, dysbiosis of Faecalibacterium prausnitzii in the gut has been shown to impair the gut epithelial barrier, releasing material from the gut into systematic circulation, which triggers TH2-type immune responses to allergens in the skin [33]. As such, the importance of the human microbiota and the maintenance of its balance are appearing increasingly paramount.

However, urbanization appears to be disruptive to the human microbiome. Westernization of diet, air pollution, increased antibiotic use, and improved hygiene were notable factors known to affect human microbiota [34]. Across different regions, urbanization has been shown to exert a consistent effect on the microbiome – a study of an urbanizing Chinese city found that the microbial composition of the Chinese population converged with that of American populations [35]. Notably, migration to developed countries has also been implicated as a contributing factor to the changes in the human microbiome, with multiple studies highlighting the changes in human microbiota following migration [36]. As such, exposure to an urbanized environment following migration could affect the human microbiota, which in turn mediates immune response and allergy, leading to a change in allergic disease manifestation.

The relationship between helminthic infection and allergy has not gone unnoticed in Israel, which has received a large number of Ethiopian immigrants on whom studies have been conducted and reviewed herein [37]. In 2006, a meta-analysis of intestinal parasite infection and asthma reported that while there was a nonsignificant association of any parasite infection with asthma, stratifying the meta-analysis by species showed that Ascaris lumbricoides was significantly associated with an increased odd of asthma while hookworm infection was associated with a significantly decreased odd of asthma in a dose-response manner [38]. Later, a 2022 meta-analysis found no overall association between helminth infections and allergic diseases, but A. lumbricoides infections were associated with an increased risk of bronchial hyperresponsiveness in children and atopy in adults [39]. Concerning eczema, epidemiological studies have found that the association with helminth infection varies from positive to negative [40]. Helminth infections were associated with decreased skin test reactivity in several epidemiological studies; on the other hand, studies evaluating anthelmintic treatment and atopy showed that anthelminthic therapy was associated with an increased incidence of skin reactivity to house dust mites [40]. Interestingly, yet another meta-analysis has shown that helminth infection is associated with an increased gut bacterial diversity, which has been shown to regulate immune response, as discussed above [41].

Overall, confounding factors added levels of complexity to the analysis of the association between helminth infection and outcomes of interest, owing to the possibility of infection with more than one species of parasite, formerly infected individuals being erroneously classified as currently infected individuals due to testing methodology, and the unlikelihood of said infection being the sole mediator of studied outcomes. Taken together, it is possible that the effect of parasitic infections on allergic diseases is confined to specific species, and the association is confounded by other factors, environmental and otherwise. Indeed, studies have demonstrated that IL-10 induced by helminth infection downregulates the production of IgE, but helminth infection is also associated with increased IgE cross-reactivity to various allergens, including house dust mites [42]. As such, there appears to be a highly complex interaction involving multiple environmental and biomolecular processes, rendering this topic a complicated one to study.

Nonetheless, helminth infections and their treatment following migration could be a contributing factor to the changes in the prevalence of allergic diseases among immigrants as compared to populations in destination countries. Moreover, helminth infections remain relevant in many developing parts of the globe [43].

Diet has been shown to modulate immune functions, with studies showing the mechanisms of the effect of various macro- and micronutrients on immune regulation [44]. Moreover, diet and nutrition have been implicated in the pathogenesis and pathophysiology of allergic diseases – dietary components may directly affect innate immune responses or adaptive immune responses via nutrients and metabolites, while their effects on the gut microbiota and the resulting bacterial metabolites may also modulate immune function [45]. Epidemiological evidence supporting the association of different diets with the risk of allergic diseases has been published. Western dietary patterns that are high in energy, saturated fat, and processed foods but low in fiber consumption were associated with increased asthma and AR risk, while diets based on high-fiber whole foods – characteristic of a Mediterranean diet – were associated with lower asthma and AR risk [46]. Sufficient fiber and micronutrient intake were also associated with a reduction in the symptoms of allergic diseases [47, 48].

There is increasing epidemiological evidence for the relationship between air pollution and allergic diseases [49]. NO₂ and O₃ have been found to be associated with asthma exacerbations and enhanced allergic responses to aeroallergens [49]. Additionally, high traffic density resulting in traffic-related air pollution was associated with increased incidence of asthma symptoms and bronchodilator use [50]. D Diesel exhaust particles have been found to induce proinflammatory responses in lung epithelial cells and aggravate TH2 immune responses which have been implicated in asthma [51]. Besides respiratory disorders, exposure to traffic-related pollution has been linked to the manifestation and exacerbation of AD, possibly due to oxidative stress of the skin or genetic mutation induced by air pollutants, leading to skin barrier dysfunction and immune dysregulation [52].

Increased access to healthcare and better education could also explain the increased diagnoses of allergic diseases. Moreover, the initial language barrier following immigration could result in poor knowledge of allergic diseases and a greater barrier to health care services. Following adaptation to the region, a better grasp of language, and a changing perception of one’s health relative to their native counterparts, there would be a likely increase in healthcare-seeking behavior. Indeed, studies measuring acculturation, which includes gauging the individual’s usage of the local language, have found an increased risk of asthma among highly acculturated subjects [53, 54].

Inevitably, the movement of individuals from one region to another would result in a change in overall environmental exposure due to the state of development, differing availability of food, and social situation in the destination region. The effect of migration on allergic diseases is unlikely to be due to a single cause but a multitude of contributing factors working in conjunction with each other.

With evidence listing a variety of environmental factors that potentially work in complex interactions to influence allergic disease, discerning the risk factors responsible for the observed association between migration and allergic diseases is challenging. Moreover, it has been well established that genetics form a strong basis for the manifestation of allergic diseases [55]. As such, migration and its effect on allergic diseases further involve a complex gene-environment interaction. We propose that DNA methylation studies can help further the understanding of the migration-allergy relationship. DNA methylation refers to the attachment of a methyl group to the C5 position of the cytosine ring in DNA, catalyzed by DNA methyltransferase [56]. Notably, regulation of gene expression by the environment has been proposed to be via the process of DNA methylation [57]. Associations for DNA methylation with air pollution, microbial composition, and even mental state have been discovered and linked to the risk of asthma or AR [58]. Although this field remains to be thoroughly explored, the possibility of novel studies targeting other environmental exposures associated with allergic diseases via DNA methylation gives exciting hope to better understand the influence of migration on allergic diseases.

The findings of this review were limited by the primarily cross-sectional nature of the included articles. In an ideal setting, a longitudinal study would give a better idea of the HIE on allergic diseases, particularly with regards to whether age at immigration influences the risk of allergic diseases, and where reference to the population remaining in the origin country needs to be made. Additionally, allergic disease outcomes were frequently classified using questionnaire data and could be subject to the perception of the respondents, predisposing the studies to a potential source of bias and diminishing the reliability of this review. Objective diagnoses of allergic disease, such as using the spirometry of bronchodilator reversibility test for asthma, could add to the reliability of the outcomes. Furthermore, immigrant groups were highly nonspecific, with little distinction between their country of origin. Nonetheless, the current review was able to obtain 50 studies relevant to migration and allergic disease, with most studies having a low overall risk of bias. Additionally, these studies were identified via a justifiably comprehensive search of the literature. Despite the heterogeneity between studies, a pOR could be obtained to provide readers with an effect size for the association between migration and the allergic diseases.

In conclusion, we have systematically reviewed the existing literature on migration and allergic disease. A reasonably comprehensive summary of the literature was provided, and where appropriate, a meta-analysis was conducted. pORs obtained from the meta-analysis indicated that migration was significantly associated with a decreased risk of asthma and AR, but not with AD. Likewise, residing for more than 10 years in the destination country was associated with an increased risk of AR and asthma. Conversely, immigrating before the age of 5 was not significantly associated with asthma manifestation. We have also discussed the prevailing hypotheses and existing evidence. Finally, we posit that DNA methylation studies have the potential to help expand our understanding of migration and allergic diseases.

The authors would like to thank Avinaash Subramaniam for proofreading this review and providing valuable inputs to the manuscript.

An ethics statement is not applicable because this study is based exclusively on published literature.

F.T.C. reports grants from Singapore Ministry of Education Academic Research Fund, Singapore Immunology Network, National Medical Research Council (Singapore), Biomedical Research Council (Singapore), National Research Foundation (NRF) (Singapore), Singapore Food Agency (SFA), and the Agency for Science Technology and Research (Singapore), during the conduct of the study; and has received consultancy fees from Sime Darby Technology Centre, First Resources Ltd, Genting Plantation, Olam International, and Syngenta Crop Protection, outside the submitted work. The other authors declare no other competing interests.

F.T.C. received grants from the National University of Singapore (N-154-000-038-001), Singapore Ministry of Education Academic Research Fund (R-154-000-191-112; R-154-000-404-112; R-154-000-553-112; R-154-000-565-112; R-154-000-630-112; R-154-000-A08-592; R-154-000-A27-597; R-154-000-A91-592; R-154-000-A95-592; R154-000-B99-114), Biomedical Research Council (BMRC) (Singapore) (BMRC/01/1/21/18/077; BMRC/04/1/21/19/315; BMRC/APG2013/108), Singapore Immunology Network (SIgN-06-006; SIgN-08-020), National Medical Research Council (NMRC) (Singapore) (NMRC/1150/2008; OFIRG20nov-0033), National Research Foundation (NRF) (Singapore) (NRF-MP-2020-0004), Singapore Food Agency (SFA) (SFS_RND_SUFP_001_04; W22W3D0006), and the Agency for Science Technology and Research (A*STAR) (Singapore) (H17/01/a0/008; and APG2013/108). The funding agencies had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

F.T.C. conceived, supervised, and reviewed the current research study. Q.Y.A.W. conducted the literature review, collected, and analyzed the data, and wrote the manuscript. Both authors read and approved the final manuscript. All authors have read and consented to the publication of this manuscript.

Edited by: H.-U. Simon, Bern.This review was not registered.

All data generated or analyzed during this study are included in this article and its supplementary material files. Further inquiries can be directed to the corresponding author.