Annex E Sensitivity analyses on the use of different ... · behalf of European Food Safety...

Annex E - Appropriate age of introduction of complementary feeding – sensitivity analyses

www.efsa.europa.eu/efsajournal 1 EFSA Journal 20YY;volume(issue):NNNN

Annex to:

EFSA NDA Panel (EFSA Panel on Nutrition, Novel Foods and Food Allergens), Castenmiller J, de

Henauw S, Hirsch-Ernst K-I, Kearney J, Maciuk A, Mangelsdorf I, McArdle HJ, Naska A, Pelaez C, Pentieva K, Siani A, Thies F, Tsabouri S, Vinceti M, Bresson J-L, Fewtrell M, Kersting M, Przyrembel H,

Dumas C, Titz A and Turck D, 20YY. Scientific opinion on the appropriate age for the introduction of complementary feeding into an infant’s diet. EFSA Journal 20XX; volume(issue): NNNN, XXX47 pp.

doi: 10.2903/j.efsa.20YY.NNNN

© 20XX European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on

behalf of European Food Safety Authority.

Annex E – Sensitivity analyses on the use of different between-study variance estimators in the random effects meta-analyses

Sensitivity analyses were conducted for all relevant endpoints to evaluate the relative performance of different estimators of between-study variability, i.e. the DerSimonian and Laird and the Paul and

Mandel approaches (DerSimonian and Laird, 1986; Paule and Mandel, 1989), both with and without the Hartung and Knapp modification (Knapp and Hartung, 2003). This was done, because

performance has been shown to vary according to many factors, including true levels of

heterogeneity, the number of studies in the pool, the size of the studies (their sampling error) and whether sizes are unequal (Veroniki et al., 2016). In addition, it has been suggested that the Hartung

and Knapp modification does not perform well in situations when τ2 is zero.

For each endpoint, estimates of pooled effect measures (empty circles) and their 95% confidence

intervals (grey lines) were plotted by subgroup (combinations of study design and tier of reliability

reported in columns). When the Hartung and Knapp modification was not applied a Wald-type confidence interval was estimated. When it was applied, the t-distribution with k-1 degrees of freedom

was used for confidence intervals.

I2 was estimated based on the Cochran’s Q-statistic as per the DerSimonian-Laird approach across all

sensitivity analyses. 95% CIs of I2 could only be derived when >2 studies were meta analysed.

I2 is presented below each plot for each subgroup once. The tables below each plot report the

corresponding figures for the pooled estimate, its confidence interval and τ2.

For information on how the results of the sensitivity analyses were used, refer to section 2.2.3.2 of

the opinion.

http://www.efsa.europa.eu/efsajournal



WAZ comparing early introduction with later introduction of CFs

I2 [95% CI] 0% 74% [28%; 91%] 54% [0%; 83%]

CI: confidence interval; DL: DerSimonian-Laird; PC: prospective cohort; PE: pooled estimate; PM: Paule-Mandel; RCT:

randomised controlled trial; TRUE or FALSE refer to whether the Hartung‐Knapp modification was applied or not, respectively.

Method

1_RCT Tier 1+2 2_PC Tier 1+2 3_PC Tier 3

PM_TRUE PE -0.01 -0.03 0.08

95%CI -0.28 to 0.27 -0.24 to 0.18 -0.18 to 0.34

tau2 0 0.01 0.02

PM_FALSE PE -0.01 -0.03 0.08

95%CI -0.10 to 0.09 -0.16 to 0.10 -0.10 to 0.26

tau2 0 0.01 0.02

DL_TRUE PE -0.01 -0.03 0.08

95%CI -0.28 to 0.27 -0.24 to 0.18 -0.18 to 0.34

tau2 0 0.02 0.02

DL_FALSE PE -0.01 -0.03 0.08

95%CI -0.10 to 0.09 -0.18 to 0.11 -0.09 to 0.26

tau2 0 0.02 0.02




WAZ by feeding mode (exclusive BF or FF) for studies in Tier 1 and

2 comparing early introduction with later introduction of CFs

I2 [95% CI] 17% [0%; 87%] n/a (k=1)

Method

BF FF

PM_TRUE PE -0.07 0.02

95%CI -0.20 to 0.06 -0.17 to 0.21

tau2 0 n/a

PM_FALSE PE -0.07 0.02

95%CI -0.15 to 0.01 -0.17 to 0.21

tau2 0 n/a

DL_TRUE PE -0.07 0.02

95%CI -0.20 to 0.06 -0.17 to 0.21

tau2 0 n/a

DL_FALSE PE -0.07 0.02

95%CI -0.16 to 0.01 -0.17 to 0.21

tau2 0 n/a

BF: breast-fed; CI: confidence interval; DL: DerSimonian-Laird; FF: formula-fed; n/a: not applicable; PE: pooled estimate; PM:

Paule-Mandel; TRUE or FALSE refer to whether the Hartung‐Knapp modification was applied or not, respectively.




Attained weight comparing early introduction with later

introduction of CFs

I2 [95% CI] 0% [0%; 38%] 0% [0%; 2%] 0% [0%; 74%]

Method


PM_TRUE PE -40 123 384

95%CI -199 to 118 -8 to 254 79 to 689

tau2 0 0 0

PM_FALSE PE -40 123 384

95%CI -217 to 136 -80 to 327 141 to 628

tau2 0 0 0

DL_TRUE PE -40 123 384

95%CI -199 to 118 -8 to 254 79 to 689

tau2 0 0 0

DL_FALSE PE -40 123 384

95%CI -217 to 136 -80 to 327 141 to 628

tau2 0 0 0






Attained weight by feeding mode (exclusive BF or FF) for studies in Tier 1 and 2 comparing early introduction with later introduction of CFs

I2 [95% CI] 0% 0% [0%; 69%]

Method

BF FF

PM_TRUE PE -23 54

95%CI -633 to 587 -193 to 301

tau2 0 0

PM_FALSE PE -23 54

95%CI -225 to 179 -162 to 271

tau2 0 0

DL_TRUE PE -23 54

95%CI -633 to 587 -193 to 301

tau2 0 0

DL_FALSE PE -23 54

95%CI -225 to 179 -162 to 271

tau2 0 0

BF: breast-fed; CI: confidence interval; DL: DerSimonian-Laird; FF: formula-fed; PE: pooled estimate; PM: Paule-Mandel; TRUE

or FALSE refer to whether the Hartung‐Knapp modification was applied or not, respectively.




WL(H)Z comparing early introduction with later introduction of

CFs

I2 [95% CI] n/a 51% [0%; 86%]

Method

1_RCT Tier 1+2 2_PC Tier 1+2

PM_TRUE PE -0.01 -0.02

95%CI -0.10 to 0.08 -0.33 to 0.28

tau2 n/a 0.01

PM_FALSE PE -0.01 -0.02

95%CI -0.10 to 0.08 -0.16 to 0.11

tau2 n/a 0.01

DL_TRUE PE -0.01 -0.02

95%CI -0.10 to 0.08 -0.33 to 0.28

tau2 n/a 0.01

DL_FALSE PE -0.01 -0.02

95%CI -0.10 to 0.08 -0.15 to 0.10

tau2 n/a 0.01

CI: confidence interval; DL: DerSimonian-Laird; n/a: not applicable; PC: prospective cohort; PE: pooled estimate; PM: Paule-

Mandel; RCT: randomised controlled trial; TRUE or FALSE refer to whether the Hartung‐Knapp modification was applied or not,

respectively.




L(H)AZ comparing early introduction with later introduction of CFs

I2 [95% CI] 0% 55% [0%; 80%] 0% [0%; 73%]

Method


PM_TRUE PE 0.04 0.03 0.11

95%CI -0.22 to 0.30 -0.06 to 0.12 -0.04 to 0.26

tau2 0.00 0.01 0.00

PM_FALSE PE 0.04 0.03 0.11

95%CI -0.06 to 0.14 -0.04 to 0.10 -0.01 to 0.22

tau2 0.00 0.01 0.00

DL_TRUE PE 0.04 0.03 0.11

95%CI -0.22 to 0.30 -0.05 to 0.12 -0.04 to 0.26

tau2 0.00 0.01 0.00

DL_FALSE PE 0.04 0.03 0.11

95%CI -0.06 to 0.14 -0.04 to 0.10 -0.01 to 0.22

tau2 0.00 0.01 0.00






L(H)AZ by feeding mode (exclusive BF or FF) for studies in Tier 1

and 2 comparing early introduction with later introduction of CFs

I2 [95% CI] 36% [0%; 79%] n/a (k=1)

Method

BF FF

PM_TRUE PE 0.10 -0.13

95%CI -0.20 to 0.40 -0.34 to 0.08

tau2 0.01 n/a

PM_FALSE PE 0.10 -0.13

95%CI -0.04 to 0.23 -0.34 to 0.08

tau2 0.01 n/a

DL_TRUE PE 0.10 -0.13

95%CI -0.20 to 0.41 -0.34 to 0.08

tau2 0.01 n/a

DL_FALSE PE 0.10 -0.13

95%CI -0.04 to 0.25 -0.34 to 0.08

tau2 0.01 n/a

BF: breast-fed; CI: confidence interval; DL: DerSimonian-Laird; FF: formula-fed; n/a: not applicable; PE: pooled estimate; PM:

Paule-Mandel; TRUE or FALSE refer to whether the Hartung‐Knapp modification was applied or not, respectively.




Attained length (height) comparing early introduction with later

introduction of CFs

I2 [95% CI] 0% [0%; 0%] 0% [0%; 34%] 17%

Method


PM_TRUE PE 0.8 -1.8 10.0

95%CI -0.5 to 2.2 -7.1 to 3.4 -48.9 to 69.0

tau2 0 0 7.35

PM_FALSE PE 0.8 -1.8 10.0

95%CI -3.4 to 5.0 -7.9 to 4.2 0.9 to 19.1

tau2 0 0 7.3

DL_TRUE PE 0.8 -1.8 10.0

95%CI -0.5 to 2.2 -7.1 to 3.4 -48.9 to 69.0

tau2 0 0 7.3

DL_FALSE PE 0.8 -1.8 10.0

95%CI -3.4 to 5.0 -7.9 to 4.2 0.9 to 19.1

tau2 0 0 7.3






Attained length by feeding mode (exclusive BF or FF) for studies in Tier 1 and 2 comparing early introduction with later introduction of CFs

I2 [95% CI] 0% 0% [0% to 25%]

Method

BF FF

PM_TRUE PE 0.8 -0.9

95%CI -5.5 to 7.1 -4.4 to 2.7

tau2 0 0

PM_FALSE PE 0.8 -0.9

95%CI -4.1 to 5.7 -5.8 to 4.0

tau2 0 0

DL_TRUE PE 0.8 -0.9

95%CI -5.5 to 7.1 -4.4 to 2.7

tau2 0 0

DL_FALSE PE 0.8 -0.9

95%CI -4.1 to 5.7 -5.8 to 4.0

tau2 0 0






Attained head circumference comparing early introduction with

later introduction of CFs

I2 [95% CI] 0% [0%; 0%] n/a (k=1)

Method


PM_TRUE PE 0.5 5

95%CI -0.3 to 1.2 -3.0 to 13

tau2 0 n/a

PM_FALSE PE 0.5 5

95%CI -1.2 to 2.2 -3.0 to 13

tau2 0 n/a

DL_TRUE PE 0.5 5

95%CI -0.3 to 1.2 -3.0 to 13

tau2 0 n/a

DL_FALSE PE 0.5 5

95%CI -1.2 to 2.2 -3.0 to 13

tau2 0 n/a



respectively.




BMI z-score comparing early introduction with later introduction

of CFs

I2 [95% CI] 0% 32% [0%; 68%] 94% [89%; 96%]

Method


PM_TRUE PE -0.03 0.07 -0.05

95%CI -0.43 to 0.37 -0.01 to 0.16 -0.28 to 0.19

tau2 0 0.01 0.05

PM_FALSE PE -0.03 0.07 -0.05

95%CI -0.12 to 0.06 -0.006 to 0.15 -0.22 to 0.13

tau2 0 0.01 0.05

DL_TRUE PE -0.03 0.07 -0.05

95%CI -0.43 to 0.37 0.004 to 0.13 -0.28 to 0.19

tau2 0 0 0.03

DL_FALSE PE -0.03 0.07 -0.05

95%CI -0.12 to 0.06 0.02 to 0.12 -0.19 to 0.09

tau2 0 0 0.03






BMI z-score by feeding mode (exclusive BF or FF) for studies in Tier 1 and 2 comparing early introduction with later introduction of CFs

I2 [95% CI] 0% [0%; 79%] 73% [10%; 92%]

Method

BF FF

PM_TRUE PE -0.03 0.10

95%CI -0.14 to 0.09 -0.72 to 0.92

tau2 0 0.09

PM_FALSE PE -0.03 0.10

95%CI -0.11 to 0.05 -0.27 to 0.47

tau2 0 0.09

DL_TRUE PE -0.03 0.11

95%CI -0.14 to 0.09 -0.69 to 0.91

tau2 0 0.05

DL_FALSE PE -0.03 0.11

95%CI -0.11 to 0.05 -0.19 to 0.41

tau2 0 0.05






Attained BMI comparing early introduction with later introduction

of CFs

I2 [95% CI] 0% 0% 63% [0%; 88%]

Method


PM_TRUE PE -0.03 0.23 0.23

95%CI -0.56 to 0.50 -0.46 to 0.93 -0.38 to 0.84

tau2 0 0 0.07

PM_FALSE PE -0.03 0.23 0.23

95%CI -0.16 to 0.10 -0.02 to 0.48 -0.14 to 0.60

tau2 0 0 0.07

DL_TRUE PE -0.03 0.23 0.25

95%CI -0.56 to 0.50 -0.46 to 0.93 -0.36 to 0.86

tau2 0 0 0.11

DL_FALSE PE -0.03 0.23 0.25

95%CI -0.16 to 0.10 -0.02 to 0.48 -0.18 to 0.67

tau2 0 0 0.11






Chance of being obese comparing early introduction with later

introduction of CFs

I2 [95% CI] 50% [0%; 76%] 0% [0%; 84%]

Method

2_PC Tier 1+2 3_PC Tier 3

PM_TRUE PE 1.14 1.16

95%CI -0.76 to 1.70 -0.80 to 1.67

tau2 0.22 0

PM_FALSE PE 1.14 1.16

95%CI -0.80 to 1.61 -0.93 to 1.43

tau2 0.22 0

DL_TRUE PE 1.12 1.16

95%CI -0.87 to 1.42 -0.80 to 1.67

tau2 0.02 0

DL_FALSE PE 1.12 1.16

95%CI -0.94 to 1.31 -0.93 to 1.43

tau2 0.02 0






Chance of being obese comparing early introduction with later

introduction of CFs, retrospective studies

I2 [95% CI] 46% [0%; 82%]

Method

Retrospective

PM_TRUE PE 0.69

95%CI 0.38 to 1.25

tau2 0.05

PM_FALSE PE 0.69

95%CI 0.48 to 0.99

tau2 0.05

DL_TRUE PE 0.69

95%CI 0.38 to 1.25

tau2 0.06

DL_FALSE PE 0.69

95%CI 0.47 to 1.01

tau2 0.06

CI: confidence interval; DL: DerSimonian-Laird; PE: pooled estimate; PM: Paule-Mandel; TRUE or FALSE refer to whether the

Hartung‐Knapp modification was applied or not, respectively.




Chance of being (at least) overweight comparing early

introduction with later introduction of CFs

I2 [95% CI] n/a (k=1) 68% [40%; 83%] 59% [19%; 79%]

Method


PM_TRUE PE 4 1.13 1.22

95%CI 0.43 to 37.35 0.80 to 1.57 1.12 to 1.32

tau2 n/a 0.22 0

PM_FALSE PE 4.00 1.13 1.22

95%CI 0.43 to 37.35 0.84 to 1.51 1.14 to 1.31

tau2 n/a 0.22 0

DL_TRUE PE 4 1.06 1.28

95%CI 0.43 to 37.35 0.87 to 1.30 1.18 to 1.39

tau2 n/a 0.02 0.01

DL_FALSE PE 4 1.06 1.28

95%CI 0.43 to 37.35 0.80 to 1.58 1.13 to 1.32

tau2 n/a 0.02 0.01



respectively.




Chance of being (at least) overweight comparing early

introduction with later introduction of CFs, retrospective studies

I2 [95% CI] 51% [15%; 71%]

Method

Retrospective

PM_TRUE PE 1.04

95%CI 0.87 to 1.26

tau2 0.07

PM_FALSE PE 1.04

95%CI 0.88 to 1.24

tau2 0.07

DL_TRUE PE 1.02

95%CI 0.86 to 1.21

tau2 0.03

DL_FALSE PE 1.02

95%CI 0.89 to 1.17

tau2 0.03






Fat mass comparing early introduction with later introduction of

CFs

I2 [95% CI] n/a (k=1) n/a (k=1) 0% [0%; 25%]

Method


PM_TRUE PE -103 140 124

95%CI -332 to 126 -195 to 475 -13 to 261

tau2 n/a n/a 0

PM_FALSE PE -103 140 124

95%CI -332 to 126 -195 to 475 -52 to 299

tau2 n/a n/a 0

DL_TRUE PE -103 140 124

95%CI -332 to 126 -195 to 475 -13 to 261

tau2 n/a n/a 0

DL_FALSE PE -103 140 124

95%CI -332 to 126 -195 to 475 -52 to 299

tau2 n/a n/a 0



respectively.




Asthma-like symptoms and CFs – general population – comparing

early introduction with later introduction

I2 [95% CI] n/a (k=1) 27% 32% [0%; 74%]

Method


PM_TRUE PE 0.98 1.04 0.81

95%CI 0.46 to 2.04 0.26 to 4.05 0.52 to 1.24

tau2 n/a 0.01 0.03

PM_FALSE PE 0.98 1.04 0.81

95%CI 0.46 to 2.04 0.84 to 1.27 0.59 to 1.09

tau2 n/a 0.01 0.03

DL_TRUE PE 0.98 1.04 0.81

95%CI 0.46 to 2.04 0.26 to 4.05 0.53 to 1.24

tau2 n/a 0.01 0.04

DL_FALSE PE 0.98 1.04 0.81

95%CI 0.46 to 2.04 0.84 to 1.27 0.59 to 1.11

tau2 n/a 0.01 0.04



respectively.




Asthma-like symptoms and CFs – at risk group – comparing early

introduction with later introduction

I2 [95% CI] 0% 0%

Method



95%CI 0.05 to 6.05 0.15 to 16.19

tau2 0 0


95%CI 0.35 to 1.01 0.72 to 3.47

tau2 0 0


95%CI 0.05 to 6.05 0.15 to 16.19

tau2 0 0


95%CI 0.35 to 1.01 0.72 to 3.47

tau2 0 0

CI: confidence interval; DL: DerSimonian-Laird; PC: prospective cohort; PE: pooled estimate; PM: Paule-Mandel; TRUE or FALSE

refer to whether the Hartung‐Knapp modification was applied or not, respectively.




Asthma-like symptoms and cereals – general population –

comparing early introduction with later introduction

I2 [95% CI] 48% [0%; 85%] n/a (k=1)

Method



95%CI 0.46 to 1.65 0.87 to 1.20

tau2 0.03 n/a


95%CI 0.66 to 1.17 0.87 to 1.20

tau2 0.03 n/a


95%CI 0.46 to 1.65 0.87 to 1.20

tau2 0.03 n/a


95%CI 0.65 to 1.17 0.87 to 1.20

tau2 0.03 n/a


Mandel; TRUE or FALSE refer to whether the Hartung‐Knapp modification was applied or not, respectively.




Asthma-like symptoms and fish – general population – comparing

early introduction with later introduction

I2 [95% CI] 0% [0%; 15%] n/a (k=1)

Method



95%CI 0.94 to 1.38 1.06 to 2.18

tau2 0 n/a


95%CI 0.88 to 1.46 1.06 to 2.18

tau2 0 n/a


95%CI 0.94 to 1.38 1.06 to 2.18

tau2 0 n/a


95%CI 0.88 to 1.46 1.06 to 2.18

tau2 0 n/a






Eczema and CFs – general population – comparing early


I2 [95% CI] 46% [0%; 80%] 75% [52%; 87%]

Method



95%CI 0.67 to 1.63 0.62 to 1.29

tau2 0.07 0.17


95%CI 0.77 to 1.43 0.66 to 1.22

tau2 0.07 0.17


95%CI 0.69 to 1.60 0.68 to 1.31

tau2 0.04 0.07


95%CI 0.81 to 1.37 0.76 to 1.17

tau2 0.04 0.07






Eczema and CFs – at risk group – comparing early introduction

with later introduction

I2 [95% CI] 53% [0%; 80%] 0% [0%; 80%]

Method



95%CI 0.47 to 1.53 0.48 to 1.18

tau2 0.22 0


95%CI 0.52 to 1.36 0.56 to 1.00

tau2 0.22 0


95%CI 0.47 to 1.51 0.48 to 1.18

tau2 0.18 0


95%CI 0.54 to 1.31 0.56 to 1.00

tau2 0.18 0






Eczema and CFs – general population – comparing early

introduction with later introduction, retrospective studies

I2 [95% CI] 66% [35%; 82%]

Method

Retrospective

PM_TRUE PE 1.13

95%CI 0.81 to 1.59

tau2 0.17

PM_FALSE PE 1.13

95%CI 0.84 to 1.53

tau2 0.17

DL_TRUE PE 1.14

95%CI 0.82 to 1.58

tau2 0.11

DL_FALSE PE 1.14

95%CI 0.88 to 1.47

tau2 0.11






Eczema and egg – general population – comparing early


I2 [95% CI] n/a (k=1) 45% [0%; 83:]

Method



95%CI 0.87 to 1.39 0.50 to 1.74

tau2 n/a 0.03


95%CI 0.87 to 1.39 0.71 to 1.24

tau2 n/a 0.03


95%CI 0.87 to 1.39 0.50 to 1.74

tau2 n/a 0.03


95%CI 0.87 to 1.39 0.70 to 1.25

tau2 n/a 0.03






Eczema and egg – at risk group – comparing early introduction

with later introduction*

I2 [95% CI] 69% 37% n/a (k=1)

* The CIs for PM_TRUE and DL_FALSE for 1_RCT Tier 1+2 and 2_PC Tier 1+2, respectively, are not shown for

visibility reasons as they are too wide to present.

Method


PM_TRUE PE 0.82 0.83 1.00

95%CI 0.005 to 130.12 0.002 to 267.93 0.59 to 1.67

tau2 0.22 0.24 n/a

PM_FALSE PE 0.82 0.83 1.00

95%CI 0.37 to 1.79 0.34 to 2.03 0.59 to 1.67

tau2 0.22 0.24 n/a

DL_TRUE PE 0.82 0.83 1.00

95%CI 0.005 to 130.12 0.002 to 267.93 0.59 to 1.67

tau2 0.22 0.24 n/a

DL_FALSE PE 0.82 0.83 1.00

95%CI 0.377 to 1.79 0.34 to 2.03 0.59 to 1.67

tau2 0.22 0.24 n/a



respectively.




Eczema and cereals – general population – comparing early


I2 [95% CI] 71% 17% [0%; 91%]

Method



95%CI 0.09 to 10.00 0.63 to 1.40

tau2 0.05 0


95%CI 0.68 to 1.39 0.78 t 1.12

tau2 0.05 0


95%CI 0.09 to 10.00 0.63 to 1.40

tau2 0.05 0


95%CI 0.68 to 1.39 0.78 to 1.12

tau2 0.05 0






Eczema and fish – general population – comparing early


I2 [95% CI] 0% 0% [0%; 77%]

Method



95%CI 0.88 to 1.13 0.79 to 1.28

tau2 0 0


95%CI 0.81 to 1.22 0.85 to 1.18

tau2 0 0


95%CI 0.88 to 1.13 0.79 to 1.28

tau2 0 0


95%CI 0.81 to 1.22 0.85 to 1.18

tau2 0 0






Allergic rhinitis and CFs – general population - comparing early


I2 [95% CI] n/a (k=1) 1% [0%; 85%]

Method

1_RCT Tier 1+2 3_PC Tier 3


95%CI 0.56 to 1.79 0.63 to 1.54

tau2 n/a 0


95%CI 0.56 to 1.79 0.75 to 1.30

tau2 n/a 0


95%CI 0.56 to 1.79 0.63 to 1.54

tau2 n/a 0


95%CI 0.56 to 1.79 0.75 to 1.30

tau2 n/a 0



respectively.




Food allergy and CFs – general population – comparing early

introduction with later introduction*

I2 [95% CI] n/a (k=1) 78% 0%

* The CIs for PM_TRUE and DL_FALSE for 2_PC Tier 1+2 are not shown for visibility reasons as they are too wide

to present.

Method


PM_TRUE PE 0.80 2.01 0.61

95%CI 0.51 to 1.25 0.00 to 5906.16 0.05 to 6.48

tau2 n/a 0.63 0

PM_FALSE PE 0.80 2.01 0.61

95%CI 0.51 to 1.25 0.58 to 6.88 0.39 to 0.93

tau2 n/a 0.63 0

DL_TRUE PE 0.80 2.01 0.61

95%CI 0.51 to 1.25 0.00 to 5906.17 0.05 to 6.48

tau2 n/a 0.63 0

DL_FALSE PE 0.80 2.01 0.61

95%CI 0.51 to 1.25 0.58 to 6.88 0.39 to 0.93

tau2 n/a 0.63 0



respectively.




Sensitisation and CFs – general population – comparing early


I2 [95% CI] n/a (k=1) 79% [50%; 91%] n/a (k=1)

Method


PM_TRUE PE 0.88 0.75 0.33

95%CI 0.61 to 1.24 0.31 to 1.78 0.11 to 0.92

tau2 n/a 0.39 n/a

PM_FALSE PE 0.88 0.75 0.33

95%CI 0.61 to 1.24 0.40 to 1.38 0.11 to 0.92

tau2 n/a 0.39 n/a

DL_TRUE PE 0.88 0.75 0.33

95%CI 0.61 to 1.24 0.31 to 1.78 0.11 to 0.92

tau2 n/a 0.31 n/a

DL_FALSE PE 0.88 0.75 0.33

95%CI 0.61 to 1.24 0.43 to 1.31 0.11 to 0.92

tau2 n/a 0.31 n/a



respectively.




Sensitisation and CFs – at risk group – comparing early


I2 [95% CI] 59% [0%; 86%]

Method

2_PC Tier 1+2

PM_TRUE PE 0.56

95%CI 0.23 to 1.30

tau2 0.21

PM_FALSE PE 0.56

95%CI 0.32 to 0.94

tau2 0.21

DL_TRUE PE 0.59

95%CI 0.27 to 1.25

tau2 0.08

DL_FALSE PE 0.59

95%CI 0.40 to 0.85

tau2 0.08






Food allergy and egg – at risk group – comparing early


I2 [95% CI] 0% [0%; 45%]

Method

1_RCT Tier 1+2

PM_TRUE PE 0.69

95%CI 0.50 to 0.93

tau2 0

PM_FALSE PE 0.69

95%CI 0.49 to 0.94

tau2 0

DL_TRUE PE 0.69

95%CI 0.50 to 0.93

tau2 0

DL_FALSE PE 0.69

95%CI 0.49 to 0.94

tau2 0

CI: confidence interval; DL: DerSimonian-Laird; PE: pooled estimate; PM: Paule-Mandel; RCT: randomised controlled trial; TRUE

or FALSE refer to whether the Hartung‐Knapp modification was applied or not, respectively




Sensitisation and egg – at risk group – comparing early


I2 [95% CI] 0% [0%; 87%]

Method

1_RCT Tier 1+2

PM_TRUE PE 0.71

95%CI 0.43 to 1.15

tau2 0

PM_FALSE PE 0.71

95%CI 0.54 to 0.91

tau2 0

DL_TRUE PE 0.71

95%CI 0.43 to 1.15

tau2 0

DL_FALSE PE 0.71

95%CI 0.54 to 0.91

tau2 0

CI: confidence interval; DL: DerSimonian-Laird; PE: pooled estimate; PM: Paule-Mandel; RCT: randomised controlled trial; TRUE





Coeliac disease and gluten comparing early introduction with later

introduction

I2 [95% CI] n/a (k=1) 73% [44%; 87%]

Method



95%CI 0.79 to 1.91 0.40 to 2.69

tau2 n/a 0.12


95%CI 0.79 to 1.91 0.47 to 2.28

tau2 n/a 0.12


95%CI 0.79 to 1.91 0.48 to 1.82

tau2 n/a 0.15


95%CI 0.79 to 1.91 0.65 to 1.33

tau2 n/a 0.15



respectively.




Coeliac disease and gluten comparing early introduction with later

introduction, retrospective studies

I2 [95% CI] 26% [0%; 71%]

Method

Retrospective

PM_TRUE PE 1.20

95%CI 0.89 to 1.62

tau2 0.03

PM_FALSE PE 1.20

95%CI 0.79 to 1.81

tau2 0.03

DL_TRUE PE 1.20

95%CI 0.89 to 1.60

tau2 0.02

DL_FALSE PE 1.20

95%CI 0.79 to 1.81

tau2 0.02






Coeliac disease autoimmunity and gluten comparing early


I2 [95% CI] n/a (k=1) 56% [0%; 82%]

Method



95%CI 0.75 to 1.71 0.58 to 2.34

tau2 n/a 0.07


95%CI 0.75 to 1.71 0.69 to 1.99

tau2 n/a 0.07


95%CI 0.75 to 1.71 0.63 to 1.87

tau2 n/a 0.28


95%CI 0.75 to 1.71 0.79 to 1.49

tau2 n/a 0.28



respectively.




Type 1 diabetes mellitus and CFs comparing early introduction


I2 [95% CI] 65% [17%; 86%]

Method

2_PC Tier 1+2

PM_TRUE PE 0.91

95%CI 0.44 to 1.85

tau2 0.30

PM_FALSE PE 0.91

95%CI 0.53 to 1.57

tau2 0.30

DL_TRUE PE 0.92

95%CI 0.45 to 1.85

tau2 0.24

DL_FALSE PE 0.92

95%CI 0.55 to 1.51

tau2 0.24

CI: confidence interval; DL: DerSimonian-Laird; PE: pooled estimate; PM: Paule-Mandel; PC: prospective cohort; TRUE or FALSE refer to whether the Hartung‐Knapp modification was applied or not, respectively.




Type 1 diabetes mellitus and CFs comparing early introduction

with later introduction, retrospective studies

I2 [95% CI] 79% [60%; 89%]

Method

Retrospective

PM_TRUE PE 0.97

95%CI 0.62 to 1.51

tau2 0.21

PM_FALSE PE 0.97

95%CI 0.66 to 1.40

tau2 0.21

DL_TRUE PE 0.97

95%CI 0.62 to 1.40

tau2 0.14

DL_FALSE PE 0.97

95%CI 0.70 to 1.33

tau2 0.14






Type 1 diabetes mellitus and gluten comparing early introduction


I2 [95% CI] 40% [0%; 74%]

Method

2_PC Tier 1+2

PM_TRUE PE 1.19

95%CI 0.63 to 2.21

tau2 0.29

PM_FALSE PE 1.19

95%CI 0.70 to 1.98

tau2 0.29

DL_TRUE PE 1.13

95%CI 0.66 to 1.91

tau2 0.10

DL_FALSE PE 1.13

95%CI 0.77 to 1.65

tau2 0.10

CI: confidence interval; DL: DerSimonian-Laird; PE: pooled estimate; PM: Paule-Mandel; PC: prospective cohort; TRUE or FALSE





Islet autoimmunity and gluten comparing early introduction with

later introduction

I2 [95% CI] 50% [1%; 75%]

Method

2_PC Tier 1+2

PM_TRUE PE 0.94

95%CI 0.69 to 1.27

tau2 0.09

PM_FALSE PE 0.94

95%CI 0.72 to 1.23

tau2 0.09

DL_TRUE PE 0.94

95%CI 0.69 to 1.26

tau2 0.07

DL_FALSE PE 0.94

95%CI 0.73 to 1.20

tau2 0.07






Systolic blood pressure comparing early introduction with later

introduction of CFs

I2 [95% CI] 0% [0%; 68%]

Method

2_PC Tier 1+2

PM_TRUE PE 0.62

95%CI 0.21 to 10.01

tau2 0

PM_FALSE PE 0.62

95%CI 0.27 to 0.95

tau2 0

DL_TRUE PE 0.62

95%CI 0.21 to 1.01

tau2 0

DL_FALSE PE 0.62

95%CI 0.27 to 0.95

tau2 0






Diastolic blood pressure comparing early introduction with later

introduction of CFs

I2 [95% CI] 0% [0%; 58%]

Method

2_PC Tier 1+2

PM_TRUE PE 0.49

95%CI 0.22 to 0.75

tau2 0

PM_FALSE PE 0.49

95%CI 0.22 to 0.75

tau2 0

DL_TRUE PE 0.49

95%CI 0.22 to 0.75

tau2 0

DL_FALSE PE 0.49

95%CI 0.22 to 0.75

tau2 0


refer to whether the Hartung‐Knapp modification was applied or not, respectively




Iron depletion at 6 months of age (SF <12 µg/L) in exclusively breast-fed infants comparing early introduction with later introduction of CFs

I2 [95% CI] 0% [0%; 4%]

Method

1_RCT Tier 1+2

PM_TRUE PE 0.38

95%CI 0.22 to 0.65

tau2 0

PM_FALSE PE 0.38

95%CI 0.18 to 0.80

tau2 0

DL_TRUE PE 0.38

95%CI 0.22 to 0.65

tau2 0

DL_FALSE PE 0.38

95%CI 0.18 to 0.80

tau2 0

CI: confidence interval; DL: DerSimonian-Laird; PM: Paule-Mandel; PE: pooled estimate; RCT: randomised controlled trial; SF:

serum ferritin; TRUE or FALSE refer to whether the Hartung‐Knapp modification was applied or not, respectively.




References

DerSimonian R and Laird N, 1986. Meta-analysis in clinical trials. Controlled Clinical Trials, 7, 177-188.

Knapp G and Hartung J, 2003. Improved tests for a random effects meta-regression with a single

covariate. Statistics in Medicine, 22, 2693-2710.

Paule RC and Mandel J, 1989. Consensus values, regressions, and weighting factors. Journal of

research of the National Institute of Standards and Technology, 94, 197-203.

Veroniki AA, Jackson D, Viechtbauer W, Bender R, Bowden J, Knapp G, Kuss O, Higgins JP, Langan D

and Salanti G, 2016. Methods to estimate the between-study variance and its uncertainty in meta-

analysis. Research Synthesis Methods, 7, 55-79.

Abbreviations

BF breast-fed

BMI body mass index

CF complementary food

CI confidence interval

DL DerSimonian-Laird between study-variance estimator

FALSE Hartung‐Knapp modification was not applied

FF formula-fed

L(H)AZ Length-(height)-for-age z-score

PC prospective cohort

PE pooled estimate

PM Paule-Mandel between study-variance estimator

RCT randomised controlled trial

SF serum ferritin

TRUE Hartung‐Knapp modification was applied

WAZ weight-for-age z-score

WL(H)Z weight-for-length(height) z-score


Annex E Sensitivity analyses on the use of different ... · behalf of European Food Safety...

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