Phase 1: questionnaire development
Face-to-face interviews were analyzed qualitatively for 11 interviews with specialists (Table 1). The risk factors categorized into 10 domains (background of disease, drug use, environmental factors, lifestyle factors, nutritional factors, occupational factors, expose to radiation due to medical diagnosis or treatment, reproductive factors, socio-demographic factors and birth characteristics) by two independent researchers using the qualitative technique of content analysis30, and dual extraction and categorization of risk factors with senior discussion if discrepancies occurred31. A domain was identified as a wide range of risk factors; for example, the domain hormonal risk factors, included the use of OCPs, HRT, ART, early menarche, late menopause, low parity, and…. After removing duplicate and similar items, a questionnaire containing 202 risk factors for breast cancer was prepared. Due to the time consuming and difficulty of answering a long 202-question questionnaire, some similar risk factors were combined and finally, after several sessions of consultation with the research team, a questionnaire containing 119 risk factors was obtained.
Characteristics of the participants in the first round are presented in the following tables. The first round of Delphi took place from March 2020 to February 2021.
Table 1
Characteristics of the specialists' participants of the first round of qualitative Delphi
Variable
|
Number (percent)
|
Specialty
|
Oncology
|
4 (37)
|
Gynecology
(Oncology fellow)
|
2 (18)
|
Nutrition
|
1 (9)
|
Surgery (general- breast)
|
3 (27)
|
Palliative care
|
1 (9)
|
Length of Experience
|
10-19
|
3 (27)
|
20-29
|
8 (73)
|
Place of Interview
|
Specialized clinics
|
5 (45)
|
Private office
|
2 (18)
|
Office of specialty group in hospital or faculty
|
4 (37)
|
Phase 2: Delphi consensus methods
In the second round of Delphi, draft of questionnaire obtained from a literature review and the first round of Delphi, were sent to specialists via e-mail.
A total of 60 specialists from ten convince of Iran were invited to participate in round 2. Of these,
30 (50 percent) responded; 25 (9⋅0 percent) declined, 3 (5 percent) experts said they were not active in the breast cancer field and 2 (3.3 percent) postponed the answer to a time beyond the study time. The characteristics of the specialists participating in the second round of Delphi were as follows: three reproductive health specialists, twelve radio-oncologists, eleven general or breast surgeons, four gynecologists-gynecological oncology fellowships. Participants were from Kerman, Shiraz, Mashhad, Rasht, Tehran, Tabriz, Babol-Babolsar, Ahvaz and Isfahan. The average length of participants' experience in BC management was 18.2 years.
In round 2, 43 (36 percent) risk factors were diagnosed as "low important" and met the exclusion criteria (Table 2), 25 (21 percent) risk factors with "very important" label included in primary draft of risk assessment instrument (Table 3) and 51 (43 percent) risk factors were carried forward to round 3. The second round of Delphi lasted six months (February to August 2020) due to the COVID-19 pandemic.
Table 2
The risk factors diagnosed as "low important" in second round of Delphi according to specialists opinion
No
|
Risk factor
|
Median
|
IQR
|
Mean
|
SD
|
1
|
cholecystitis
|
1
|
2
|
2.13
|
1.78
|
2
|
Allergy (serum IgE)
|
1
|
1
|
1.6
|
1
|
3
|
Multiple sclerosis
|
2
|
3
|
2.6
|
1.94
|
4
|
Rheumatoid Arthritis
|
2
|
4
|
3
|
2.07
|
5
|
Parkinson
|
1
|
2
|
2
|
1.55
|
6
|
Migraine
|
1
|
1
|
1.57
|
0.97
|
7
|
Tonsillectomy
|
1
|
0
|
1.5
|
1.11
|
8
|
Bone high density
|
2
|
2
|
2.6
|
2.11
|
9
|
Hypothyroidism
|
1
|
1
|
1.83
|
1.21
|
10
|
Mononucleosis/
IgG antibody of cytomegalovirus
|
2
|
2
|
2.27
|
1.41
|
11
|
Insulin
|
2
|
2
|
2.4
|
1.45
|
12
|
Antidepressant drugs
|
2
|
3
|
2.5
|
1.57
|
13
|
Multivitamins
|
1
|
1
|
1.57
|
0.86
|
14
|
Antibiotics
|
1
|
1
|
1.37
|
0.67
|
15
|
Lowering cholesterol statins
|
1
|
0
|
1.33
|
0.71
|
16
|
Antihypertensive drugs
|
1
|
1
|
1.4
|
0.68
|
17
|
Diuretics
|
1
|
1
|
1.4
|
0.72
|
18
|
Digoxin
|
1
|
1
|
1/47
|
0.73
|
19
|
Traffic noise
|
2
|
2
|
2.37
|
1.562
|
20
|
Cleaning / Detergent / Air freshener Products
|
2
|
2
|
2.53
|
1.41
|
21
|
Wearing tight bra
|
2
|
3
|
2.83
|
2.35
|
22
|
Egg consumption
|
2
|
2
|
2.17
|
1.6
|
23
|
Calcium deficiency
|
2
|
2
|
2.93
|
1.91
|
24
|
Black tea
|
1
|
1
|
1.47
|
0/73
|
25
|
High Calcium intake
|
1
|
1
|
1.63
|
1.07
|
26
|
Vegetable oil
|
1
|
1
|
1.67
|
1.18
|
27
|
Olive oil
|
1
|
1
|
1.63
|
1.25
|
28
|
High consumption of milk/ Dairy products
|
2
|
2
|
2.2
|
1.54
|
29
|
Animal oil (Kermanshahi)
|
2
|
2
|
2.4
|
1.71
|
30
|
High Fe diet
|
1
|
1
|
1.4
|
0.86
|
31
|
Vitamin deficiency
|
2.5
|
3
|
2.4
|
1.85
|
32
|
Cabin attendants
|
2.5
|
3
|
2.8
|
1.79
|
33
|
Housewife
|
1
|
1
|
1.7
|
1.21
|
34
|
Teacher
|
1.5
|
2
|
1.87
|
1.07
|
35
|
Farmer
|
1
|
1
|
1.7
|
1.21
|
36
|
Pregnancy
|
2
|
6
|
3.73
|
3.3
|
37
|
Taller height
|
1
|
2
|
2
|
1.49
|
38
|
occupied
|
2
|
4
|
2.87
|
1.87
|
39
|
Higher age of parents at birth
|
2
|
2
|
2.07
|
1.34
|
40
|
High birth weight
|
1
|
1
|
1.87
|
1.31
|
41
|
Mother's overweight at beginning the pregnancy
|
2
|
2
|
2.23
|
1.63
|
42
|
Preterm
|
1.5
|
1
|
1.7
|
0.79
|
43
|
post term
|
1
|
1
|
1.7
|
0.88
|
Table 3
The risk factors diagnosed as "very important" in second round of Delphi according to specialists opinion
No
|
Risk factor
|
Median
|
IQR
|
Mean
|
SD
|
1
|
immunodeficiency
|
6.5
|
6
|
5.4
|
2.85
|
2
|
Dense breast
|
6
|
3
|
5.7
|
2.47
|
3
|
Breast atypical hyperplasia
|
7
|
4
|
6.4
|
2.3
|
4
|
History of breast cancer
|
9
|
1
|
8.33
|
1.24
|
5
|
History of breast biopsy
|
6
|
4
|
5.67
|
2.72
|
6
|
Oral contraceptive pills
|
6
|
2
|
5.93
|
1.87
|
7
|
Androgen therapy
|
6
|
3
|
5.3
|
2.48
|
8
|
Ovary stimulators/IVF drugs
|
6
|
2
|
6.13
|
1.61
|
9
|
Hormone replacement therapy/
Menopausal hormone therapy
|
7
|
3
|
6.47
|
1
|
10
|
Unopposed estrogen
|
6.5
|
3
|
6.43
|
2.13
|
11
|
Environmental ionizing ray
|
6
|
4
|
5.73
|
2.46
|
12
|
Smoking/ passive smoking
|
6
|
2
|
6
|
1.84
|
13
|
Stressful life
|
7
|
5
|
6.3
|
2.25
|
14
|
High BMI/ Obesity/ Overweight
|
6
|
3
|
6.57
|
1.68
|
15
|
High dose chest radiation
|
7.5
|
5
|
6.57
|
2.69
|
16
|
High age at first child birth
|
6
|
4
|
6.4
|
2.28
|
17
|
Early menarche
|
6
|
5
|
5.6
|
2.59
|
18
|
Late menopause
|
6
|
6
|
5.63
|
2.85
|
19
|
Nulliparity
|
6
|
6
|
5.47
|
2.8
|
20
|
Family history of breast cancer
|
9
|
1
|
8.23
|
1.14
|
21
|
Family history of breast cancer under 40 years
|
9
|
1
|
8.5
|
0.86
|
22
|
Family history of ovary cancer
|
8.5
|
2
|
7.8
|
1.65
|
23
|
Family history of sarcoma
|
6
|
4
|
5.43
|
2.39
|
24
|
Female gender
|
9
|
1
|
8.33
|
1.35
|
25
|
Increasing age
|
7.5
|
4
|
6.83
|
2.23
|
Phase 3: consensus round
The third round of Delphi took place in September 2020. All round 2 respondents were invited to participate in round 3. Participants were asked (similar to the previous round) to determine the importance of each factor based on the 9-point Likert scale. Of these, 22 (73.3 percent) completed and returned the questionnaire. Also, 4 specialists (different from the second round) who were a surgeon and 3 oncologists were also participating in round 3 (Tumor Board Meeting of Ghaem Hospital – 17/8/2020). So we had a total of 26 responses, and the response rate in round 3 was 86.7%. Demographics of professional participants were similar between rounds 1 and 2. The characteristics of the participants of the third round of Delphi were as follows: 7 surgeons (general-breast), 10 oncologists, 2 reproductive health specialists, 7 gynecological oncology fellowships, from Mashhad, Tehran, Ahvaz, Rasht, Isfahan, Shiraz, Kerman and Tabriz. The average length of work experience of the participants was 19 years.
In the third round, 70% of participants (at least 18 people) did not agree on the importance of any of the risk factors.
So, a questionnaire containing 25 important risk factors for breast cancer, according to Iranian context, remained in the primary draft. Of these 25 items, "female gender" and "personal history of breast cancer" were excluded. Because the tool is designed to assess the risk of breast cancer in Iranian women and to start screening on time based on the personal risk. So naturally it does not include women who have a positive history of breast cancer. Therefore, a questionnaire containing 23 risk factors entered the instrument development process. The final results of the third round of the Delphi are shown in Table 4.
Table 4
Risk factors that were reprioritized in the third round of Delphi according to specialists' opinion
No
|
Risk factor
|
Median
|
IQR
|
Mean
|
SD
|
Consensus (%)
|
1
|
Infertility
|
8
|
4
|
7.21
|
2.02
|
62.5
|
2
|
Metabolic syndrome
|
5
|
3
|
5.29
|
2.1
|
45.8
|
3
|
Diabetes type 2
|
6
|
2
|
5.42
|
2.13
|
54.2
|
4
|
Hyperprolactinemia
|
3
|
2
|
3.17
|
1.66
|
12.5
|
5
|
Systemic lupus erythematosus
|
2.5
|
3
|
2.92
|
2.13
|
16.7
|
6
|
Endometriosis
|
3.5
|
3.75
|
3.46
|
2.21
|
20.8
|
7
|
Uterine leiomyoma
|
2
|
2.75
|
2.88
|
1.92
|
12.5
|
8
|
Ovarian cyst/ Polycystic ovary syndrome
|
5.5
|
3
|
5.33
|
1.83
|
50
|
9
|
Psychiatric disorders
|
4
|
2
|
4.04
|
1.85
|
16.7
|
10
|
Breast proliferative benign disease
|
5
|
2.75
|
4.71
|
1.83
|
45.8
|
11
|
Mastalgia
|
4
|
3
|
4.63
|
2.02
|
37.5
|
12
|
Progestrons
|
5
|
3.75
|
4.5
|
2.04
|
29.2
|
13
|
Hormonal intrauterine device
|
3
|
3.75
|
3.8
|
1.72
|
20.8
|
14
|
Contraceptive implants
|
3.5
|
3
|
3.92
|
1.93
|
16.7
|
15
|
Residence near a food or beverage factory
|
3
|
4
|
3.92
|
2.17
|
33.3
|
16
|
Residence near industrial factory (ceramics, detergents)
|
3
|
3.75
|
4.25
|
2.27
|
29.2
|
17
|
Exposure to light at night
|
3
|
2.75
|
3.46
|
1.53
|
8.33
|
18
|
Pesticides/ insecticides
|
4.5
|
3
|
4.5
|
1.98
|
33.3
|
19
|
Air pollution
|
4.5
|
3.75
|
4.83
|
2.06
|
37.5
|
20
|
Water pollution
|
5
|
4
|
4.79
|
2.11
|
41.7
|
21
|
Exposure to strong electromagnetic fields
|
5
|
3.75
|
5.08
|
2.17
|
37.5
|
22
|
Exposure to electromagnetic fields of home appliances
|
4.5
|
4.5
|
4.67
|
2.18
|
33.3
|
23
|
Living in a low sunny area
|
5
|
1
|
4.38
|
1.49
|
16.7
|
24
|
Sedentary life
|
6
|
2.75
|
6
|
1.47
|
58.33
|
25
|
Alcohol consumption
|
6.5
|
2.75
|
6.04
|
1.97
|
58.33
|
26
|
Insufficient sleep / short sleep
|
5
|
3
|
5.25
|
1.87
|
41.7
|
27
|
Excessive use of cosmetics
|
4.5
|
4
|
3.96
|
2.07
|
29.2
|
28
|
Singleness over the age of 30
|
6
|
2.75
|
6.08
|
1.53
|
62.5
|
29
|
Vitamin D deficiency
|
5
|
2
|
5.08
|
1.44
|
29.2
|
30
|
Consumption of factory and canned food
|
5
|
2
|
5
|
1.18
|
29.2
|
31
|
High calorie/ energy intake
|
6
|
2
|
5.96
|
1.57
|
58.33
|
32
|
Full fat/ fried diet
|
6
|
3
|
5.5
|
1.79
|
54.2
|
33
|
Meaty diet
|
5
|
3
|
5.46
|
1.69
|
45.8
|
34
|
Low consumption of fruit and fresh vegetables
|
5
|
3
|
5.25
|
1.92
|
37.5
|
35
|
Consume food or drink in plastic containers
|
5
|
2
|
4.42
|
1.56
|
20.8
|
36
|
Irregular meals
|
3.5
|
2
|
4
|
1.72
|
20.8
|
37
|
Night work/ Shift work
|
5
|
3.75
|
5.17
|
2.1
|
37.5
|
38
|
Work in garment factories / textile weaving / canning / industries (metal, plastic, dyeing)
|
3
|
3
|
3.5
|
1.87
|
20.8
|
39
|
Makeup artists/hairdresser
|
5
|
3
|
4.42
|
1.79
|
37.5
|
40
|
Contact with volatile organic chemicals (laboratory personnel, army personnel)
|
3
|
2.75
|
3.88
|
1.62
|
26
|
41
|
Diagnostic radiation (mammography)
|
4
|
3.75
|
4.58
|
2.3
|
33.3
|
42
|
Frequent chest x-ray in tuberculosis
|
4.5
|
3
|
4.67
|
2.14
|
37.5
|
43
|
Induced abortion
|
4
|
3
|
4.33
|
1.83
|
29.2
|
44
|
Spontaneous abortion
|
4
|
3
|
3.46
|
1.56
|
8.33
|
45
|
Low parity
|
6
|
2.75
|
5.88
|
1.83
|
62.5
|
46
|
Low breastfeeding
|
5
|
3.75
|
5.58
|
2.10
|
50
|
47
|
High socio-economic status
|
5
|
3.75
|
4.71
|
1.92
|
41.7
|
48
|
Low socio-economic status
|
5
|
3.75
|
4.75
|
1.65
|
33.3
|
49
|
Big breast
|
5
|
2.75
|
4.75
|
1.73
|
29.2
|
50
|
Family history of gastrointestinal cancer
|
5
|
2.75
|
5.46
|
1.93
|
45.8
|
51
|
Late marriage
|
6
|
3
|
5.83
|
1.93
|
58.33
|