Upload
vuduong
View
224
Download
1
Embed Size (px)
Citation preview
BackgroundMethods
ResultsDiscussion
Disruption of Circadian Rhythms of preterm PAand PPROM
Department of EpidemiologyMiguel Angel Luque-Fernandez
Ananth C.V., Sanchez S.E., Qui Chun-fang, Hernandez-Diaz S., Unnur ValdimarsdottirBizu Gelaye, Michelle A. Williams
June 24, 2014
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Outline1 Background
IntroductionThe hypothesisJustificationObjectives
2 MethodsData, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
3 ResultsResultsReplication: NCPP study
4 DiscussionMain findingsLimitationsInterpretationConclusions
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
IntroductionThe hypothesisJustificationObjectives
Background
Background
Globally, 15 million preterm deliveries are estimated to take placeevery year.
Around 1 million children die each year due to complications ofprematurity and placental abruption (PA).
PA is a significant contributor to maternal mortality and it occurs in1% of pregnancies worldwide.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
IntroductionThe hypothesisJustificationObjectives
Background
Background
Globally, 15 million preterm deliveries are estimated to take placeevery year.
Around 1 million children die each year due to complications ofprematurity and placental abruption (PA).
PA is a significant contributor to maternal mortality and it occurs in1% of pregnancies worldwide.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
IntroductionThe hypothesisJustificationObjectives
Background
Background
Globally, 15 million preterm deliveries are estimated to take placeevery year.
Around 1 million children die each year due to complications ofprematurity and placental abruption (PA).
PA is a significant contributor to maternal mortality and it occurs in1% of pregnancies worldwide.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
IntroductionThe hypothesisJustificationObjectives
Background
Background
Globally, 15 million preterm deliveries are estimated to take placeevery year.
Around 1 million children die each year due to complications ofprematurity and placental abruption (PA).
PA is a significant contributor to maternal mortality and it occurs in1% of pregnancies worldwide.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
IntroductionThe hypothesisJustificationObjectives
The hypothesis
The hypothesis
The time of onset of preterm PA and extremely and very PPROMcases may be characterized by a disrupted circadian patternassociated with fetal immaturity.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
IntroductionThe hypothesisJustificationObjectives
The justification
Justification
The disruption of circadian rhythms driven by fetal immaturity mayhelp to explain tocolytics failure to prevent delivery of veryand extremely PPROM cases, and therefore could help toorientate the clinical practice.
The time of the onset of PPROM and PA cases has not beenmodeled with the most appropriate methodology . Therefore, anappropriate methodological approach could help to test moreconsistently the hypothesis.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
IntroductionThe hypothesisJustificationObjectives
The justification
Justification
The disruption of circadian rhythms driven by fetal immaturity mayhelp to explain tocolytics failure to prevent delivery of veryand extremely PPROM cases, and therefore could help toorientate the clinical practice.
The time of the onset of PPROM and PA cases has not beenmodeled with the most appropriate methodology . Therefore, anappropriate methodological approach could help to test moreconsistently the hypothesis.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
IntroductionThe hypothesisJustificationObjectives
The justification
Justification
The disruption of circadian rhythms driven by fetal immaturity mayhelp to explain tocolytics failure to prevent delivery of veryand extremely PPROM cases, and therefore could help toorientate the clinical practice.
The time of the onset of PPROM and PA cases has not beenmodeled with the most appropriate methodology . Therefore, anappropriate methodological approach could help to test moreconsistently the hypothesis.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
IntroductionThe hypothesisJustificationObjectives
Rabiddran R. et al. BJOG 2010;117:1656-1657
𝒙𝟐
Lindow S.W. et al. British Journal of Obstetrics and Gynecology 2000;107:1145-1148
Time plot
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
IntroductionThe hypothesisJustificationObjectives
The objectives
Objectives
1 To model, with the appropriate methodology (time series theory andcircular time), the time of onset of PPROM and PA cases.
2 To evaluate the presence of circadian rhythms for PPROM and PAcases.
3 To examine the extent to which the circadian rhythms vary based ongestational age at onset.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
IntroductionThe hypothesisJustificationObjectives
The objectives
Objectives
1 To model, with the appropriate methodology (time series theory andcircular time), the time of onset of PPROM and PA cases.
2 To evaluate the presence of circadian rhythms for PPROM and PAcases.
3 To examine the extent to which the circadian rhythms vary based ongestational age at onset.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
IntroductionThe hypothesisJustificationObjectives
The objectives
Objectives
1 To model, with the appropriate methodology (time series theory andcircular time), the time of onset of PPROM and PA cases.
2 To evaluate the presence of circadian rhythms for PPROM and PAcases.
3 To examine the extent to which the circadian rhythms vary based ongestational age at onset.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
IntroductionThe hypothesisJustificationObjectives
The objectives
Objectives
1 To model, with the appropriate methodology (time series theory andcircular time), the time of onset of PPROM and PA cases.
2 To evaluate the presence of circadian rhythms for PPROM and PAcases.
3 To examine the extent to which the circadian rhythms vary based ongestational age at onset.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
METHODS
Data, setting and sample size.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Data, settings and sample size
Data, setting and sample size
A total of 232 PPROM and 163 PA singleton spontaneous caseswere identified at three hospitals in Lima, Peru, between January2009 and July 2010.
Exclusions: Multiplicity, labor induction and/or artificial rupture ofmembranes and gestational age unknown.
Gestational age: based on the date of the LMP and confirm by anultrasound before 20 weeks of gestation.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Data, settings and sample size
Data, setting and sample size
A total of 232 PPROM and 163 PA singleton spontaneous caseswere identified at three hospitals in Lima, Peru, between January2009 and July 2010.
Exclusions: Multiplicity, labor induction and/or artificial rupture ofmembranes and gestational age unknown.
Gestational age: based on the date of the LMP and confirm by anultrasound before 20 weeks of gestation.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Data, settings and sample size
Data, setting and sample size
A total of 232 PPROM and 163 PA singleton spontaneous caseswere identified at three hospitals in Lima, Peru, between January2009 and July 2010.
Exclusions: Multiplicity, labor induction and/or artificial rupture ofmembranes and gestational age unknown.
Gestational age: based on the date of the LMP and confirm by anultrasound before 20 weeks of gestation.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Data, settings and sample size
Data, setting and sample size
A total of 232 PPROM and 163 PA singleton spontaneous caseswere identified at three hospitals in Lima, Peru, between January2009 and July 2010.
Exclusions: Multiplicity, labor induction and/or artificial rupture ofmembranes and gestational age unknown.
Gestational age: based on the date of the LMP and confirm by anultrasound before 20 weeks of gestation.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Methods: Case definition
Study Case definition
A certified nurse midwife abstracted detailed information includingthe time of onset of PPROM and PA cases from maternal medicalrecords.
The time of onset of spontaneous PPROM was defined as womenself-reported starting time of leaking or gushing of fluid from thevagina, and confirmed by medical exploration at the time of theadmission.
The time of the onset of PA was defined as women’s self-reportedstarting of profuse external bleeding accompanied by uterinetenderness or hypertonia plus intense back pain, confirmed bymedical anamnesis at the moment of the admission.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Methods: Case definition
Study Case definition
A certified nurse midwife abstracted detailed information includingthe time of onset of PPROM and PA cases from maternal medicalrecords.
The time of onset of spontaneous PPROM was defined as womenself-reported starting time of leaking or gushing of fluid from thevagina, and confirmed by medical exploration at the time of theadmission.
The time of the onset of PA was defined as women’s self-reportedstarting of profuse external bleeding accompanied by uterinetenderness or hypertonia plus intense back pain, confirmed bymedical anamnesis at the moment of the admission.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Methods: Case definition
Study Case definition
A certified nurse midwife abstracted detailed information includingthe time of onset of PPROM and PA cases from maternal medicalrecords.
The time of onset of spontaneous PPROM was defined as womenself-reported starting time of leaking or gushing of fluid from thevagina, and confirmed by medical exploration at the time of theadmission.
The time of the onset of PA was defined as women’s self-reportedstarting of profuse external bleeding accompanied by uterinetenderness or hypertonia plus intense back pain, confirmed bymedical anamnesis at the moment of the admission.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Methods: Case definition
Study Case definition
A certified nurse midwife abstracted detailed information includingthe time of onset of PPROM and PA cases from maternal medicalrecords.
The time of onset of spontaneous PPROM was defined as womenself-reported starting time of leaking or gushing of fluid from thevagina, and confirmed by medical exploration at the time of theadmission.
The time of the onset of PA was defined as women’s self-reportedstarting of profuse external bleeding accompanied by uterinetenderness or hypertonia plus intense back pain, confirmed bymedical anamnesis at the moment of the admission.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
METHODS
METHODS
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Methods
Time in a linear scale
The truth is never linear!Or almost never!
But often the linearity assumption is good enough.When its not:
Time in circular scale
Circular time: trigonometric models or cosinor models
Polynomials, trigonometric polynomials, fractional polynomials
Splines, restricted cubic splines, smoothed splines...
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Methods
Time in a linear scale
The truth is never linear!Or almost never!But often the linearity assumption is good enough.
When its not:
Time in circular scale
Circular time: trigonometric models or cosinor models
Polynomials, trigonometric polynomials, fractional polynomials
Splines, restricted cubic splines, smoothed splines...
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Methods
Time in a linear scale
The truth is never linear!Or almost never!But often the linearity assumption is good enough.When its not:
Time in circular scale
Circular time: trigonometric models or cosinor models
Polynomials, trigonometric polynomials, fractional polynomials
Splines, restricted cubic splines, smoothed splines...
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Methods
Time in a linear scale
The truth is never linear!Or almost never!But often the linearity assumption is good enough.When its not:
Time in circular scale
Circular time: trigonometric models or cosinor models
Polynomials, trigonometric polynomials, fractional polynomials
Splines, restricted cubic splines, smoothed splines...
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Methods
Time in a linear scale
The truth is never linear!Or almost never!But often the linearity assumption is good enough.When its not:
Time in circular scale
Circular time: trigonometric models or cosinor models
Polynomials, trigonometric polynomials, fractional polynomials
Splines, restricted cubic splines, smoothed splines...
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Methods
Time in a linear scale
The truth is never linear!Or almost never!But often the linearity assumption is good enough.When its not:
Time in circular scale
Circular time: trigonometric models or cosinor models
Polynomials, trigonometric polynomials, fractional polynomials
Splines, restricted cubic splines, smoothed splines...
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Methods general overview
Circular Time
-1
0
1
-(1/2)
(1/2)y
-1 1Circumference of Radious 1
Circular time
Assessing periodicity : FourierTimes Series Transformation(Periodogram).
Describing periodicity : Datareduction.Modeling periodicity :Trigonometric predictors with sineand cosine terms (Trigonometricregression or cosinor model).
Circular time modeling assumptions�� ��Sinusoidal pattern ————————�� ��Stationary time series
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Methods general overview
Circular Time
-1
0
1
-(1/2)
(1/2)y
-1 1Circumference of Radious 1
Circular time
Assessing periodicity : FourierTimes Series Transformation(Periodogram).Describing periodicity : Datareduction.
Modeling periodicity :Trigonometric predictors with sineand cosine terms (Trigonometricregression or cosinor model).
Circular time modeling assumptions�� ��Sinusoidal pattern ————————�� ��Stationary time series
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Methods general overview
Circular Time
-1
0
1
-(1/2)
(1/2)y
-1 1Circumference of Radious 1
Circular time
Assessing periodicity : FourierTimes Series Transformation(Periodogram).Describing periodicity : Datareduction.Modeling periodicity :Trigonometric predictors with sineand cosine terms (Trigonometricregression or cosinor model).
Circular time modeling assumptions�� ��Sinusoidal pattern ————————�� ��Stationary time series
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Methods general overview
Circular Time
-1
0
1
-(1/2)
(1/2)y
-1 1Circumference of Radious 1
Circular time
Assessing periodicity : FourierTimes Series Transformation(Periodogram).Describing periodicity : Datareduction.Modeling periodicity :Trigonometric predictors with sineand cosine terms (Trigonometricregression or cosinor model).
Circular time modeling assumptions�� ��Sinusoidal pattern ————————�� ��Stationary time series
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
Methods general overview
Circular Time
-1
0
1
-(1/2)
(1/2)y
-1 1Circumference of Radious 1
Circular time
Assessing periodicity : FourierTimes Series Transformation(Periodogram).Describing periodicity : Datareduction.Modeling periodicity :Trigonometric predictors with sineand cosine terms (Trigonometricregression or cosinor model).
Circular time modeling assumptions�� ��Sinusoidal pattern ————————�� ��Stationary time series
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Data, settings and sample sizeStatistical analysis: Circular Time and Fourier Transformation
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
RESULTS
RESULTS AND COMMENTS ONMETHODS
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
Results: Describing/assessing periodicity
Describing the data: Data reduction
Aggregated number of cases and percentages by hours and the foursegments of the day.
Prevalence ratios (PRs) of the aggregated number of cases bysegments of the day with night as reference(PRs were derived using a generalized linear Poisson model with linklog and scaled error standards to account for over-dispersion).
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
Results: Describing/assessing periodicity
Describing the data: Data reduction
Aggregated number of cases and percentages by hours and the foursegments of the day.
Prevalence ratios (PRs) of the aggregated number of cases bysegments of the day with night as reference(PRs were derived using a generalized linear Poisson model with linklog and scaled error standards to account for over-dispersion).
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
Results: Describing/assessing periodicity
Describing the data: Data reduction
Aggregated number of cases and percentages by hours and the foursegments of the day.
Prevalence ratios (PRs) of the aggregated number of cases bysegments of the day with night as reference(PRs were derived using a generalized linear Poisson model with linklog and scaled error standards to account for over-dispersion).
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
Results: assessing periodicity
Kernel smoother and Fourier Transformation
1 We used a non-parametric Kernel density estimation to estimate theprobability density function of PPROM and PA cases over time (24hours).
2 We used a periodogram (Fourier transformation: sine and cosinefunctions) to identify any periodicity: higher frequencies in thedistribution of the observed data.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
Results: assessing periodicity
Kernel smoother and Fourier Transformation
1 We used a non-parametric Kernel density estimation to estimate theprobability density function of PPROM and PA cases over time (24hours).
2 We used a periodogram (Fourier transformation: sine and cosinefunctions) to identify any periodicity: higher frequencies in thedistribution of the observed data.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
Results: assessing periodicity
Kernel smoother and Fourier Transformation
1 We used a non-parametric Kernel density estimation to estimate theprobability density function of PPROM and PA cases over time (24hours).
2 We used a periodogram (Fourier transformation: sine and cosinefunctions) to identify any periodicity: higher frequencies in thedistribution of the observed data.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
Assessing periodicity: distributions and Periodogram
MA Luque-Fernandez et al., non published data. Under review
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
Results: TESTING PERIODICITY
Testing periodicity: Cosinor models
Modeling the time of onset of PPROM AND PA: Cosinor models
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
The cosinor Model: trigonometric regression
Cosinor
The Cosinor model: Generalized Linear Model
g(Y )t = c cos(wt) + s sin(wt)
t=1,...,24.Scaling time to a circular scale.
We compute wt as follow:
wt = 2π ft
where
ft =timet − 0.5
24hours
g(.) = Onsets counts; family: Poisson andscaled S.E (φ=
√χ2/df )
Deriving the amplitude and testing thestatistical significance of the circadian rhythm
Where the Amplitude is derived as follows:
A =√
c2 + s2 , (A ≥ 0)
Then we test the following Null HypothesisThe amplitude is A= 0
Using the following test:Z=nA2
Where:A =
√c2 + s2
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
The cosinor Model: trigonometric regression
Cosinor
The Cosinor model: Generalized Linear Model
g(Y )t = c cos(wt) + s sin(wt)
t=1,...,24.Scaling time to a circular scale.
We compute wt as follow:
wt = 2π ft
where
ft =timet − 0.5
24hours
g(.) = Onsets counts; family: Poisson andscaled S.E (φ=
√χ2/df )
Deriving the amplitude and testing thestatistical significance of the circadian rhythm
Where the Amplitude is derived as follows:
A =√
c2 + s2 , (A ≥ 0)
Then we test the following Null HypothesisThe amplitude is A= 0
Using the following test:Z=nA2
Where:A =
√c2 + s2
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
The cosinor Model: trigonometric regression
Cosinor
The Cosinor model: Generalized Linear Model
g(Y )t = c cos(wt) + s sin(wt)
t=1,...,24.Scaling time to a circular scale.
We compute wt as follow:
wt = 2π ft
where
ft =timet − 0.5
24hours
g(.) = Onsets counts; family: Poisson andscaled S.E (φ=
√χ2/df )
Deriving the amplitude and testing thestatistical significance of the circadian rhythm
Where the Amplitude is derived as follows:
A =√
c2 + s2 , (A ≥ 0)
Then we test the following Null HypothesisThe amplitude is A= 0
Using the following test:Z=nA2
Where:A =
√c2 + s2
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
The cosinor Model: trigonometric regression
Cosinor
The Cosinor model: Generalized Linear Model
g(Y )t = c cos(wt) + s sin(wt)
t=1,...,24.Scaling time to a circular scale.
We compute wt as follow:
wt = 2π ft
where
ft =timet − 0.5
24hours
g(.) = Onsets counts; family: Poisson andscaled S.E (φ=
√χ2/df )
Deriving the amplitude and testing thestatistical significance of the circadian rhythm
Where the Amplitude is derived as follows:
A =√
c2 + s2 , (A ≥ 0)
Then we test the following Null HypothesisThe amplitude is A= 0
Using the following test:Z=nA2
Where:A =
√c2 + s2
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
The cosinor Model: trigonometric regression
Cosinor
The Cosinor model: Generalized Linear Model
g(Y )t = c cos(wt) + s sin(wt)
t=1,...,24.Scaling time to a circular scale.
We compute wt as follow:
wt = 2π ft
where
ft =timet − 0.5
24hours
g(.) = Onsets counts; family: Poisson andscaled S.E (φ=
√χ2/df )
Deriving the amplitude and testing thestatistical significance of the circadian rhythm
Where the Amplitude is derived as follows:
A =√
c2 + s2 , (A ≥ 0)
Then we test the following Null HypothesisThe amplitude is A= 0
Using the following test:Z=nA2
Where:A =
√c2 + s2
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
The cosinor Model: trigonometric regression
Cosinor
The Cosinor model: Generalized Linear Model
g(Y )t = c cos(wt) + s sin(wt)
t=1,...,24.Scaling time to a circular scale.
We compute wt as follow:
wt = 2π ft
where
ft =timet − 0.5
24hours
g(.) = Onsets counts; family: Poisson andscaled S.E (φ=
√χ2/df )
Deriving the amplitude and testing thestatistical significance of the circadian rhythm
Where the Amplitude is derived as follows:
A =√
c2 + s2 , (A ≥ 0)
Then we test the following Null HypothesisThe amplitude is A= 0
Using the following test:Z=nA2
Where:A =
√c2 + s2
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
The cosinor Model: trigonometric regression
Cosinor
The Cosinor model: Generalized Linear Model
g(Y )t = c cos(wt) + s sin(wt)
t=1,...,24.Scaling time to a circular scale.
We compute wt as follow:
wt = 2π ft
where
ft =timet − 0.5
24hours
g(.) = Onsets counts; family: Poisson andscaled S.E (φ=
√χ2/df )
Deriving the amplitude and testing thestatistical significance of the circadian rhythm
Where the Amplitude is derived as follows:
A =√
c2 + s2 , (A ≥ 0)
Then we test the following Null Hypothesis
The amplitude is A= 0Using the following test:
Z=nA2
Where:A =
√c2 + s2
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
The cosinor Model: trigonometric regression
Cosinor
The Cosinor model: Generalized Linear Model
g(Y )t = c cos(wt) + s sin(wt)
t=1,...,24.Scaling time to a circular scale.
We compute wt as follow:
wt = 2π ft
where
ft =timet − 0.5
24hours
g(.) = Onsets counts; family: Poisson andscaled S.E (φ=
√χ2/df )
Deriving the amplitude and testing thestatistical significance of the circadian rhythm
Where the Amplitude is derived as follows:
A =√
c2 + s2 , (A ≥ 0)
Then we test the following Null HypothesisThe amplitude is A= 0
Using the following test:
Z=nA2
Where:A =
√c2 + s2
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
The cosinor Model: trigonometric regression
Cosinor
The Cosinor model: Generalized Linear Model
g(Y )t = c cos(wt) + s sin(wt)
t=1,...,24.Scaling time to a circular scale.
We compute wt as follow:
wt = 2π ft
where
ft =timet − 0.5
24hours
g(.) = Onsets counts; family: Poisson andscaled S.E (φ=
√χ2/df )
Deriving the amplitude and testing thestatistical significance of the circadian rhythm
Where the Amplitude is derived as follows:
A =√
c2 + s2 , (A ≥ 0)
Then we test the following Null HypothesisThe amplitude is A= 0
Using the following test:Z=nA2
Where:A =
√c2 + s2
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
The cosinor Model: trigonometric regression
Cosinor
The Cosinor model: Generalized Linear Model
g(Y )t = c cos(wt) + s sin(wt)
t=1,...,24.Scaling time to a circular scale.
We compute wt as follow:
wt = 2π ft
where
ft =timet − 0.5
24hours
g(.) = Onsets counts; family: Poisson andscaled S.E (φ=
√χ2/df )
Deriving the amplitude and testing thestatistical significance of the circadian rhythm
Where the Amplitude is derived as follows:
A =√
c2 + s2 , (A ≥ 0)
Then we test the following Null HypothesisThe amplitude is A= 0
Using the following test:Z=nA2
Where:A =
√c2 + s2
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
The cosinor Model: trigonometric regression
Cosinor
The Cosinor model: Generalized Linear Model
g(Y )t = c cos(wt) + s sin(wt)
t=1,...,24.Scaling time to a circular scale.
We compute wt as follow:
wt = 2π ft
where
ft =timet − 0.5
24hours
g(.) = Onsets counts; family: Poisson andscaled S.E (φ=
√χ2/df )
Deriving the amplitude and testing thestatistical significance of the circadian rhythm
Where the Amplitude is derived as follows:
A =√
c2 + s2 , (A ≥ 0)
Then we test the following Null HypothesisThe amplitude is A= 0
Using the following test:Z=nA2
Where:A =
√c2 + s2
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
The cosinor Model: trigonometric regression
Cosinor
The Cosinor model: Generalized Linear Model
g(Y )t = c cos(wt) + s sin(wt)
t=1,...,24.Scaling time to a circular scale.
We compute wt as follow:
wt = 2π ft
where
ft =timet − 0.5
24hours
g(.) = Onsets counts; family: Poisson andscaled S.E (φ=
√χ2/df )
Deriving the amplitude and testing thestatistical significance of the circadian rhythm
Where the Amplitude is derived as follows:
A =√
c2 + s2 , (A ≥ 0)
Then we test the following Null HypothesisThe amplitude is A= 0
Using the following test:Z=nA2
Where:A =
√c2 + s2
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
Amplitude
One cycle per 2π units of time
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
Preterm Premature Rupture of Membranes in Lima, Peru, n= 232
c©MA Luque-Fernandez et al., non published data. Under review
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
Preterm Premature Rupture of Membranes in Lima, Peru, n= 232
c©MA Luque-Fernandez et al., non published data. Under review
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
Placental Abruption cases, in Lima, Peru, n= 163
c©MA Luque-Fernandez et al., non published data. Under review
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
Placental Abruption cases, in Lima, Peru, n= 163
c©MA Luque-Fernandez et al., non published data. Under review
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
NCPP REPLICATION
NCPP REPLICATION
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
Description of the NCCP study
The US National Collaborative Perinatal Project (NCPP)
This study was a prospective cohort study of 60,000 pregnantwomen between 1959-1966.
The NCPP was specifically designed to identify determinants ofcerebral palsy and other neurological defects.
We applied the same restriction as we did with the Peruvian data toobtain (2,262 PPROM and 374 PA cases).
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
Description of the NCCP study
The US National Collaborative Perinatal Project (NCPP)
This study was a prospective cohort study of 60,000 pregnantwomen between 1959-1966.
The NCPP was specifically designed to identify determinants ofcerebral palsy and other neurological defects.
We applied the same restriction as we did with the Peruvian data toobtain (2,262 PPROM and 374 PA cases).
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
Description of the NCCP study
The US National Collaborative Perinatal Project (NCPP)
This study was a prospective cohort study of 60,000 pregnantwomen between 1959-1966.
The NCPP was specifically designed to identify determinants ofcerebral palsy and other neurological defects.
We applied the same restriction as we did with the Peruvian data toobtain (2,262 PPROM and 374 PA cases).
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
Description of the NCCP study
The US National Collaborative Perinatal Project (NCPP)
This study was a prospective cohort study of 60,000 pregnantwomen between 1959-1966.
The NCPP was specifically designed to identify determinants ofcerebral palsy and other neurological defects.
We applied the same restriction as we did with the Peruvian data toobtain (2,262 PPROM and 374 PA cases).
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
PA ≥37 gestation weeks
NCCP TERM PA cases
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
TERM Placental Abruption NCPP, n= 231
Term spontaneous, singleton PA cases, (N=231, >=37 gestation weeks)
Circadian Test p-value <0.050
5
10
15
20
No
PA
cas
es
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Time in 24 hours
c©MA Luque-Fernandez et al., non published data. Under review
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
ResultsReplication: NCPP study
DISCUSSION
DISCUSSION
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Main findings
Disruption of Circadian Rhythms
We found a significant diurnal circadian pattern in the timing of theonset of PPROM cases and some evidence among term PA cases inLima, Peru.
We did not find evidence of a circadian pattern among cases of veryand extremely PPROM and PA.
NCPP replication analysis confirm our main findings.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Main findings
Disruption of Circadian Rhythms
We found a significant diurnal circadian pattern in the timing of theonset of PPROM cases and some evidence among term PA cases inLima, Peru.
We did not find evidence of a circadian pattern among cases of veryand extremely PPROM and PA.
NCPP replication analysis confirm our main findings.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Main findings
Disruption of Circadian Rhythms
We found a significant diurnal circadian pattern in the timing of theonset of PPROM cases and some evidence among term PA cases inLima, Peru.
We did not find evidence of a circadian pattern among cases of veryand extremely PPROM and PA.
NCPP replication analysis confirm our main findings.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Main findings
Disruption of Circadian Rhythms
We found a significant diurnal circadian pattern in the timing of theonset of PPROM cases and some evidence among term PA cases inLima, Peru.
We did not find evidence of a circadian pattern among cases of veryand extremely PPROM and PA.
NCPP replication analysis confirm our main findings.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
LIMITATIONS
LIMITATIONS
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Limitations
Limitations
Measurement error due to maternal self-reports starting signs andsymptoms.
High specificity for severe cases of PPROM and PA thoughcompromise in sensitivity for mild PA and PPROM cases.
The circadian test is dependent on the sample size.
Need of more replication studies in other geographic regions andpopulations.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Limitations
Limitations
Measurement error due to maternal self-reports starting signs andsymptoms.
High specificity for severe cases of PPROM and PA thoughcompromise in sensitivity for mild PA and PPROM cases.
The circadian test is dependent on the sample size.
Need of more replication studies in other geographic regions andpopulations.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Limitations
Limitations
Measurement error due to maternal self-reports starting signs andsymptoms.
High specificity for severe cases of PPROM and PA thoughcompromise in sensitivity for mild PA and PPROM cases.
The circadian test is dependent on the sample size.
Need of more replication studies in other geographic regions andpopulations.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Limitations
Limitations
Measurement error due to maternal self-reports starting signs andsymptoms.
High specificity for severe cases of PPROM and PA thoughcompromise in sensitivity for mild PA and PPROM cases.
The circadian test is dependent on the sample size.
Need of more replication studies in other geographic regions andpopulations.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Limitations
Limitations
Measurement error due to maternal self-reports starting signs andsymptoms.
High specificity for severe cases of PPROM and PA thoughcompromise in sensitivity for mild PA and PPROM cases.
The circadian test is dependent on the sample size.
Need of more replication studies in other geographic regions andpopulations.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
INTERPRETATION
INTERPRETATION
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Interpretation
Interpretation
Our findings are consistent with previous evidence and may beexplained by a biological mechanism (HPA-axis).
The fetal immaturity of the HPA-axis may account for the absenceof circadian rhythms in extremely preterm deliveries.
Other mechanisms driven by infection (chorioamnionitis) andinflammation may explain the triggering of parturition in extremelyand very preterm cases.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Interpretation
Interpretation
Our findings are consistent with previous evidence and may beexplained by a biological mechanism (HPA-axis).
The fetal immaturity of the HPA-axis may account for the absenceof circadian rhythms in extremely preterm deliveries.
Other mechanisms driven by infection (chorioamnionitis) andinflammation may explain the triggering of parturition in extremelyand very preterm cases.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Interpretation
Interpretation
Our findings are consistent with previous evidence and may beexplained by a biological mechanism (HPA-axis).
The fetal immaturity of the HPA-axis may account for the absenceof circadian rhythms in extremely preterm deliveries.
Other mechanisms driven by infection (chorioamnionitis) andinflammation may explain the triggering of parturition in extremelyand very preterm cases.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Interpretation
Interpretation
Our findings are consistent with previous evidence and may beexplained by a biological mechanism (HPA-axis).
The fetal immaturity of the HPA-axis may account for the absenceof circadian rhythms in extremely preterm deliveries.
Other mechanisms driven by infection (chorioamnionitis) andinflammation may explain the triggering of parturition in extremelyand very preterm cases.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
CONCLUSIONS
CONCLUSIONS
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Conclusions
Conclusions
The time of onset of very PPROM and preterm PA cases ischaracterized by a disrupted circadian pattern.
This disrupted circadian pattern underlies other pathologicalmechanisms associated with the time of onset of PPROM and PAcase rather than a normal biological circadian rhythm.
The disrupted circadian pattern driven by fetal immaturity may helpto explain tocolytic failure to prevent delivery of very and extremelyPPROM cases.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Conclusions
Conclusions
The time of onset of very PPROM and preterm PA cases ischaracterized by a disrupted circadian pattern.
This disrupted circadian pattern underlies other pathologicalmechanisms associated with the time of onset of PPROM and PAcase rather than a normal biological circadian rhythm.
The disrupted circadian pattern driven by fetal immaturity may helpto explain tocolytic failure to prevent delivery of very and extremelyPPROM cases.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Conclusions
Conclusions
The time of onset of very PPROM and preterm PA cases ischaracterized by a disrupted circadian pattern.
This disrupted circadian pattern underlies other pathologicalmechanisms associated with the time of onset of PPROM and PAcase rather than a normal biological circadian rhythm.
The disrupted circadian pattern driven by fetal immaturity may helpto explain tocolytic failure to prevent delivery of very and extremelyPPROM cases.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Conclusions
Conclusions
The time of onset of very PPROM and preterm PA cases ischaracterized by a disrupted circadian pattern.
This disrupted circadian pattern underlies other pathologicalmechanisms associated with the time of onset of PPROM and PAcase rather than a normal biological circadian rhythm.
The disrupted circadian pattern driven by fetal immaturity may helpto explain tocolytic failure to prevent delivery of very and extremelyPPROM cases.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
References
Some important references
1 A. G. Barnett, A. J. Dobson, E. Library., Analyzing seasonal health data,Springer, 2010.
2 N. I. Fisher, Statistical analysis of circular data, Cambridge University Press,Cambridge, 1993.
3 P. Bloomfield, Fourier analysis of time series: an introduction, 2nd Edition,Wiley series in probability and statistics Applied probability and statistics,Wiley, New York ; Chichester, 2000.
4 T. W. Korner, Fourier analysis, Cambridge University Press, Cambridge, 1988
5 J. W. Hardin, J. Hilbe, Generalized linear models and extensions, 3rdEdition, Stata Press, College Station, Tex., 2012.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Acknowledgments
Acknowledgments
Professor Michelle A. Williams. Chair of the EpidemiologyDepartment, Harvard School of Public Health.
Dr.Bizu Gelaye, Director of the MIRT program, EpidemiologyDepartment, Harvard School of Public Health.
Rose Traveling Fellowship Program in Chronic Disease Epidemiologyand Biostatistics.
Dr. Unnur Valdimoarsdottir, Center of Public Health Sciences,Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Dr. Sixto Sanchez, AC. PROESA and the Instituto NacionalMaterno Perinatal, Lima, Peru.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Thank You
Alhambra: Granada, Spain
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Methods: Case definitions ICD-10
Case definition based on
ICD-10 O42 (PPROM) and O45 (PA).
ICD-10-O42 (PPROM): Spontaneous tearing of the membranessurrounding the fetus any time before the onset of obstetric laborprior 37 gestation weeks. Rupture of membranes will show poolingof fluid in the vagina or leakage of fluid from the cervix.
ICD-10-O45 (PA): Premature separation of the normally implantedplacenta from the uterus. Signs of varying degree of severity includeuterine bleeding, uterine muscle hypertonia, and fetal distress orfetal death.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Methods: Case definitions ICD-10
Case definition based on
ICD-10 O42 (PPROM) and O45 (PA).
ICD-10-O42 (PPROM): Spontaneous tearing of the membranessurrounding the fetus any time before the onset of obstetric laborprior 37 gestation weeks. Rupture of membranes will show poolingof fluid in the vagina or leakage of fluid from the cervix.
ICD-10-O45 (PA): Premature separation of the normally implantedplacenta from the uterus. Signs of varying degree of severity includeuterine bleeding, uterine muscle hypertonia, and fetal distress orfetal death.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Methods: Case definitions ICD-10
Case definition based on
ICD-10 O42 (PPROM) and O45 (PA).
ICD-10-O42 (PPROM): Spontaneous tearing of the membranessurrounding the fetus any time before the onset of obstetric laborprior 37 gestation weeks. Rupture of membranes will show poolingof fluid in the vagina or leakage of fluid from the cervix.
ICD-10-O45 (PA): Premature separation of the normally implantedplacenta from the uterus. Signs of varying degree of severity includeuterine bleeding, uterine muscle hypertonia, and fetal distress orfetal death.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Methods: Case definitions ICD-10
Case definition based on
ICD-10 O42 (PPROM) and O45 (PA).
ICD-10-O42 (PPROM): Spontaneous tearing of the membranessurrounding the fetus any time before the onset of obstetric laborprior 37 gestation weeks. Rupture of membranes will show poolingof fluid in the vagina or leakage of fluid from the cervix.
ICD-10-O45 (PA): Premature separation of the normally implantedplacenta from the uterus. Signs of varying degree of severity includeuterine bleeding, uterine muscle hypertonia, and fetal distress orfetal death.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Preterm PROM Placental AbruptionTime in 24h n % n %01h:00’ 10 4.3 5 3.102h:00’ 6 2.6 14 8.603h:00’ 11 4.7 4 2.504h:00’ 0 0.0 1 0.605h:00’ 15 6.5 5 3.106h:00’ 26 11.2 12 7.407h:00’ 14 6.0 11 6.808h:00’ 17 7.3 13 8.009h:00’ 9 3.9 10 6.110h:00’ 27 11.6 5 3.111h:00’ 7 3.0 7 4.312h:00’ 8 3.5 6 3.713h:00’ 4 1.7 5 3.114h:00’ 7 3.0 4 2.515h:00’ 5 2.2 10 6.116h:00’ 8 3.5 5 3.117h:00’ 8 3.5 3 1.818h:00’ 9 3.9 4 2.519h:00’ 2 0.9 9 5.520h:00’ 13 5.6 6 3.721h:00’ 5 2.2 8 4.922h:00’ 12 5.2 8 4.923h:00’ 6 2.6 5 3.124h:00’ 3 1.3 3 1.8
Table: Counts of preterm PROM and PA onsets by hour per day, in Lima, Peru,2009-2010 (Preterm PROM, n=232 and Placental Abruption, n= 163)
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Preterm PROM Placental AbruptionTime in 24h n % n %01h:00’ 10 4.3 5 3.102h:00’ 6 2.6 14 8.603h:00’ 11 4.7 4 2.504h:00’ 0 0.0 1 0.605h:00’ 15 6.5 5 3.106h:00’ 26 11.2 12 7.407h:00’ 14 6.0 11 6.808h:00’ 17 7.3 13 8.009h:00’ 9 3.9 10 6.110h:00’ 27 11.6 5 3.111h:00’ 7 3.0 7 4.312h:00’ 8 3.5 6 3.713h:00’ 4 1.7 5 3.114h:00’ 7 3.0 4 2.515h:00’ 5 2.2 10 6.116h:00’ 8 3.5 5 3.117h:00’ 8 3.5 3 1.818h:00’ 9 3.9 4 2.519h:00’ 2 0.9 9 5.520h:00’ 13 5.6 6 3.721h:00’ 5 2.2 8 4.922h:00’ 12 5.2 8 4.923h:00’ 6 2.6 5 3.124h:00’ 3 1.3 3 1.8
Table: Counts of preterm PROM and PA onsets by hour per day, in Lima, Peru,2009-2010 (Preterm PROM, n=232 and Placental Abruption, n= 163)
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
PPROM onsets
Distribution of preterm PROM onsets by segment of the day and gestation weeks, in Lima,Peru, 2009-2010 (Preterm PROM, n=232)
Preterm Premature Rupture of Membranes (n= 232)(≥32-<37 weeks, n=154) (<32 weeks, n=78)
Segments of the day n(%) PR*(95%CI) n(%) PR(95%CI)Night01h:00’ to 06h:00’ 50(32.5) 1.64(1.39, 1.94) 18(23.1) 1.45(1.16, 1.83)Morning07h:00’ to 12:00’ 56(36.4) 1.67(1.45, 1.92) 26(33.3) 1.47(1.24, 1.75)Afternoon13h:00’ to 18h:00’ 25(16.2) 0.76(0.67, 0.88) 16(20.5) 0.74(0.65, 0.85)Evening/night19h:00’ to 24h:00’ 23(14.9) Ref. 18(23.1) Ref.* PR: Prevalence Ratio
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
PPROM onsets
Distribution of preterm PROM onsets by segment of the day and gestation weeks, in Lima,Peru, 2009-2010 (Preterm PROM, n=232)
Preterm Premature Rupture of Membranes (n= 232)(≥32-<37 weeks, n=154) (<32 weeks, n=78)
Segments of the day n(%) PR*(95%CI) n(%) PR(95%CI)Night01h:00’ to 06h:00’ 50(32.5) 1.64(1.39, 1.94) 18(23.1) 1.45(1.16, 1.83)Morning07h:00’ to 12:00’ 56(36.4) 1.67(1.45, 1.92) 26(33.3) 1.47(1.24, 1.75)Afternoon13h:00’ to 18h:00’ 25(16.2) 0.76(0.67, 0.88) 16(20.5) 0.74(0.65, 0.85)Evening/night19h:00’ to 24h:00’ 23(14.9) Ref. 18(23.1) Ref.* PR: Prevalence Ratio
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Assessing Periodicity: Periodogram
Number of cycles in 2π time
The periodogram I(wj) is always positive,and it will be larger at frequencies thatare strongly represented in the data.Therefore the number of time pointsneeded to complete a cycle of 2π couldbe computed as the inverse of theFourier frequency using:
1/fj =2π
wj
Formulae
I (wj) =2
n(C 2 + S2) j = 1, ...n/2
C 2 = 2n∑
t=1
yt cos(wj t)/n,
S2 = 2n∑
t=1
yt sin(wj t)/n,
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Assessing Periodicity: Periodogram
Number of cycles in 2π time
The periodogram I(wj) is always positive,and it will be larger at frequencies thatare strongly represented in the data.Therefore the number of time pointsneeded to complete a cycle of 2π couldbe computed as the inverse of theFourier frequency using:
1/fj =2π
wj
Formulae
I (wj) =2
n(C 2 + S2) j = 1, ...n/2
C 2 = 2n∑
t=1
yt cos(wj t)/n,
S2 = 2n∑
t=1
yt sin(wj t)/n,
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Example
Periodogram of 25OHD serum concentrations and highest frequency
0.083 Highest frequency: Annual cycle (12 months)
-6.0
0-4
.00
-2.0
00.
002.
004.
006.
00
Tot
al 2
5OH
D le
vel
Log
Per
iodo
gram
0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50
Frequency
Evaluated at the natural frequencies
c©MA Luque-Fernandez et al.Seasonal Variation of 25-Hydroxyvitamin D among non-Hispanic Black and White PregnantWomen from Three US Pregnancy Cohorts. Pediatrics and Perinatal Epidemiology 2013
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Sine and Cosine
Sine and Cosine functions
The steady rise-and-fall of the cosine and sine functions makes themideal for modeling seasonality or circadian patterns.
This rise-and-fall pattern is repeat.
This repeating property of the sine and cosine functions means thatwe only need to consider times from 0 to ≤ 2π.
Circular Time
The value of 2π is a key constant because it is the circumference of circlewith radius 1.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Sine and Cosine
Sine and Cosine functions
The steady rise-and-fall of the cosine and sine functions makes themideal for modeling seasonality or circadian patterns.
This rise-and-fall pattern is repeat.
This repeating property of the sine and cosine functions means thatwe only need to consider times from 0 to ≤ 2π.
Circular Time
The value of 2π is a key constant because it is the circumference of circlewith radius 1.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Sine and Cosine
Sine and Cosine functions
The steady rise-and-fall of the cosine and sine functions makes themideal for modeling seasonality or circadian patterns.
This rise-and-fall pattern is repeat.
This repeating property of the sine and cosine functions means thatwe only need to consider times from 0 to ≤ 2π.
Circular Time
The value of 2π is a key constant because it is the circumference of circlewith radius 1.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Sine and Cosine
Sine and Cosine functions
The steady rise-and-fall of the cosine and sine functions makes themideal for modeling seasonality or circadian patterns.
This rise-and-fall pattern is repeat.
This repeating property of the sine and cosine functions means thatwe only need to consider times from 0 to ≤ 2π.
Circular Time
The value of 2π is a key constant because it is the circumference of circlewith radius 1.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Sine and Cosine
Sine and Cosine functions
The steady rise-and-fall of the cosine and sine functions makes themideal for modeling seasonality or circadian patterns.
This rise-and-fall pattern is repeat.
This repeating property of the sine and cosine functions means thatwe only need to consider times from 0 to ≤ 2π.
Circular Time
The value of 2π is a key constant because it is the circumference of circlewith radius 1.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Sine and Cosine Functions
One cycle per 2π units of time Two cycles per 4π units of time
-1-.
50
.51
0 p/2 p 3p/2 2p
TIME (x)
sine
cosine
c©MA Luque-Fernandez
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Sine and Cosine Functions
One cycle per 2π units of time Two cycles per 4π units of time
-1-.
50
.51
0 p/2 p 3p/2 2p
TIME (x)
sine
cosine
c©MA Luque-Fernandez
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Results: assessing periodicity
Kernel smoother and Fourier Transformation
We used a non-parametric EPANECHNIKOV Kernel densityestimation to estimate the probability density function of PPROMand PA cases over time (24 hours).
We used an OPTIMAL smoothing parameter because its densityestimate is close to the true density.
Fourier transformation (Periodogram).Transformation of time in a wave of sine and cosine functions inorder to identify the higher frequency of the observed data, andtherefore to identify a periodicity.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Results: assessing periodicity
Kernel smoother and Fourier Transformation
We used a non-parametric EPANECHNIKOV Kernel densityestimation to estimate the probability density function of PPROMand PA cases over time (24 hours).
We used an OPTIMAL smoothing parameter because its densityestimate is close to the true density.
Fourier transformation (Periodogram).
Transformation of time in a wave of sine and cosine functions inorder to identify the higher frequency of the observed data, andtherefore to identify a periodicity.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Results: assessing periodicity
Kernel smoother and Fourier Transformation
We used a non-parametric EPANECHNIKOV Kernel densityestimation to estimate the probability density function of PPROMand PA cases over time (24 hours).
We used an OPTIMAL smoothing parameter because its densityestimate is close to the true density.
Fourier transformation (Periodogram).Transformation of time in a wave of sine and cosine functions inorder to identify the higher frequency of the observed data, andtherefore to identify a periodicity.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Results: assessing periodicity
Kernel smoother and Fourier Transformation
We used a non-parametric EPANECHNIKOV Kernel densityestimation to estimate the probability density function of PPROMand PA cases over time (24 hours).
We used an OPTIMAL smoothing parameter because its densityestimate is close to the true density.
Fourier transformation (Periodogram).Transformation of time in a wave of sine and cosine functions inorder to identify the higher frequency of the observed data, andtherefore to identify a periodicity.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Sensitivity analysis: cosinor vs. the best good need of fit.
Restricted Cubic spline function with K knots
f (x) =3∑
j=0
β0jxj +
k∑k=1
βi (x − tk)3
yi = f (xi ) + εi
Different number of Knots were placed at regularly spaced intervals (two hours, four and sixhours).
Polynomial trigonometric regression
Yi = β0 + β1 sin(wt) + β2 cos(wt) + β3 sin2(wt) + β4 cos
2(wt) + (...) + βdxd + εi
The number of trigonometric terms in the polynomial regression was selected using a k-foldcross validation strategy.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Sensitivity analysis: cosinor vs. the best good need of fit.
Restricted Cubic spline function with K knots
f (x) =3∑
j=0
β0jxj +
k∑k=1
βi (x − tk)3
yi = f (xi ) + εi
Different number of Knots were placed at regularly spaced intervals (two hours, four and sixhours).
Polynomial trigonometric regression
Yi = β0 + β1 sin(wt) + β2 cos(wt) + β3 sin2(wt) + β4 cos
2(wt) + (...) + βdxd + εi
The number of trigonometric terms in the polynomial regression was selected using a k-foldcross validation strategy.
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Moderate PPROM 32 to 36 gestation weeks
NCCP MODERATE PPROM CASES (32 to 36 gestation weeks)
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Moderate Preterm Premature Rupture of Membranes NCPP, n= 1736
NCPP spontaneous singleton PPROM cases, (N=1736, 32 to 36 gestation weeks)
Circadian Test p-value <0.0140
60
80
100
120
No
of P
PR
OM
cas
es
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Time in 24 hours
c©MA Luque-Fernandez et al., non published data. Under review
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
PPROM <32 gestation weeks
NCCP EXTREMELY AND VERY PPROM CASES (<32 gestationweeks)
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Extremely and Very Preterm Premature Rupture of Membranes NCPP, n= 526
Circadian Test p-value >0.05
NCPP PPROM spontaneous singleton cases,(N= 526, <32 gestation weeks)
10
15
20
25
30
35N
o P
PR
OM
cas
es
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Time in 24 hours
c©MA Luque-Fernandez et al., non published data. Under review
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
MODERATE PRETERM PA 32 to 36 gestation weeks
NCCP MODERATE PRETERM PAcases
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Moderate Preterm Placental Abruption NCPP, n= 83
NCPP Preterm spontaneous singleton PA cases, (N=83, 32 to 36 gestation weeks)
Circadian Test p-value >0.050
2
4
6
8
10N
o P
A c
ases
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Time in 24 hours
c©MA Luque-Fernandez et al., non published data. Under review
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
PA <32 gestation weeks
NCCP EXTREMELY AND VERYPRETERM PA cases
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM
BackgroundMethods
ResultsDiscussion
Main findingsLimitationsInterpretationConclusions
Extremely and Very Placental Abruption cases, NCPP, n= 60
NCPP spontaneous singleton PA cases, (N=60, <32 gestation weeks)
Circadian Test p-value >0.050
2
4
6N
o P
A c
ases
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Time in 24 hours
c©MA Luque-Fernandez et al., non published data. Under review
HSPH-Department of Epidemiology Disruption of Circadian Rhythms of preterm PA and PPROM