Online Appendix 1: Systematic review search strategy We used

Online Appendix 1: Systematic review search strategy
We used Medline (Ovid MEDLINE 1950 to July 2009 and updated to May 2012) and EMBASE
(Ovid EMBASE 1980 to July 2009). In addition we searched for additional studies by checking
the bibliographies of papers, scanned relevant conference abstracts and by discussion with
selected researchers to identify unpublished studies
Database: MEDLINE
1. Pulse/cl, mt, an, is, ae, ct, td, mo, ut, ph [Classification, Methods, Analysis, Instrumentation,
Adverse Effects, Contraindications, Trends, Mortality, Utilization, Physiology]
2. Aorta/us, ab, ul, ph, pa, an, pp [Ultrasonography, Abnormalities, Ultrastructure, Physiology,
Pathology, Analysis, Physiopathology]
3. Elasticity/st, ph, mt, is [Standards, Physiology, Methods, Instrumentation]
4. Blood Flow Velocity/mt, st, ae, is, ut, ph, an [Methods, Standards, Adverse Effects,
Instrumentation, Utilization, Physiology, Analysis]
5. aortic stiff$.tw.
6. arterial stiff$.tw.
7. Pulsatile Flow/ph [Physiology]
8. pulse wave
9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8
10. Follow-Up Studies/
11 Cohort Studies/
12. Prospective Studies/
13. "Predictive Value of Tests"/
14. Survival Analysis/
15. Mortality/
16. 10 or 11 or 12 or 13 or 14 or 15
17. Coronary Disease/di, ph, mo, et, pp, pa, ep [Diagnosis, Physiology, Mortality, Etiology,
Physiopathology, Pathology, Epidemiology]
18. Cardiovascular Diseases/pp, pa, di, ph, et, mo, ep, co [Physiopathology, Pathology,
Diagnosis, Physiology, Etiology, Mortality, Epidemiology, Complications]
19. Arteriosclerosis/pp [Physiopathology]
20. Hypertension/pp, co, et, mo, ep, ph, pa [Physiopathology, Complications, Etiology,
Mortality, Epidemiology, Physiology, Pathology]
21. 17 or 18 or 19 or 20
22. 9 and 16 and 21
23. limit 22 to humans
Database: Ovid EMBASE
1. pulse wave or pulse wave/
2. exp cardiovascular disease/
3. major clinical study/
4. 1 and 2 and 3
5. limit 4 to humans
Online Appendix 2: Sources of funding and approvals for individual studies
Caerphilly Prospective Study (CaPS): The Caerphilly cohort was set up by The MRC
Epidemiology unit, South Wales (intra-mural funding) by Prof. Peter Elwood and colleagues.
The British Heart Foundation funded the new collection of data on pulse wave velocity. The
School of Social and Community Medicine, University of Bristol maintain the data archive.
Ethical approval for phase V which collected the PWV data was obtained from Gwent Research
Ethics Committee. Mortality data are provided through record linkage from the Health and
Social Care Information Centre of the National Health Centre.
Baltimore Longitudinal Study of Aging (BLSA): The BLSA is funded by the Intramural
Research Program of the National Institute on Aging, National Institutes of Health. The study is
approved by the Institutional Review Board of the MedStar Health Research Institute
Broussais study (Boutouyrie et al. Hypertension 2002): French Medicine Agency (1996) and
INSERM (1996-2002) and following institutional guidelines.
Belgian Transplant Cohort (Verbeke et al. 2011): The study was approved by the local
research ethics committee
CORD (Verbeke et al. 2011): The study was sponsored by Genzyme. The ethics committee at
each centre approved the study.
Cruickshank (Cruickshank et al. 2002): The original work was supported by the British Heart
Foundation and the Wellcome Trust. The Mason Medical Foundation funded some equipment.
The Northwick Park and Central Middlesex Hospital committees granted ethical permission for
all baseline measurements and mortality follow-up.
EDIVA (Moldanado et al. 2011): The EDIVA Project was supported and sponsored by Clínica
da Aveleira and Medinfar Farmacêutica, SA. The study was approved by the Portuguese Data
Protection Commission and the Ethics Committees of the hospitals involved.
Framingham Heart Study (Mitchell et al. 2010): Data collection and analysis for the
Framingham Heart Study was supported by the National Heart, Lung and Blood Institute's
Framingham Heart Study (Contract No. N01-HC-25195) and by HL076784, AG028321,
HL070100, HL060040, HL080124, HL071039, HL077447, 2-K24-HL04334 and a grant from
the Donald W. Reynolds Foundation.
Health ABC (Sutton-Tyrrell et al. 2005): The study was supported by funding through the
National Institute on Aging contracts N01-AG-6-2106, 2102, 2103. It was approved by the IRBs
of the University of Pittsburgh and Tennessee.
Ilyas et al. (2009): This work was supported by the British Heart Foundation (PG/2001/128) and
was carried out in the Edinburgh Wellcome Trust Clinical Research Facility with the necessary
local research ethics approval.
Non-invasive Atherosclerotic Evaluation in Hypertension study (NOAH) (Terai et al. 2008)
– No specific funding. Ethics approval provided by Osaka Hospital.
Pannier et al. (unpublished). No funding source. Hospital ethic committee and the French
National institution: “Comité National d’Informatique et des Libertés (CNIL)” gave us
authorization to conduct the study. The authors thank the Caisse Nationale d’Assurance Maladie
(CNAM), the Caisse Primaire d’Assurance Maladie de Paris (CPAM-Paris) and the Institut
National de la Santé et de la Recherche Médicale (INSERM), Paris for help with this work.
Hawaii-Los Angeles-Hiroshima study (Shokawa et al. 2005) Approved by the ethics
committee of Hiroshima University School of Medicine.
Wang et al. (2009): This work was supported in part by the intramural grants from the Taipei
Veterans General Hospital (grant no. V95C1-052), grants in aid from the Research Foundation
of Cardiovascular Medicine (91-02-032, 93-02-014), Taipei, Taiwan, Research and Development
contract no. 1-AG-1-2118 and the Intramural Research Program of the
National Institute on Aging, National Institutes of Health. IRB approval was from John Hopkins
Willum Hansen et al. (2006): The Danish Heart Foundation (grant 01-2-9-9A-22914) and the
Lundbeck Fonden (grant R32-A2740) supported the studies in Copenhagen. The Ethics
committee of Copenhagen County approved the study.
Zoungas et al. (2007): Independent project grant from the National Health and Medical
Research Council of Australia. The research ethics committee of each institution approved the
Supplemental Figure Legend
Web Figure 1: Box and whisker plot of raw PWV measures across all studies
Data from all 17 studies. Note that the Cruickshank study was considered as 2 separate samples
for analysis (participants with and without diabetes).
Web Figure 2: Forest plot for aPWV with other outcomes according to pre-specified
(a) All cause, (b) CHD events, (c) CVD mortality, (d) stroke
Online Appendix 3: Additional information on methods and results
Missing covariates: Four studies had missing covariate data (2/17 studies had 2 covariates
missing (one missing diabetes, one missing smoking, both missing blood pressure medication)
and 2/17 had 1 covariate missing (HDL-cholesterol)) and could only partially adjust for
covariates in the final model.
NRI confidence intervals: Uncertainty around the whole sample NRI, for both 5-year and 10year overall reclassification, is demonstrated with 95% confidence intervals for the NRI
estimates, calculated using the svy set of commands within Stata. Strata were defined as each
study, and the within-study uncertainty calculated; variances were calculated separately for
reclassification amongst events and non-events and then summed (since the two groups are
independent by definition). This variance was then used to calculate the standard error of the
NRI and thus the 95% confidence interval. Note that studies with too few events to calculate the
variance were not included in these calculations: Cruickshank (Diabetic), Boutouyrie & Shokawa
for CVD mortality 5–year clinical NRI; Cruickshank (Population) for all-cause mortality & CHD
events 10-year clinical NRI.
Sensitivity analyses: We repeated the sub-group analysis for renal function also dichotomising at
an eGFR ≥60 versus eGFR<60 ml/min/1.73 m2. In both analyses, cohorts who had recruited
patients with end-stage renal disease or who had renal transplantation were coded as poor renal
function. To examine whether the NRI was sensitive to differences in length of study, we used
10-year predicted risk instead of 5-year predicted risk using those studies with at least 8 years of
follow-up. In further sensitivity analyses, we examined change in reclassification due to
inclusion of aPWV in the model over a single threshold firstly at an absolute 5-year risk of 5% to
estimate the additional numbers of people who experienced events that would have been eligible
for treatment and those who did not experience events that would have been prevented from
being unnecessarily treated; and secondly at the within-study’s median predicted risk, under the
model without loge aPWV, for those experiencing an event. PWV values will depend, in part, on
the measured path length i.e. the distance over which the pulse waveform travels. Path length is
typically measured using one of two approaches: the direct distance between the carotid and
femoral measurement sites (“direct” method), or the distance between the suprasternal notch and
femoral site minus that between the suprasternal notch and carotid site (“subtraction” method).
Although conversion equations between the two methods have been published previously 8, path
length data was not available for all studies included in the current analysis. We therefore
undertook a sub-group analysis by classifying studies as either using the direct method or the
subtraction method and excluding studies where the method was unclear or neither of these two
approaches. We also grouped the studies into two groups depending on geographical location
(Far East versus rest) and tested for any evidence of heterogeneity. All analyses were conducted
in Stata version 12.
Sensitivity results: There was no material difference between the NRI calculated using the
studies with 8-years follow-up compared with that using studies included in the 5-year risk
model. For an absolute risk of 5% in 5-years the overall NRI was lower, 0.43% for all cause
morality, 3.70% for CVD mortality, 0.90% for CHD, 1.11% for cardiovascular events and 0.22% for stroke. For a threshold defined by the within-study median predicted risk for those
experiencing an event, the overall NRI was 1.88% for all-cause mortality, 5.54% for CVD
mortality, 2.16% for CHD, 2.15% for cardiovascular events and 4.93% for stroke. The results
from the sub-group analysis comparing the direct or subtraction method failed to find any
evidence of heterogeneity for any of the outcomes (p-values varied from 0.53 to 0.93). Similar
the results for studies from the Far East were similar to those from Europe or North America (pvalues varied from 0.32 to 0.78).