Are negative findings all down to confounding factors?
-
Upload
yasir-hameed -
Category
Education
-
view
32 -
download
0
description
Transcript of Are negative findings all down to confounding factors?
![Page 1: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/1.jpg)
Are negative findings all down to
confounding factors?
Irene Petersen, PhD
Primary Care & Population Health
![Page 2: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/2.jpg)
Introduction
• Reader (Statistics and Epidemiology)
• Research team epidemiologists/statisticians/PhD students
• Primary care databases THIN and CPRD - 60+ studies
• Research topics
– Prescribed medicine in pregnancy
– Mental health
– Methodological questions
• Missing data
• Regression Discontinuity Design (RDD)
• Confounding (by indication)
• http://www.ucl.ac.uk/pcph/research-groups-themes/thin-pub/
• Or just google THIN UCL
![Page 3: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/3.jpg)
Acknowledgments and funding
• Serious team work – Irwin Nazareth
– Stephen Evans
– Shuk Li Man
– Rachel McCrea
– and many others….
• Funding: MRC, National School of Primary Care
Research, NIHR, HTA
• No funding from companies producing psychotropic
medication
![Page 4: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/4.jpg)
Today
• Antidepressants and pregnancy – do they cause
autism?
• What are the consequences?
![Page 5: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/5.jpg)
Antidepressants and pregnancy – do they
cause autism?
• It is a good question!
![Page 6: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/6.jpg)
What do we know….
• Number of women in child bearing age on
antidepressants is increasing
However, few women continue antidepressants in
pregnancy (come back to this later)
• Number of children diagnosed with autism is
increasing
![Page 7: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/7.jpg)
Autism
• Spectrum
• Cause is still unclear
• Exposure in childhood
– For many years focus
was on MMR
– No link to MMR
![Page 8: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/8.jpg)
Link between antidepressants in pregnancy
and autism??
![Page 9: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/9.jpg)
Is this another red herring?
![Page 10: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/10.jpg)
Before we start to make causal links between
antidepressants and autism….
• Genetics
• Indication for treatment
– Depression/Anxiety
• Other characteristics of
the women
![Page 11: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/11.jpg)
The genetic link
• Hypothesis:
• Same genes may predispose depression/anxiety
and autism
![Page 12: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/12.jpg)
Children of depressive/anxious mothers
• Hypothesis:
• Pregnancy exposure
– Depression/anxiety has a negative impact on the
unborn child
• Early childhood exposure
– Depression/anxious in mothers may ‘trigger’ autism
![Page 13: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/13.jpg)
Other factors/characteristics
• Hypothesis
• Other factors/characteristics may cause autism
![Page 14: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/14.jpg)
So let’s take a look at antidepressant prescribing
in pregnancy
• The Health Improvement Network (THIN)
• Primary care database
• 5% of UK population
• Drugs prescribed in primary care
• Diagnosis and symptoms (Read codes)
• Cohort of pregnant women and their children
– Household Id
– Child birth and delivery date
![Page 15: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/15.jpg)
Antidepressants in pregnancy
• Identified women who were on antidepressants
• Time to last prescription
– Pregnant women
– Non-pregnant women
![Page 16: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/16.jpg)
Time to last antidepressant prescription
0.0
00
.25
0.5
00
.75
1.0
0
start six weeks 2nd trimester 3rd trimester
non-pregnant pregnant
Time to last prescription
• Many women stop antidepressants once they are
aware of the pregnancy
• Before pregnancy
HR 1.70 (95% CI: 1.62 to 1.70)
• First six weeks
HR 5.19 (95% CI: 4.85 to 5.56)
• Rest of pregnancy
HR 1.57 (95% CI: 1.45 to 1.71)
35%
10%
65%
Petersen et al (2011) Pregnancy - a major determinant for discontinuation of antidepressants. Journal
Clinical Psychiatry
![Page 17: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/17.jpg)
This suggests
• Pregnant women more likely to discontinue
antidepressants and they do so early in pregnancy
• There are serious concerns about safety of
antidepressant prescribing in pregnancy
• Women who continue antidepressants in
pregnancy may be different from those who stop
![Page 18: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/18.jpg)
Factors associated with discontinuation of
antidepressants in pregnancy – who stop?
• Those with limited prior experience
– HR 1.73 (95% CI: 1.63 to 1.84) for 0-1 Rx vs. 2+ Rx
• Younger women more likely to stop
– HR 1.31 (95% CI 1.19 to 1.43) for 15-24 year vs. 35+
– HR 1.15 (95% CI 1.06 to 1.24) for 25-35 vs. 35+
![Page 19: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/19.jpg)
Later we examined this in more detail…
• Cohorts of women
• Women who received Rx of SSRIs in 1st trimester
• Women who received Rx before pregnancy
• Women NOT on SSRI before or in pregnancy
![Page 20: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/20.jpg)
Characteristics of women on antidepressant
treatment in pregnancy in more detail
Three cohorts:
Not on antidepressants (N = 200,213)
On SSRI in before pregnancy (N= 5,154)
On SSRI in 1st trimester (N = 2,776)
![Page 21: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/21.jpg)
Characteristics of pregnant women
Not on SSRI
(%)
On SSRI
before
(%)
On SSRI in
pregnancy
(%)
N 200,213 5,154 2,776
Diabetics 5,188 (2.6) 178 (3.5) 127 (4.6)
Alcohol problems 735 (0.4) 80 (1.6) 114 (4.1)
Illicit drug 867 (0.4) 83 (1.6) 118 (4.3)
Smoking 39,358 (19.7) 1,625 (31.5) 984 (35.5)
Obese 9,782 (4.9) 426 (8.3) 296 (10.7)
![Page 22: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/22.jpg)
Women who continued antidepressant
treatment in pregnancy
• Also more likely to be prescribed other
psychotropic medication
– Anxiolytics
– Hypnotics
– Antipsychotics
– AED
• Although it is a small proportion of women on
multiple drugs in pregnancy
![Page 23: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/23.jpg)
Link between antidepressants in pregnancy
and autism??
![Page 24: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/24.jpg)
Link between antidepressants in pregnancy
and autism??
![Page 25: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/25.jpg)
Link between antidepressants in pregnancy
and autism??
![Page 26: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/26.jpg)
Before we can make link….
Other factors
Genetics
Antidepressants Autism
in pregnancy
![Page 27: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/27.jpg)
Before we can make link we have to exclude
the indication for treatment Other factors
Genetics
Depression
Antidepressants Autism
in pregnancy
![Page 28: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/28.jpg)
Before we can make link we have to exclude
the genetic component Other factors
Genetics
Depression
Antidepressants Autism
in pregnancy
![Page 29: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/29.jpg)
Before we can make link we have to exclude
other factors Other factors
Genetics
Depression
Antidepressants Autism
in pregnancy
![Page 30: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/30.jpg)
Is it all down to confounding factors?
• I don’t know
• Need to be much more cautious about making a
link
• Confounding is a serious issue in observational
data
![Page 31: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/31.jpg)
The risk of communicating risk….
• Just a few words about communication of risk
![Page 32: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/32.jpg)
Think about the message we communicate to
pregnant women
• What does a relative risk of 1.5 mean?
• 50% increased risk
• In absolute terms:
• 10 out of 10 000 children (9990 without) versus
• 15 out of 10 000 children (9985 without)
![Page 33: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/33.jpg)
Need to think about how women perceive the
risk?
![Page 34: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/34.jpg)
Need to think about the consequences of
stopping antidepressants in pregnancy
• Some women may be fine without antidepressants
• Others may not….
![Page 35: Are negative findings all down to confounding factors?](https://reader035.fdocuments.us/reader035/viewer/2022081403/555cb13fd8b42ab2358b5388/html5/thumbnails/35.jpg)
How do we weigh up risks and benefits?
Guilt
Depression
Autism
Anxiety
Self medication
Antidepressants