Nomogram for the Individualized Prediction of Survival Among Patients with H7N9 Infection

Figures & data

Figure 1 Workflow in this study. Patients being treated were defined as patients with an antiviral drug therapy during the course of study.

Table 1 Definitions of This Study

Variables	Definitions
Profession	Including in-service (such as farmers, teacher, pupils, business services, nurses and nannies, waiters, business services, hospital staffs, herdsmen, fisherman, seafarers and long-distance drivers, official staffs, migrant worker, worker, jobless and vagrant persons) and being retired.
A history of chronic diseases	Chronic diseases including chronic cardiovascular disease (i.e., hypertension, coronary heart disease, myocardiopathy, and valvular diseases), chronic liver disease (i.e., chronic hepatitis, liver cirrhosis and liver tumor), chronic metabolic diseases (i.e., obesity, diabetes, fatty liver disease and some cancers), chronic respiratory diseases (i.e., chronic obstructive pulmonary disease and chronic bronchitis), and rheumatic diseases.
A history of surgery	Surgery including all types of human surgery (i.e. tumor enucleation).
Hand hygiene	Referred to hand hygiene practices before the disease onset such as antiseptic hand wash, antiseptic hand rub, or surgical hand antisepsis, and hand-washing frequently, i.e., after contact with animals, before meals, and after using the toilet, etc. Hand hygiene practices including poor hand hygiene (such as not using antiseptic hand wash prepped with 75% alcohol, or not washing hands with soap and water, or other detergents containing an antiseptic agent, or not washing hands frequently after contacting poultry or other animals) and eligible hand hygiene (like using antiseptic handwash prepped with 75% alcohol, or washing hands with soap and water, or other detergents containing an antiseptic agent, or washing hands frequently after contacting poultry or other animals).
A history of smoking	The smoking was defined as 1 cigarette and more per day.
A history of drinking	The drinking was defined as 1 or more drinks at one sitting at least once per week.
First symptoms Patients being treated Patients with loss to follow up	Including cough, expectoration, fever, chest distress, shivering, diarrhea, asthma, headache, pharyngeal pain, abdominal pain, chest pain, and muscle ache. Patients being treated were defined as patients with an antiviral drug therapy during the course of study. Referred to H7N9 patients who could not be investigated such as lost patients and a patient who refused investigation during the course of study.
A random sampling method PaO2/FiO2 ratio (PFR, mmHg) Peak C-reactive protein (CRP)	In this study, the first stage with a random sampling method was to assign a number from 1 to N to each element in all subjects. The next stage was to pick a sample of n of these numbers by using a table of random numbers. By using this method, it must be assured that the numbers chosen were all different, and that none were larger than N. Once the numbers were selected, the individuals corresponding to these numbers were viewed as the sample. PFR is defined as the ratio of arterial oxygen partial pressure to fractional inspired oxygen, and at sea level normal is > 500mmHg. Referred to the value of peak CRP during hospitalization.
Initial white blood cell (WBC) count (10^9/L)	Including decreased (i.e., WBC count < 3.50), increased (i.e., WBC count > 9.50) and normal (i.e., WBC count is between 3.50 and 9.50) WBC.
Initial neutrophil percentage (INP, %)	Including increased (i.e., INP > 75.0), normal (i.e., INP is between 40.0 and 75.0), and decreased (i.e., INP< 40.0) INP.
Initial lymphocyte percentage (ILP, %)	Including increased (i.e., ILP > 50.0), normal (i.e., ILP is between 20.0 and 50.0), and decreased (i.e., ILP < 20.0) ILP.
Initial value of hemoglobin (IVH, g/L)	Including increased (i.e., IVH > 175.0), normal (i.e., IVH is between 130.0 and 175.0), and decreased (i.e., IVH <130.0) IVH.
Initial blood platelet count (IBPC, 10^9/L)	Including increased (i.e., IBPC > 350.0), normal (i.e., IBPC is between 125.0 and 350.0), and decreased (i.e., IBPC < 125.0) IBPC.

Table 2 Baseline Characteristics of Patients with H7N9 Virus Infection in the Study Population

Characteristics	Training Set			Validation Set
	Fatalities	Survivors	P-value	Fatalities	Survivors	P-value
	[N =56, Mean±SD or N (%)]	[N =115, Mean±SD or N (%)]		[N =17, Mean±SD or N (%)]	[N =39, Mean±SD or N (%)]
Age (years,)	64.38 ± 14.15	54.99 ± 12.99	<0.001^a	63.35 ± 17.02	55.23 ± 11.28	0.040^a
Gender
Male	38 (67.86)	78 (67.83)	0.997^b	11 (64.71)	26 (66.67)	0.887^b
Female	18 (32.14)	37 (32.17)		6 (35.29)	13 (33.33)
Onset time (year)
2013	10 (17.86)	27 (23.48)	0.257^b	3 (17.65)	7 (17.95)	1.000^b
2014	22 (39.29)	29 (25.22)		3 (17.65)	8 (20.51)
2015	11 (19.64)	18 (15.65)		4 (23.53)	8 (20.51)
2016	9 (16.07)	30 (26.09)		5 (29.41)	10 (25.64)
2017	4 (7.14)	11 (9.56)		2 (11.76)	6 (15.39)
Incidence area(city)
Hangzhou	36 (64.29)	69 (60.00)	0.589^b	8 (47.06)	15 (38.46)	0.548^b
Outside of Hangzhou	20 (35.71)	46 (40.00)		9 (52.94)	24 (61.54)

Notes: ^aIndependent samples t-test was used. ^bPearson Chi-square test was used. Significant P values are in bold type.

Abbreviations: SD, standard deviation.

Table 3 Univariable Cox Proportional Hazard Regression Analysis of Predictors for the Survival with Influenza A (H7N9) in Zhejiang Province, China

Variables	Training Set (n = 171)		Validation Set (n = 56)
	P-value	HR (95% CI)	P-value	HR (95% CI)
Age (years)
≥ 60	0.002	2.92 (1.50–5.69)	0.010	2.27 (1.06–8.77)
< 60	Reference
Type of residence
Urban areas	0.195	1.55 (0.80–3.02)	0.848	0.89 (0.28–2.85)
Rural areas	Reference
Profession
Being retired	0.014	2.48 (1.21–5.12)	0.013	1.52 (1.31–1.87)
In-service	Reference
Education level
Primary school or illiteracy	0.233	0.83 (0.62–1.12)	0.006	1.33 (1.15–2.78)
Junior middle school or higher	Reference
A history of chronic diseases
Yes	0.018	2.44 (1.17–5.12)	0.015	13.71 (1.65–43.81)
No	Reference
A history of surgery
Yes	0.810	0.92 (0.46–1.83)	0.773	0.83 (0.24–2.87)
No	Reference
Hand hygiene
Poor	<0.001	6.80 (2.52–18.33)	0.002	8.27 (2.21–30.97)
Eligible	Reference
A history of smoking
Yes	0.215	1.51 (0.79–2.88)	0.411	1.62 (0.52–5.09)
No	Reference
A history of drinking
Yes	0.557	1.21 (0.64–2.30)	0.641	1.31 (0.42–4.11)
No	Reference
Direct contact with poultry or birds during the 14 days before illness onset
Yes	0.987	1.01 (0.50–2.04)	0.164	0.40 (0.11–1.45)
No	Reference
Visiting the market where live poultry or birds during the 14 days efore illness onset
Yes	0.545	1.25 (0.61–2.54)	0.283	2.03 (0.56–7.40)
No	Reference
First symptom count
≥ 4	0.429	1.09 (0.88–1.34)	0.718	0.93 (0.62–1.39)
<4	Reference
Incubation period (days)
≤ 5	<0.001	4.75 (2.35–9.59)	0.037	4.43 (1.10–17.91)
> 5	Reference
Body temperature peak
37.3–39°C	0.559	1.20 (0.65–2.22)	0.420	1.67 (0.48–5.80)
39.1–41°C	Reference
The peak of C-reactive protein (mg/L)
≥120	<0.001	4.58 (2.27–9.23)	0.034	3.64 (1.10–11.97)
<120	Reference
Initial white blood cell count (10^9/L)
Decreased	0.475	0.75 (0.30–1.75)	0.093	0.16 (0.02–1.37)
Increased	0.663	1.26 (0.38–3.88)	0.358	0.45 (0.08–2.48)
Normal	Reference
Initial neutrophil percentage (%)
Increased	0.002	3.72 (1.61–8.59)	0.043	1.23 (1.06–7.40)
Normal	Reference
Initial lymphocyte percentage (%)
Decreased	0.237	1.54 (0.72–3.43)	0.773	1.20 (0.35–4.14)
Normal	Reference
Initial value of hemoglobin (g/L)
Decreased	0.215	1.50 (0.75–3.00)	0.641	0.76 (0.24–2.39)
Normal	Reference
Initial blood platelet count (10^9/L)
Decreased	0.363	0.74 (0.37–1.49)	0.121	0.24 (0.17–1.81)
Normal	Reference
Initial lung infection
Infection of bilateral lungs	0.007	2.66 (1.31–5.39)	0.324	1.66 (0.61–4.57)
Infection of single lung	Reference
Initial PaO2/FiO2 ratio (mmHg)
≤ 300	<0.001	4.99 (2.86–8.71)	<0.001	5.07 (1.76–10.98)
>300	Reference
The peak of C-reactive protein (mg/L)	0.004	1.01 (1.00–1.01)	0.241	1.01 (0.99–1.01)
Initial white blood cell count (10^9/L)	0.288	1.05 (0.96–1.16)	0.264	1.12 (0.92–1.37)
Initial neutrophil percentage (%)	0.011	1.05 (1.01–1.09)	0.459	1.03 (0.96–1.10)
Initial lymphocytes percentage (%)	0.298	0.98 (0.94–1.02)	0.995	1.00 (0.93–1.08)
Initial value of hemoglobin (g/L)	0.175	0.99 (0.98–1.00)	0.731	1.00 (0.98–1.03)
Initial blood platelet count (10^9/L)	0.201	1.00 (0.99–1.01)	0.112	1.01 (0.87–1.02)
Time from illness onset to the first medical visit (days)	0.021	1.81 (1.08–1.97)	0.034	1.62 (1.04–2.76)
Time from illness onset to hospitalization (days)	0.579	0.97 (0.86–1.09)	0.038	0.72 (0.53–0.98)
Time from illness onset to oseltamivir treatment (days)	0.192	1.04 (0.98–1.10)	0.347	1.04 (0.96–1.14)
Time from illness onset to admission to the Intensive Care Unit (days)	0.409	1.03 (0.96–1.11)	0.339	1.05 (0.95–1.17)
Time from illness onset to laboratory-confirmed (days)	0.302	1.03 (0.97–1.10)	0.188	1.07 (0.97–1.20)
Time from illness onset to report (days)	0.791	1.01 (0.95–1.06)	0.494	1.03 (0.95–1.11)
Time from illness onset to treatment outcome (days)	0.003	0.98 (0.96–0.99)	0.542	0.99 (0.96–1.02)
Time treated in an outpatient clinic (days)	0.004	0.97 (0.96–0.99)	0.733	0.95 (0.73–1.25)
Time treated in a hospital (days)	0.002	0.97 (0.96–0.99)	0.608	0.99 (0.96–1.02)
Incubation period (days)	<0.001	0.76 (0.65–0.88)	0.045	0.77 (0.59–0.99)

Notes: Significant P values are in bold type.

Abbreviations: HR, hazard ratio; CI, confidence interval.

Figure 2 The nomogram for individualized predicting the 1-, 2-, and 3-month probabilities of survival from influenza A (H7N9).

Abbreviations: PHH, poor hand hygiene; CD, chronic diseases; IP, incubation period; TIOFMV, time from illness onset to the first medical visit (days); CRP, C-reactive protein; IBLI, initial bilateral lung infection; IPFR, initial PaO2/FiO2 ratio.

Table 4 Multivariable Cox Proportional Hazard Regression Model for the Survival on Patients with H7N9 Virus Infection in Zhejiang Province, China

Variables	Training Set (n = 171)		Validation Set (n = 56)
	P-value	HR (95% CI)	P-value	HR (95% CI)
Age (years)	0.101	1.12 (0.91–2.03)	0.167	1.25 (0.73–3.31)
Age ≥ 60 years	0.069	1.89 (0.95–3.73)	0.093	1.38 (0.91–2.36)
Education level	NA	NA	0.269	0.17 (0.03–2.01)
Being retired	0.219	1.36 (0.94–2.34)	0.764	1.87 (0.14–8.16)
Chronic diseases	0.008	2.92 (1.32–6.44)	0.024	1.99 (1.12–9.34)
Poor hand hygiene	0.005	4.18 (1.55–11.29)	0.035	4.03 (1.14–10.26)
Initial bilateral lung infection	0.015	2.41 (1.19–4.88)	NA	NA
The peak of C-reactive protein (mg/L)	0.241	0.86 (0.68–1.16)	NA	NA
Peak C-reactive protein ≥ 120 mg/L	0.015	4.40 (1.33–14.54)	0.024	4.16 (1.19–13.24)
Increased initial neutrophil percentage (%)	0.101	2.72 (0.82–9.05)	0.306	2.03 (0.75–7.86)
Initial neutrophil percentage (%)	0.609	0.97 (0.88–1.08)	NA	NA
Incubation period (days)	0.527	1.07 (0.87–1.32)	0.661	1.01 (0.29–3.03)
Incubation period of ≤ 5 days	0.028	3.88 (1.16–12.99)	0.041	2.84 (1.13–13.21)
Initial PaO2/FiO2 ratio ≤ 300 mmHg	<0.001	5.90 (2.99–11.64)	<0.001	4.56 (1.10–13.98)
Time from illness onset to the first medical visit (days)	0.005	1.89 (1.07–3.04)	0.016	1.31(1.04–4.25)
Time from illness onset to hospitalization (days)	NA	NA	0.674	1.16 (0.33–3.98)
Time treated in an outpatient clinic (days)	0.510	1.07(0.87–1.31)	NA	NA
Time treated in a hospital (days)	0.201	0.83 (0.43–2.54)	NA	NA
Time from illness onset to treatment outcome (days)	0.455	1.29(0.64–2.83)	NA	NA

Notes: Significant P values are in bold type.

Abbreviations: HR, hazard ratio; CI, confidence interval; NA, not applicable.

Figure 3 The calibration curves for predicting the probability of survival from influenza A (H7N9) at each time point in the training set. Nomogram predicted the 1-, 2- and 3-month probabilities of survival from influenza A (H7N9) which are plotted on the X-axis and observed the 1-, 2- and 3-month probabilities of survival from influenza A (H7N9) which are plotted on the Y-axis.

Figure 4 The calibration curves for predicting the probability of survival from influenza A (H7N9) at each time point in the external validation set. Nomogram predicted the 1-, 2- and 3-month probabilities of survival from influenza A (H7N9) which are plotted on the X-axis and observed the 1-, 2- and 3-month probabilities of survival from influenza A (H7N9) which are plotted on the Y-axis.

Table 5 Predicting an Individual H7N9 Patient’s Survival

Independent Predictors	Value	Points
Age ≥ 60 years	Yes	20.0
Chronic diseases	Yes	11.0
Poor hand hygiene	No	0
Initial PaO2/FiO2 ratio ≤ 300 mmHg	Yes	55.0
Peak C-reactive protein ≥ 120 mg/L	Yes	31.5
Initial bilateral lung infection	Yes	11.5
Incubation period of ≤ 5 days	Yes	27.0
Time from illness onset to the first medical visit (days)	14	19.0
Total points	175.0
Estimate of survival probability, %
Probability of 1-month survival	25.0
Probability of 2-month survival	21.0
Probability of 3-month survival	19.0