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Social network analysis of Staphylococcus aureus carriage in a general youth population

  • Author Footnotes
    # These authors have contributed equally to the development of the manuscript.
    Dina B. Stensen
    Correspondence
    Corresponding author: Dina B. Stensen, Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Hansine Hansens veg 18, 9019 Tromsø, Norway. Fax: (0047) 77627015.
    Footnotes
    # These authors have contributed equally to the development of the manuscript.
    Affiliations
    Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, 9019 Tromsø, Norway

    Division of Internal Medicine, University Hospital of North Norway, 9019, Tromsø, Norway
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  • Author Footnotes
    # These authors have contributed equally to the development of the manuscript.
    Rafael A. Nozal Cañadas
    Footnotes
    # These authors have contributed equally to the development of the manuscript.
    Affiliations
    Department of Computer Science, UiT The Arctic University of Norway, 9019, Tromsø, Norway
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  • Lars Småbrekke
    Affiliations
    Department of Pharmacy, Faculty of Health Sciences, UiT The Arctic University of Norway, 9019, Tromsø, Norway
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  • Karina Olsen
    Affiliations
    Department of Microbiology and Infection Control, Division of Internal Medicine, University Hospital of North Norway, 9019, Tromsø, Norway
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  • Christopher Sivert Nielsen
    Affiliations
    Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, 0473 Oslo, Norway

    Department of Pain Management and Research, Division of Emergencies and Critical Care, Oslo University Hospital, 0424 Oslo, Norway
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  • Kristian Svendsen
    Affiliations
    Department of Pharmacy, Faculty of Health Sciences, UiT The Arctic University of Norway, 9019, Tromsø, Norway
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  • Anne Merethe Hanssen
    Affiliations
    Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, 9019 Tromsø, Norway
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  • Johanna U. Ericson
    Affiliations
    Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, 9019 Tromsø, Norway
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  • Gunnar Skov Simonsen
    Affiliations
    Department of Microbiology and Infection Control, Division of Internal Medicine, University Hospital of North Norway, 9019, Tromsø, Norway

    Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, 9019 Tromsø, Norway
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  • Lars Ailo Bongo
    Affiliations
    Department of Computer Science, UiT The Arctic University of Norway, 9019, Tromsø, Norway
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  • Anne-Sofie Furberg
    Affiliations
    Department of Microbiology and Infection Control, Division of Internal Medicine, University Hospital of North Norway, 9019, Tromsø, Norway

    Faculty of Health and Social Sciences, Molde University College, 6410 Molde, Norway
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  • Author Footnotes
    # These authors have contributed equally to the development of the manuscript.
Open AccessPublished:August 31, 2022DOI:https://doi.org/10.1016/j.ijid.2022.08.018

      Highlights

      • Social network analysis can be used to evaluate the direct transmission of Staphylococcus aureus.
      • The risk of carriage increases by 5% for each additional S. aureus positive contact.
      • Male sex is a biological risk factor for S. aureus carriage.

      Abstract

      Objectives

      Staphylococcus aureus carriage increases the risk of infection. We used social network analysis to evaluate whether contacts have the same S. aureus genotype indicating direct transmission or whether contagiousness is an indirect effect of contacts sharing the same lifestyle or characteristics.

      Methods

      The Fit Futures 1 study collected data on social contact among 1038 high school students. S. aureus carriage was determined from two nasal swab cultures and the genotype was determined by spa-typing of positive throat swabs.

      Results

      S. aureus carriage and spa-type were transmitted in the social network (P < 0.001). The probability of carriage increased by 5% for each S. aureus positive contact. Male sex was associated with a 15% lower risk of transmission compared to the female sex, although the carriage prevalence was higher for men (36% vs 24%). Students with medium physical activity levels, medium/high alcohol use, or normal weight had a higher number of contacts and an increased risk of transmission (P < 0.002).

      Conclusion

      We demonstrated the direct social transmission of S. aureus. Lifestyle factors are associated with the risk of transmission, suggesting the effects of indirect social groups on S. aureus carriage, such as friends having more similar environmental exposures. The male predominance in the carriage is determined by sex-specific predisposing host characteristics as the social transmission is less frequent in males than females. Information on social networks may add to a better understanding of S. aureus epidemiology.

      Keywords

      Introduction

      Nasal carriage of Staphylococcus aureus has a prevalence of 20-30% in the general adult population (
      • Olsen K
      • Falch BM
      • Danielsen K
      • Johannessen M
      • Ericson Sollid JU
      • Thune I
      • Grimnes G
      • Jorde R
      • Simonsen GS
      • Furberg AS
      Staphylococcus aureus nasal carriage is associated with serum 25-hydroxyvitamin D levels, gender and smoking status. The Tromso staph and skin Study.
      ;
      • Stensen DB
      • Småbrekke L
      • Olsen K
      • Grimnes G
      • Nielsen CS
      • Sollid JUE
      • Simonsen GS
      • Almås B
      • Furberg AS.
      Circulating sex-steroids and Staphylococcus aureus nasal carriage in a general female population.
      ) and 40-50 % in older children and adolescents (
      • Stensen DB
      • Småbrekke L
      • Olsen K
      • Grimnes G
      • Nielsen CS
      • Simonsen GS
      • Sollid JUE
      • Furberg AS.
      Hormonal contraceptive use and Staphylococcus aureus nasal and throat carriage in a Norwegian youth population.
      ) and is more common among men than women (
      • Olsen K
      • Falch BM
      • Danielsen K
      • Johannessen M
      • Ericson Sollid JU
      • Thune I
      • Grimnes G
      • Jorde R
      • Simonsen GS
      • Furberg AS
      Staphylococcus aureus nasal carriage is associated with serum 25-hydroxyvitamin D levels, gender and smoking status. The Tromso staph and skin Study.
      ). Carriers have an increased risk of autoinfection (
      • Bode LG
      • Kluytmans JA
      • Wertheim HF
      • Bogaers D
      • Vandenbroucke-Grauls CM
      • Roosendaal R
      • Troelstra A
      • Box AT
      • Voss A
      • van der Tweel I
      • van Belkum A
      • Verbrugh HA
      • Vos MC.
      Preventing surgical-site infections in nasal carriers of Staphylococcus aureus.
      ;
      • Wertheim HF
      • Melles DC
      • Vos MC
      • van Leeuwen W
      • van Belkum A
      • Verbrugh HA
      • Nouwen JL.
      The role of nasal carriage in Staphylococcus aureus infections.
      ). Therefore, prevention of nasal carriage may reduce the disease burden of S. aureus (
      • Bode LG
      • Kluytmans JA
      • Wertheim HF
      • Bogaers D
      • Vandenbroucke-Grauls CM
      • Roosendaal R
      • Troelstra A
      • Box AT
      • Voss A
      • van der Tweel I
      • van Belkum A
      • Verbrugh HA
      • Vos MC.
      Preventing surgical-site infections in nasal carriers of Staphylococcus aureus.
      ). Epidemiologic studies have searched for modifiable risk factors for S. aureus nasal carriage as potential targets for interventions, including body mass index (BMI), serum glucose and vitamin D, exogenous and endogenous hormones, and smoking (
      • Johannessen M
      • Sollid JE
      • Hanssen AM.
      Host- and microbe determinants that may influence the success of S. aureus colonization.
      ;
      • Olsen K
      • Falch BM
      • Danielsen K
      • Johannessen M
      • Ericson Sollid JU
      • Thune I
      • Grimnes G
      • Jorde R
      • Simonsen GS
      • Furberg AS
      Staphylococcus aureus nasal carriage is associated with serum 25-hydroxyvitamin D levels, gender and smoking status. The Tromso staph and skin Study.
      ;
      • Olsen K
      • Danielsen K
      • Wilsgaard T
      • Sangvik M
      • Sollid JU
      • Thune I
      • Eggen AE
      • Simonsen GS
      • Furberg AS.
      Obesity and Staphylococcus aureus nasal colonization among women and men in a general population.
      ;
      • Sangvik M
      • Olsen RS
      • Olsen K
      • Simonsen GS
      • Furberg AS
      • Sollid JU.
      Age- and gender-associated Staphylococcus aureus spa types found among nasal carriers in a general population: the Tromso staph and Skin Study.
      ;
      • Stensen DB
      • Småbrekke L
      • Olsen K
      • Grimnes G
      • Nielsen CS
      • Simonsen GS
      • Sollid JUE
      • Furberg AS.
      Hormonal contraceptive use and Staphylococcus aureus nasal and throat carriage in a Norwegian youth population.
      ;
      • Wertheim HF
      • Melles DC
      • Vos MC
      • van Leeuwen W
      • van Belkum A
      • Verbrugh HA
      • Nouwen JL.
      The role of nasal carriage in Staphylococcus aureus infections.
      ). However, these studies did not adjust for social contact.
      Direct transmission of S. aureus is primarily through physical contact (
      • Knox J
      • Uhlemann AC
      • Lowy FD.
      Staphylococcus aureus infections: transmission within households and the community.
      ); however, no other study has evaluated the direct social transmission of S. aureus carriage in young populations. In studies that involve transmissible pathogens, an extensive problem with identifying the risk factors is the lack of adjustment for social contact. Biological host risk factors for S. aureus carriage may also be determinants of friendship, thereby producing an association by confounding. Predisposing lifestyle risk factors may be contagious with the consequence of researchers incorrectly assuming the transmission of the pathogen. Prevention of S. aureus carriage is dependent on identifying key transmission pathways and causal risk factors to correctly evaluate targets for interventions.
      Infectious diseases like tuberculosis, HIV infection, and sexually transmitted diseases have been strongly connected to social networks (
      • Jolly AM
      • Wylie JL.
      Gonorrhoea and chlamydia core groups and sexual networks in Manitoba.
      ;
      • Klovdahl AS
      • Graviss EA
      • Yaganehdoost A
      • Ross MW
      • Wanger A
      • Adams GJ
      • Musser JM.
      Networks and tuberculosis: an undetected community outbreak involving public places.
      ;
      • Rothenberg RB
      • Potterat JJ
      • Woodhouse DE
      • Muth SQ
      • Darrow WW
      • Klovdahl AS.
      Social network dynamics and HIV transmission.
      ). These studies demonstrate that the degree and type of contact between individuals play a significant role in disease incidence. One study showed that the introduction of S. aureus into a social network of active drug users created a reservoir for the bacteria linked to the general population (
      • Gwizdala RA
      • Miller M
      • Bhat M
      • Vavagiakis P
      • Henry C
      • Neaigus A
      • Shi Q
      • Lowy FD.
      Staphylococcus aureus colonization and infection among drug users: identification of hidden networks.
      ). A recent case-control study used network analysis to reveal the transmission of methicillin-resistant S. aureus (MRSA) through social network in healthcare (
      • Moldovan ID
      • Suh K
      • Liu EY
      • Jolly A.
      Network analysis of cases with methicillin-resistant Staphylococcus aureus and controls in a large tertiary care facility.
      ). Social group effects also occur in humans, as unrelated individuals living in the same household are found to have more similar microbiota than relatives living in different households (
      • Song SJ
      • Lauber C
      • Costello EK
      • Lozupone CA
      • Humphrey G
      • Berg-Lyons D
      • Caporaso JG
      • Knights D
      • Clemente JC
      • Nakielny S
      • Gordon JI
      • Fierer N
      • Knight R.
      Cohabiting family members share microbiota with one another and with their dogs.
      ). Transmission of S. aureus has also been observed within households (
      • Miller M
      • Cook HA
      • Furuya EY
      • Bhat M
      • Lee MH
      • Vavagiakis P
      • Visintainer P
      • Vasquez G
      • Larson E
      • Lowy FD.
      Staphylococcus aureus in the community: colonization versus infection.
      ).
      Therefore, the aim of this study is to estimate the extent to which S. aureus carriage follows friendship ties and whether the data support the concept of direct social transmission. We also aim to identify host risk factors for S. aureus carriage and differentiate between the risk attributable to social contact among similar individuals compared to biologic or lifestyle-related risk.

      Methods

      Population and study design

      The Fit Futures 1 study (FF1) was a youth health survey conducted from September 2010 to April 2011, inviting all first-year students registered at 8 high schools in the municipalities of Tromsø and Balsfjord, North Norway. Altogether, 508 female and 530 male students participated in the survey (93% participation) (
      • Winther A
      • Dennison E
      • Ahmed LA
      • Furberg AS
      • Grimnes G
      • Jorde R
      • Gjesdal CG
      • Emaus N.
      The Tromso Study: Fit Futures: a study of Norwegian adolescents' lifestyle and bone health.
      ). Participants visited the Clinical Research Unit of the University Hospital of North Norway (UNN) for interviews, questionnaires, clinical examinations, and microbiological samples. Trained research nurses performed all the procedures according to a standard protocol.

      Host risk factors

      Participants wore light clothing and no shoes. Height (cm) and weight (kg) were measured on an electronic scale with participants wearing light clothing and no shoes, and BMI (kgm2) was calculated. The participants reported their sex, age, study program, tobacco use, alcohol use, and recreational physical activity through a web-based questionnaire.
      The interview covered current hormonal contraceptive use. We categorized hormonal contraceptive use into progestin-only contraceptives and combination contraceptives with high or low ethinylestradiol dosage (
      • Stensen DB
      • Småbrekke L
      • Olsen K
      • Grimnes G
      • Nielsen CS
      • Simonsen GS
      • Sollid JUE
      • Furberg AS.
      Hormonal contraceptive use and Staphylococcus aureus nasal and throat carriage in a Norwegian youth population.
      ).

      Assessment of S. aureus carriage

      The research nurses took a first set of nasal and throat swab samples at the hospital, and a second set at school after a mean interval of 17 days. Nasal vestibules were sampled using the same 0.9 % NaCl-moistened sterile rayon-tipped swab, and both tonsillar regions were sampled with another swab. The swabs were immediately placed in a transport medium (Amies Copan, Brescia, Italy) and stored at 4°C for a maximum of 3 days. All samples were analyzed at the Department of Microbiology and Infection Control, UNN, both by direct culture (
      • Olsen K
      • Falch BM
      • Danielsen K
      • Johannessen M
      • Ericson Sollid JU
      • Thune I
      • Grimnes G
      • Jorde R
      • Simonsen GS
      • Furberg AS
      Staphylococcus aureus nasal carriage is associated with serum 25-hydroxyvitamin D levels, gender and smoking status. The Tromso staph and skin Study.
      ) and enrichment culture (
      • Stensen DB
      • Småbrekke L
      • Olsen K
      • Grimnes G
      • Nielsen CS
      • Simonsen GS
      • Sollid JUE
      • Furberg AS.
      Hormonal contraceptive use and Staphylococcus aureus nasal and throat carriage in a Norwegian youth population.
      ) (Bacto Staphylococcus medium broth, Difco Laboratories, Sparks, Maryland, USA), using blood agar for growth control (Oxoid, UK) and chromID-plates for S. aureus detection (SAID, bioMérieux, Marcy I'Etoile, France and MRSA agar plates SmithMed AS/Microbiological media production, Department of Microbiology and Infection Control, UNN). The growth of any bacterial colonies on agar plates was registered as a valid sample. The dominating S. aureus colony type was frozen at - 70°C in glycerol-containing liquid medium after confirmation by Staphaurex plus agglutination test (bioMérieux, Marcy I'Etoile, France).
      We used S. aureus persistent nasal carriage as the main outcome variable in the present analysis as this has been the major phenotype of interest in infection control and epidemiologic studies (
      • van Belkum A
      • Verkaik NJ
      • De Vogel CP
      • Boelens HA
      • Verveer J
      • Nouwen JL
      • Verbrugh HA
      • Wertheim HF.
      Reclassification of Staphylococcus aureus nasal carriage types.
      ). We defined persistent carriage as having either two positive direct cultures or two positive enrichment cultures (Supplementary Figure 1). All S. aureus isolates from the first throat swab sample taken at the hospital were spa-typed (staphylococcal protein A) as part of another study by
      • Sangvik M
      • Olsen RS
      • Olsen K
      • Simonsen GS
      • Furberg AS
      • Sollid JU.
      Age- and gender-associated Staphylococcus aureus spa types found among nasal carriers in a general population: the Tromso staph and Skin Study.
      .

      Social network

      We constructed the social network based on the interview question: “Which first level high school students have you had most contact with the last week? Name up to five students at your own school or other schools in Tromsø and Balsfjord.” Reciprocity in the nomination was not mandatory. For each nomination, five “yes/no” questions assessed the type of contact: “Did you have physical contact?”, “Have you been together at school?”, “Have you been together at sports?”, “Have you been together at home?”, “Have you been together at other places?”. This gave five social networks depending on the setting: “physical contact”, “school”, “sport”, “home, and “other” networks. Adding all the relationships together formed a sixth network that was called the “overall” network. To evaluate if the friends mentioned were representative for the participants´ social network, the following question was asked: “To what degree does this list of friends give an overview of your social network? Please indicate on a scale from zero (small degree) to ten (high degree).” We excluded 134 nominated friends that did not participate in FF1.

      Statistical analysis

      We used R version 3.6.3 and R Studio 1.3.1093 for the statistical analysis. To evaluate univariable associations between host factors and S. aureus persistent carriage we used Student's t-test and chi-square test, with Yates's correction for 2 × 2 tables and Fisher's exact test, when applicable.
      In the social network analysis, nodes refer to participants in the network while edges refer to lines representing relationships between participants. To evaluate transmission of S. aureus through the social network, we analyzed edges between nodes using Exponential Random Graph Models or additive and multiplicative effects models. We analyzed patterns of connections (non-carriers connected to non-carriers, non-carriers connected to carriers, carriers connected to carriers) using the autocorrelation model Simulation Investigation for Empirical Network Analysis (
      • O'malley AJ
      • Marsden PV.
      The analysis of social networks.
      ). In further analysis, we used bootstrapping of simulated networks against the observed network, descriptive analysis, and logistic regression to evaluate the effect of host risk factors. The statistical background for our methods is described in Supplementary material.

      Results

      Transmission of S. aureus carriage in a general population

      In the general population with a mean age of 16.4 years (SD = 1.24, range 15-28), the prevalence of S. aureus persistent nasal carriage determined by direct culture was 30.3%, compared with 42.6% when using enrichment culture. No MRSA isolates were detected. Prevalence of persistent carriage was higher in male compared to female participants; 36.4% versus 24.0% for direct culture, and 48.1% versus 36.8% for enrichment culture. We found no other significant differences in carrier prevalence between groups according to host characteristics (Table 1).
      Table 1Characteristics of the study population by Staphylococcus aureus persistent nasal carriage determined by direct and enrichment culture. The Fit Futures 1 study (N = 1038).
      Direct cultureEnrichment culture
      Positive
      Positive = two consecutive nasal swab cultures positive for S. aureus Negative = one or none of two consecutive nasal swab cultures positive for S. aureus.
      Negative
      Positive = two consecutive nasal swab cultures positive for S. aureus Negative = one or none of two consecutive nasal swab cultures positive for S. aureus.
      PrevalencePositive
      Positive = two consecutive nasal swab cultures positive for S. aureus Negative = one or none of two consecutive nasal swab cultures positive for S. aureus.
      Negative
      Positive = two consecutive nasal swab cultures positive for S. aureus Negative = one or none of two consecutive nasal swab cultures positive for S. aureus.
      Prevalence
      Sex< 0.001< 0.001
      Male19333736.4 %25527548.1 %
      Female12238624.0 %18732136.8 %
      Study program0.990.08
      General11827230.3 %16322741.8 %
      Sports317329.8 %554952.9 %
      Vocational16637830.5 %22432041.2 %
      Smoking0.930.48
      Daily143429.2 %242450.0 %
      Sometimes5912931.4 %7611240.4 %
      Never23654630.2 %33344942.6 %
      Snuff use0.790.30
      Daily7317229.8 %10713843.7 %
      Sometimes438832.8 %636848.1 %
      Never19245029.9 %26337941.0 %
      Body mass index category0.210.22
      < 18.5 kg/m2357531.8 %555550.0 %
      18.5-<25 kg/m220150928.3 %28942140.7 %
      25-<30 kg/m2549336.7 %687946.3 %
      ≥30 kg/m2224532.8 %274040.3 %
      Physical activity
      Physical activity in leisure time: None = reading, watching TV, or other sedentary activity; Low level = walking, cycling, or other forms of exercise at least 4 hours a week; Medium level = participation in recreational sports, heavy outdoor activities with minimum duration of 4 hours a week; High level = Participation in heavy training or sports competitions regularly several times a week.
      0.150.07
      None8014934.9 %10712246.7 %
      Light9923929.3 %12920938.2 %
      Medium6719225.9 %10515440.5 %
      Hard6313132.5 %9310147.9 %
      Alcohol intake0.320.780
      Never8819231.4 %11516541.1 %
      <= 1 Month13428631.9 %18323743.6 %
      ≥2 Month8623227.0 %13418442.1 %
      Hormonal contraceptives
      Hormonal contraceptives: Non-user = No current use of hormonal contraceptives (women only); Progestin-only = Use of hormonal contraceptives with progestin (Cerazette, Nexplanon, Depo-provera, Implanon); Combination contraceptives, low estradiol = Use of hormonal contraceptives with progestin and ethinyl estradiol less than or equal to 20µg (Mercilon, Yasminelle, Loette 28, Nuvaring). Combination contraceptives, high estradiol = Use of hormonal contraceptives with progestin and ethinyl estradiol greater than or equal to 30µg (Marvelon, Yasmin, Microgynon, Oralcon, Diane, Synfase, Evra, Zyrona). Women taking contraceptives, but who were unable to recognize the brand were removed from the analysis.
      0.760.68
      Non-user7824923.9 %12120637.2 %
      Progestin-only31715.0 %51525.0 %
      Combination contraceptives,
      low estradiol123824.0%193138.0 %
      Combination contraceptives, high estradiol267327.1 %396039.4 %
      a Physical activity in leisure time: None = reading, watching TV, or other sedentary activity; Low level = walking, cycling, or other forms of exercise at least 4 hours a week; Medium level = participation in recreational sports, heavy outdoor activities with minimum duration of 4 hours a week; High level = Participation in heavy training or sports competitions regularly several times a week.
      b Hormonal contraceptives: Non-user = No current use of hormonal contraceptives (women only); Progestin-only = Use of hormonal contraceptives with progestin (Cerazette, Nexplanon, Depo-provera, Implanon); Combination contraceptives, low estradiol = Use of hormonal contraceptives with progestin and ethinyl estradiol less than or equal to 20µg (Mercilon, Yasminelle, Loette 28, Nuvaring). Combination contraceptives, high estradiol = Use of hormonal contraceptives with progestin and ethinyl estradiol greater than or equal to 30µg (Marvelon, Yasmin, Microgynon, Oralcon, Diane, Synfase, Evra, Zyrona). Women taking contraceptives, but who were unable to recognize the brand were removed from the analysis.
      c Positive = two consecutive nasal swab cultures positive for S. aureus Negative = one or none of two consecutive nasal swab cultures positive for S. aureus.
      We first evaluated the FF1 social network structure based on all relationships between students in the five subnetworks (Supplementary Figure 2) and information about relationships and persistent carriage status of nodes in the “overall” network diagram (Figure 1). As the population was recruited from two neighboring municipalities, there were two distinct clusters of students. The number of edges within the high school cluster was higher than outside the cluster demonstrating high school as a strong driver of friendship (homophily of 87.8) (Figure 2). Likewise, participants tended to bond with similar students with respect to sex and lifestyle factors (Supplementary Table 1 and Supplementary Figure 3).
      Figure 1
      Figure 1Overall network. The Fit Futures 1 study (N = 1038). Staphylococcus aureus persistent nasal carriage status determined by enrichment culture is highlighted for each student (Positive = S. aureus detected in two nasal swab samples; Negative = S. aureus detected in one or none of two nasal swab samples). Node size is proportional to the number of connections (undirected friendship).
      Figure 2
      Figure 2The overall social network within and between high schools, with a multidimensional scaling layout. The Fit Futures 1 study. Edges (lines) connecting nodes (students) with the same Staphylococcus aureus spa-type in throat culture are drawn in red. Edges connecting nodes with different spa-type are drawn in gray. High school ID (H1-H8) represents the eight high schools included in Fit Futures 1. H5 represents students at the high school in Balsfjord municipality (isolated cluster, upper left). All other high schools (H1-H4, H6-H8) are in Tromsø municipality. Only students with S. aureus isolated by direct or enrichment culture from the first throat swab sample are shown (N = 746). Unconnected students are not included (N = 21).
      To evaluate the effect of the social network on transmission, we assessed relationships that shared the same S. aureus spa-type in the “overall” network. We registered 212 unique spa types among S. aureus throat isolates from 746 students. The 15 most prevalent spa types are listed in Table 2. The network analysis demonstrates that each high school has a unique distribution of spa types. Overall 126 edges of S. aureus carriers shared the same spa type. A total of 105 edges (83.3%) connected within the same high school, while 21 edges (16.7%) connected across different high schools (Figure 3). This suggests that spa-type is associated with friendship. The inclusion of non-typeable S. aureus strains did not affect the results and was therefore excluded from the analysis.
      Table 2The most prevalent spa-types for Staphylococcus aureus throat carriage. The Fit Futures 1 study (N = 746). Only persistent carriers are shown. The plots are the results for enrichment culture.
      Figure 3
      Figure 3The overall social network with students grouped by high school. The Fit Futures 1 study. Edges (lines) connecting nodes (students) with the same Staphylococcus aureus spa-type in throat culture are drawn in red. Edges connecting nodes with different spa types are hidden. High school ID (H1-H8) represents the eight high schools included in the Tromsø Study Fit Futures 1. H5 represents students at the high school in Balsfjord municipality. All other high schools (H1-H4, H6-H8) are in Tromsø municipality. Only students with S. aureus isolated by direct or enrichment culture from the first throat swab sample are shown (N = 746). Unconnected students are not included (N = 21).
      To test if there was a statistically significant influence of social networks on the transmission of S. aureus, we performed simulations of the current population for the six networks (Table 3). In the “overall” network, the transmission of S. aureus could be demonstrated for the persistent carriage determined by enrichment culture (P = 0.02). Transmission could also be demonstrated in the “school” network (direct culture: P = 0.02; enrichment culture: P = 0.01) and in the “physical contact” network (direct culture: P = 0.06; enrichment culture: P = 0.04). The same simulation-based analysis for spa-types showed transmission of S. aureus genotypes in all six social networks (P < 0.001).
      Table 3Summary of 1000 simulations for each type of social network with respect to Staphylococcus aureus persistent nasal carriage and S. aureus spa-type. The Fit Futures 1 study. A detailed summary of this analysis is presented in Supplementary Table 4.
      NetworkS. aureus persistent nasal carriageS. aureusthroat colonization
      Direct culture (N = 1038)Enrichment culture (N = 1038)Spa-type (n= 746)
      Overall0.070.02< 0.001
      Physical0.060.04< 0.001
      School0.020.01< 0.001
      Sports0.120.29< 0.001
      Home0.340.39< 0.001
      Other0.080.06< 0.001
      Numbers represent P-values from t-tests. Statistically significant values highlighted in bold.

      The role of host risk factors in S. aureus transmission

      In the logistic regression analysis, female participants had the highest risk of being exposed to S. aureus through their social interaction (Table 4). Men had a relatively low risk of transmission compared to women (0.85, 95% CI = 0.805-0.884). Also, students using alcohol twiceor more per month had a higher risk of transmission of S. aureus compared to students using alcohol once per month or less (P = 0.035; direct culture). There was a higher probability of transmission among participants doing medium-level physical activity (P = 0.008) compared with the light physical activity group.
      Table 4Associations between host risk factors and transmission of Staphylococcus aureus persistent nasal carriage in the overall social network. Results from two different regression analyses producing “P-value” for the social effect of each characteristic and Relative risk for the comparison of risk of transmission between groups. Persistent nasal carriage determined by both direct culture and enrichment culture. The Fit Futures 1 study (N = 1038).
      Direct cultureEnrichment culture
      Risk factor (categories)P-valueRelative risk95% CIP-valueRelative risk95% CI
      SexFemale0.000210.0271
      Male0.9990.8450.805 - 0.8840.8430.9370.900 - 0.974
      Study programVocational0.54810.3531
      General0.5101.0020.950 - 1.0540.4100.9960.954 - 1.038
      Sport0.4031.0090.960 - 1.0590.8110.9740.935 - 1.013
      BMI
      BMI by kg/m2. Underweight = <18.5; Healthy = 18.5-24.9; Overweight = 25.0-29.9; ≥ 30.0
      Underweight0.7930.9530.905 - 1.0010.8410.9680.928 - 1.008
      Healthy0.15010.3011
      Overweight10.9010.860 - 0.9430.7630.9740.935 - 1.012
      Obese0.9140.9410.896 - 0.9870.2461.0030.959 - 1.047
      SmokeDaily0.29410.8551
      Never0.5030.9860.937 - 1.0340.4861.0220.978 - 1.066
      Sometimes0.7230.9710.922 - 1.0200.2621.0360.991 - 1.081
      SnuffDaily0.40610.5961
      Never0.4140.9990.949 - 1.0490.3101.0170.973 - 1.060
      Sometimes0.9000.9620.915 - 1.0100.8310.9860.947 - 1.025
      Alcohol≥ 2 per month0.03510.4341
      ≤1 month0.8060.9330.885 - 0.9800.6020.9910.948 - 1.034
      Never0.7390.9380.890 - 0.9860.3231.0060.964 - 1.049
      Physical activity
      Physical activity: None = reading, watching TV, or other sedentary activity; Low level = walking, cycling, or other forms of exercise at least 4 hours a week; Medium level = participation in recreational sports, heavy outdoor activities with minimum duration of 4 hours a week; High level = Participation in heavy training or sports competitions regularly several times a week.
      Light0.30110.0891
      None0.9940.9300.886 - 0.9750.8030.9520.914 - 0.990
      Medium0.0081.0530.999 - 1.1070.2670.9820.941 - 1.023
      Hard0.8830.9590.913 - 1.0050.8170.9510.913 - 0.989
      Hormonal contra-ceptives
      Hormonal contraceptives: Non-user = No current use of hormonal contraceptives (women only); Progestin-only = Use of hormonal contraceptives with progestin (Cerazette, Nexplanon, Depo-provera, Implanon); Combination contraceptives low estradiol = Use of hormonal contraceptives with progestin and ethinyl estradiol less than or equal to 20µg (Mercilon, Yasminelle, Loette 28, Nuvaring). Combination contraceptives high estradiol = Use of hormonal contraceptives with progestin and ethinyl estradiol greater than or equal to 30µg (Marvelon, Yasmin, Microgynon, Oralcon, Diane, Synfase, Evra, Zyrona). Women taking contraceptives, but who were unable to recognize the brand were removed from the analysis BMI, body mass index.
      Non-user0.44410.4941
      Progestin0.3691.126-0.230 - 2.4820.3921.239-0.576 - 3.054
      Low Estrogen0.4301.024-0.414 - 2.2640.4751.046-0.840 - 2.932
      High Estrogen0.4760.940-0.546 - 2.4250.4831.027-0.862 - 2.916
      P-values from comparison between random network against a random network with only that particular category. Participants with missing values are excluded from the analysis. Statistically significant values highlighted in bold.
      Relative risk and 95% confidence interval (95% CI) from univariable logistic regression analysis.
      a BMI by kg/m2. Underweight = <18.5; Healthy = 18.5-24.9; Overweight = 25.0-29.9; ≥ 30.0
      b Physical activity: None = reading, watching TV, or other sedentary activity; Low level = walking, cycling, or other forms of exercise at least 4 hours a week; Medium level = participation in recreational sports, heavy outdoor activities with minimum duration of 4 hours a week; High level = Participation in heavy training or sports competitions regularly several times a week.
      c Hormonal contraceptives: Non-user = No current use of hormonal contraceptives (women only); Progestin-only = Use of hormonal contraceptives with progestin (Cerazette, Nexplanon, Depo-provera, Implanon); Combination contraceptives low estradiol = Use of hormonal contraceptives with progestin and ethinyl estradiol less than or equal to 20µg (Mercilon, Yasminelle, Loette 28, Nuvaring). Combination contraceptives high estradiol = Use of hormonal contraceptives with progestin and ethinyl estradiol greater than or equal to 30µg (Marvelon, Yasmin, Microgynon, Oralcon, Diane, Synfase, Evra, Zyrona). Women taking contraceptives, but who were unable to recognize the brand were removed from the analysisBMI, body mass index.
      The mean number of friends for female students was 3.46, which was significantly higher than the average of 3.46 friends among male students (P = 0.008) (Supplementary Table 3). Students consuming alcohol more than twice a month had a higher number of friends compared to those consuming less or no alcohol (P < 0.001).
      We demonstrate that students with a higher number of friends being persistent carriers were more likely to be persistent carriers themselves. This was significant for persistent carriage defined by both direct culture (P = 0.002) and enrichment culture (P < 0.001) (Figure 3). The probability of being a carrier increased by 3.7% (95% CI = 3.52-3.94; univariable logistic regression, result not presented) on increasing the friend circle by one S. aureus positive friend (defined by direct culture), as illustrated in Figure 4 and Supplementary Table 4. Similarly, the probability increased by 3.4% (95% CI = 3.33-3.45) for persistent carriage defined by enrichment culture (result not presented).
      Figure 4
      Figure 4Probability of Staphylococcus aureus persistent nasal carriage with respect to friends’ carrier status. Univariable logistic regression analysis. Fit Futures 1 (n=1038). Red color represents persistent nasal carriage defined by direct culture. Black color represents persistent nasal carriage defined by enrichment culture.
      The scatterplots show the distribution of persistent nasal carriers (along Y = 1) and non-carriers (along Y = 0) for sub-populations of students having from 0 to 6 S. aureus positive friends.
      Boxplots show the mean (middle line) and interquartile range (box limits) of S. aureus positive friends for persistent nasal carriers (at the top of the diagram) and non-carriers (at the bottom of the diagram). Outliers with more than 6 S. aureus positive friends are excluded from the figure, but did not affect the result (N = 3). For more information see Supplementary Tables 6 and 7.
      An adapted linear autocorrelation analysis gave results comparable to the logistic regression analysis (Table 5). The probability of persistent carriage increased by 4.8% (P < 0.001) for each additional S. aureus positive friend defined by direct culture after adjusting for host risk factors. A similar increase of 6.0% (P < 0.001) was observed for the enrichment culture. The autocorrelation model also assessed the risk factors that made the participants´ friends significantly more contagious. For direct culture there was an association between sex, BMI and physical activity (P = 0.001-0.008), and for enrichment culture there was an association between study program, BMI, and physical activity (P < 0.001 for all). Because of the assumptions of the autocorrelation model, beta estimates for individual host factors could not be interpreted and sex-specific host factors (hormonal contraceptives) could not be included in the model. Females tended to have more relationships than males, which was also true for participants with normal BMI and participants with both medium and hard-level physical activity (Supplementary Table 3).
      Table 5Correlation between host risk factors and Staphylococcus aureus carrier status. Fit Futures 1 (N = 1038). Adapted multivariable linear autocorrelation model.
      Estimate
      Only estimates for the total model are valid. Beta estimates for individual host factors cannot be interpreted.
      SEP-value
      Direct culture
      ρ0.0480.011<0.001
      Sex-0.0480.0280.0016
      Study program0.0430.0220.0542
      BMI
      BMI = body mass index.
      0.1070.018<0.001
      Smoke-0.0120.0270.650
      Snuff-0.0010.0200.968
      Alcohol0.0380.0210.066
      Physical activity0.0330.0120.008
      Enrichment culture
      ρ0.0600.010<0.001
      Sex-0.0170.0300.578
      Study program0.0870.024<0.001
      Body mass index0.0850.019<0.001
      Smoke-0.0190.0290.517
      Snuff0.0010.0220.950
      Alcohol0.0700.0220.002
      Physical activity0.0460.014<0.001
      Significant values highlighted in bold.
      a Only estimates for the total model are valid. Beta estimates for individual host factors cannot be interpreted.
      b BMI = body mass index.

      Discussion

      In the present study, we demonstrated that social network is associated with S. aureus persistent-carrier status and spa type in a young population. This is, to our knowledge, the first study to analyze the transmission of S. aureus using social network analysis in a young population. We demonstrated that the probability of being a persistent carrier correlates with the number of close friends colonized with S. aureus. The autocorrelation analysis showed a 5-6% increased probability of S. aureus carriage with each additional S. aureus carrier friend. We also showed that friends tend to have the same spa types, indicating that the social network effect is partly driven by direct transmission of S. aureus. Our results coincide with former research that demonstrated comparable results in different cohorts (
      • Gwizdala RA
      • Miller M
      • Bhat M
      • Vavagiakis P
      • Henry C
      • Neaigus A
      • Shi Q
      • Lowy FD.
      Staphylococcus aureus colonization and infection among drug users: identification of hidden networks.
      ;
      • Moldovan ID
      • Suh K
      • Liu EY
      • Jolly A.
      Network analysis of cases with methicillin-resistant Staphylococcus aureus and controls in a large tertiary care facility.
      ).
      We analyzed different types of networks and found an association between transmission of S. aureus in the social network where participants confirmed they had physical contact (direct culture: P = 0.07; enrichment culture: P = 0.04). This might indicate that social contact is a key pathway for the spread of S. aureus in the community (
      • Hogea C
      • Van Effelterre T
      • Acosta CJ.
      A basic dynamic transmission model of Staphylococcus aureus in the US population.
      ), which is in line with former studies on transmission of S. aureus through a social network (
      • Moldovan ID
      • Suh K
      • Liu EY
      • Jolly A.
      Network analysis of cases with methicillin-resistant Staphylococcus aureus and controls in a large tertiary care facility.
      ). Being together at school was also significantly associated with S. aureus transmission. We did not find any significant spread of S. aureus among students who were at home or participated in sports together.
      There is also a substantial social dimension for several of the known host risk factors for S. aureus carriage, which suggests that social network effects may have contributed to associations observed in former studies. In a univariable logistic regression model, the risk of being a persistent carrier increased by 3.4-3.7% on increasing the friend circle by one S. aureus positive friend. A similar analysis (autocorrelation model) adjusted for host risk factors, showed an increase of 4.8-6.0%. The difference between the logistic regression model and the autocorrelation model may partly represent the effect of the individual risk factors.
      In our study, males had a higher prevalence of S. aureus persistent carriage compared to females which corresponds with previous studies (
      • Knox J
      • Uhlemann AC
      • Lowy FD.
      Staphylococcus aureus infections: transmission within households and the community.
      ;
      • Mascaro V
      • Capano MS
      • Iona T
      • Nobile CGA
      • Ammendolia A
      • Pavia M.
      Prevalence of Staphylococcus aureus carriage and pattern of antibiotic resistance, including methicillin resistance, among contact sport athletes in Italy.
      ). The social network analysis demonstrates that the female sex is the predominant social risk factor for carriage because of more relationships among females. This may substantiate the hypothesis of sex as a true biological risk factor for S. aureus carriage, as the male population has a higher prevalence of carriage while the relative risk of transmission is lower compared to the female population.
      We also demonstrated increased transmission of S. aureus among students engaged in medium level physical activity in leisure time compared to those with sedentary leisure time. A former study showed an increased risk of S. aureus carriage in athletes doing contact sports (
      • Mascaro V
      • Capano MS
      • Iona T
      • Nobile CGA
      • Ammendolia A
      • Pavia M.
      Prevalence of Staphylococcus aureus carriage and pattern of antibiotic resistance, including methicillin resistance, among contact sport athletes in Italy.
      ). Many of the physical activities in youth are contact sports or close-counter training. In our population a higher percentage of women engaged in medium physical activity compared to men (women = 27% and men = 23%). The increased risk of transmission related to medium physical activity could therefore be partly attributed to the observed sex differences.
      The use of alcohol more than twice a month was a social factor associated with the carriage of S. aureus by direct culture. This may reflect increased social contact with multiple friends at parties and social gatherings. Participants consuming alcohol more than twice a month had a higher number of friends than participants consuming less or no alcohol. We do not have information about the amount of alcohol consumed, and the alcohol variable is therefore lacking some precision. We also have some outliers that may have affected the results. We found no association between alcohol use and carriage defined by enrichment culture, this may be a result of a large number of statistical tests and the more homogenous variable with a high prevalence of S. aureus carriage for enrichment culture.
      The autoregression model indicates an association between BMI and transmission of S. aureus in addition to sex, alcohol use, physical activity, and study program. The effect of friendship density might be partially related to body size, as students with normal BMI had more friends.
      Excluding older outliers above 20 years (n = 36) from the network analysis did not affect the results, therefore all participants were included in the analysis. None of the interview questions on social networks provide information about the type or amount of physical contact. We also lack information on the total social network of the participants, including family and other social interactions outside school. Our model also lacks animal contacts and pets, that are known to influence transmission (
      • Loeffler A
      • Lloyd DH.
      Companion animals: a reservoir for methicillin-resistant Staphylococcus aureus in the community?.
      ).
      This will give a bias of unknown magnitude and direction. The social networks were constructed by self-reported information on social contacts one week before the study, and this could be misrepresenting of the participants’ social contact over long periods of time. We therefore asked all participants to score the representativeness of the nominated friends, and 76 % of the participants claimed a score of five or above (on a scale from one to ten). We therefore believe the representativeness of the nominations to be high (Supplementary Figure 4).
      We had complete spa-type data only from throat isolates, while nasal carriage is generally considered as the most clinically relevant phenotype. In a validation study of 100 participants with S. aureus isolated from cultures of two nasal and two throat swabs in FF1, 82 participants had the same spa type (data not shown). Therefore, we believe that our findings from social network analysis based on spa type of throat isolates also represent the transmission of nasal S. aureus. Another limitation is that we had 10 invalid nasal samples from the first swab and 51 invalid samples from the second swab. These were re-classified as negative for S. aureus. Because of the analysis of social networks, we believe that it would have introduced a larger bias in excluding parts of the social network compared with the bias of including potentially misclassified samples. The study was conducted between 2010-2011, and there may be some unknown bias in comparing results to present day. Although we believe that the prevalence of S. aureus is quite stable in the general population.
      One limitation of defining the outcome of persistent nasal carriage is the number of swabs taken and use of Staphaurex plus agglutination test for S. aureus confirmation. Although the Staphaurex plus agglutination test could give false positive reactions for other staphylococci (
      • Van Griethuysen A
      • Bes M
      • Etienne J
      • Zbinden R
      • Kluytmans J
      International multicenter evaluation of latex agglutination tests for identification of Staphylococcus aureus.
      ), we believe the combination of S. aureus selective CHROMagars and agglutination test increase sensitivity and specificity. Nouwen et al. proposed a “culture rule” that concludes that two nasal swabs taken at a week interval can accurately classify S. aureus nasal carriage (
      • Nouwen JL
      • Ott A
      • Kluytmans-Vandenbergh MF
      • Boelens HA
      • Hofman A
      • van Belkum A
      • Verbrugh HA.
      Predicting the Staphylococcus aureus nasal carrier state: derivation and validation of a "culture rule".
      ), but van Belkum et al. demonstrated a median survival of S. aureus of more than 154 days among persistent carriers, compared to 14 days among intermittent carriers and 4 days among non-carriers (
      • van Belkum A
      • Verkaik NJ
      • De Vogel CP
      • Boelens HA
      • Verveer J
      • Nouwen JL
      • Verbrugh HA
      • Wertheim HF.
      Reclassification of Staphylococcus aureus nasal carriage types.
      ). Thus, it is likely that some participants were misclassified. Both limitations are classified as non-differential bias and therefore are more likely to give underestimations of results.
      We reported results using both direct culture and enrichment. When enrichment broth is used, low bacterial loads are also detected, thereby giving an increased prevalence of S. aureus positive tests (
      • Antri K
      • Akkou M
      • Bouchiat C
      • Bes M
      • Martins-Simoes P
      • Dauwalder O
      • Tristan A
      • Meugnier H
      • Rasigade Jp
      • Etienne J
      • Vandenesch F
      • Laurent F
      • Ramdani-Bouguessa N
      High levels of Staphylococcus aureus and MRSA carriage in healthy population of Algiers revealed by additional enrichment and multisite screening.
      ). In studies of decolonization, enrichment is recommended to prevent possible eradication failure (
      • Diekema D
      • Johannsson B
      • Herwaldt L
      • Beekmann S
      • Jernigan J
      • Kallen A
      • BERRIOS-Torres S
      • Polgreen P.
      Current practice in Staphylococcus aureus screening and decolonization.
      ). The relevance of low bacterial load carriage in S. aureus epidemiology is not known, and most studies have used only direct culture. In this study, the results were similar for both definitions and might demonstrate the robustness of the findings.
      Our analysis was modeled by using one time point, while interviews with the different participants were conducted at multiple time points. Most participants nominated friends who had the same attendance date as themselves, e.g., from their own school class (Supplementary Table 5). Furthermore, persistent nasal carriage is a relatively stable phenotype (
      • van Belkum A
      • Verkaik NJ
      • De Vogel CP
      • Boelens HA
      • Verveer J
      • Nouwen JL
      • Verbrugh HA
      • Wertheim HF.
      Reclassification of Staphylococcus aureus nasal carriage types.
      ), and we therefore assume that time will not affect the present analysis.
      In summary, our data from a general youth population supports social effects on S. aureus carriage and these result from both direct social transmission and shared lifestyle risk factors for carriage among friends. We demonstrated relationships between different social networks (i.e., overall, physical contact, school) and S. aureus persistent carriage and specific spa-types. We also showed that risk of transmission differs by host lifestyle factors. The male predominance in carriage is determined by sex-specific predisposing host characteristics, as social interactions among men are weak drivers of transmission compared with women. More studies are needed to further evaluate the interplay between the social environment and host risk factors in S. aureus carriage and should include household transmission and contact with animals.

      Funding

      This work was supported by The Northern Norway regional Health Authorities [grant number HNF1457-19]. The funding source had no role in study design, collection, analysis, interpretation of data, writing the report or the decision to submit the article for publication.

      Ethical approval statement

      Each participant signed a declaration of consent. Participants younger than 16 years had to bring written consent from a parent or guardian. FF1 was approved by The Regional Committee of Medical and Health Research Ethics North Norway (REK North, reference 2009/1282) and the Norwegian Data Protection Authority. The present study was approved by REK North (reference 2011/1710) and was conducted in accordance with the Declaration of Helsinki and national and institutional standards.

      Author contributions

      Anne-Sofie Furberg, Christopher Sievert Nielsen, Gunnar Skov Simonsen and Lars Ailo Bongo contributed with the conceptualization and design of the work. Anne-Sofie Furberg and Lars Ailo Bongo supervised the work. Johanna UE Sollid performed microbiological analysis of nasal and throat samples. Rafael A. Nozal Cañadas contributed with statistical analysis and statistical methods. Karina Olsen, Lars Småbrekke, Kristian Svendsen, Dina Stensen and Anne Merethe Hanssen contributed in interpretation of data. Dina B. Stensen and Rafael A. Nozal Canadas wrote the original draft. All authors reviewed and approved the final manuscript. Rafael A. Nozal Canadas and Lars Ailo Bongo verify the underlying data.

      Data availability

      The data that support the findings of this study are available from The Fit Futures study but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon request and with permission of The Fit Futures study. Proposals for data should be directed to [email protected] Statistical analysis and consent form will be available on request. Proposals should be directed to [email protected]

      Declaration of Competing Interest

      The authors have no competing interests to declare

      Acknowledgments

      We are grateful for the contribution by the participants of The Fit Futures 1 study. We also thank the Clinical Research Department at the University Hospital of North Norway, Tromsø, for data collection. Additionally, we thank Maria Sangvik and Trine Tessem for spa-typing. We also want to thank the Department of Medical Microbiology and the Department of Community Medicine at the Faculty of Health Sciences.

      Appendix. Supplementary materials

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