Susanna Lagorio ISS - CNESPS

17-12-2008

•  The Committee of Enquiry appointed in 2001 recommended: –  to follow up the cohort of the military personnel

deployed in Bosnia and Kosovo –  to enrol the individuals that could have been exposed

to DU in a long-term programme of medical surveillance

•  Start in 2003 •  Addressed to military personnel and civilians involved in UN

missions in Bosnia and Kosovo •  Based on periodical clinical tests and brief case histories

Blood

Hemochrome Proteins with proteic electrophoresis Erythrosedimentation velocity (VES) Creatinin Bilirubin (total – conjugated – unconjugated) Serum Glutamic Pyruvate Transaminase (SGPT) Serum Glutamic Oxaloacetic Transaminase (SGOT) Gamma glutamil transpeptidase (GGT) Glycaemia Azotemia Free triiodothyronine (FT3) Free thyroxine (FT4) Thyroid-stimulating hormone (TSH)

Urine Standard urine analyses (no biomonitoring of DU)

Identification and demographics

Date of the visit Fiscal code Surname and name Gender Date and place of birth Place of residence Address and telephone number Occupation (free text)

Mission details

Place of deployment Departure date Return date Mission type (M = military /C = civilian) Tasks carried out during deployment (free text)

Health status History of past illness (free text) Present illness/es (free text) Abnormal clinical tests (if any)

•  Voluntary participation

•  Self-reported diseases

•  No information on date of diagnosis and clinical reports

•  Lack of a control group (or expected prevalence rates)

•  Time span: 2005-2009 •  Principal investigator: Dr. Arduino Verdecchia •  Initially focused on the implementation of a

military cancer registry •  September 2007: approval of a revised work plan

including epidemiologic studies •  January 2008: Agreement ISS-Defence Health

Service

•  PI: Riccardo Capocaccia (ISS) in collaboration with Franco Berrino (INT, Milan)

•  Similar to population-based cancer registries

•  Placed at the Epidemiologic Surveillance Unit of the Italian Defence Health Service

•  ISS/INT contribution technical support to the start of the registry (planning of activities, identification of data sources, training of personnel)

•  Retrospective cohort studies •  Study population

– Balkan cohort: military personnel participating in peace-keeping missions in Bosnia-Herzegovina and Kosovo in 1995-2004 (65,000 subjects; 400 expected deaths)

– Reference cohort: sample of non-deployed “Carabinieri”, of the same size, frequency-matched on date of birth and year of employment

•  Cause-specific mortality and cancer incidence •  Record-linkage studies

Study flow chart

ISS data-base

Defence Health Service

Balkan cohort

N-D military cohort

Min Defence

personnel archive (?)

Screening of certainly alive

Tax Register

List of taxpayers

Vital status and cause of death

Register Offices Vital status and death certificates

ISTAT

National Mortality Index

Min Health

Hospital Discharges

Hospitals

Clinical records

Incident cancer cases

•  Screening of candidates to active follow-up –  Record-linkage with Ministry of Defence personnel

archives •  Personnel currently on active service → “alive” •  Discharged soldiers → vital status ascertainment •  Feasibility ?

–  Inter-forces computerized archive in course of construction

–  Record-linkage with Tax Register data-base •  Included in the last available tax payers list → “alive” •  Not included → vital status ascertainment •  Not allowed by the Privacy Authority (improper use)

–  Record-linkage with the National Index of Register Offices

•  Run by the Department of Interior •  Italian residents in 2001, updated through notification of

demographic variations (births, deaths, immigrations, emigrations) by each of the 8101 Italian municipalities

•  High inter-municipality variability of the frequency of notification

•  Feasibility study on-going (critical piece of information: date of last updating of individual records)

•  Vital status - date, place and cause of death –  Request of information to the municipality of residence /

death •  ICD – cause of death

–  Record-linkage with the National Death Index (ISTAT)

Problem •  No nation-wide cancer registry in Italy •  21 population-based cancer registries •  coverage 15 million inhabitants ( 25% Italian

population) •  geographically inhomogeneous

–  Nord → 8 registries → 37% –  Centre → 4 registries → 25% –  South → 8 registries → 11%

•  Record-linkage with national data-base of hospital discharges (SDO) –  key-variable: Fiscal Code

•  Check of discharge lists at the existing 5 Military Hospitals which do not contribute date to the national SDO –  MH Principale, Milan –  Navy H, La Spezia –  MH Celio, Rome –  MH L. Bonomo, Bari –  Navy H, Taranto

•  Consultation of relevant clinical records –  Validation of discharge diagnosis code –  Retrieval of date of diagnosis from relevant reports (pathology,

imaging …)

Study flow chart revised

ISS data-base

Defence Health Service

Balkan cohort

N-D military cohort

Min Defence

Personnel

archive (?)

Screening of certainly alive

Vital status and cause of death

Register Offices Vital status and death certificates

ISTAT National Mortality

Index

Min Health

Hospital

Discharges Hospitals Clinical records

Dept Interior National Register

Index

Incident cancer cases

•  In the Swedish cohort of Balkans veterans (Gustavsson et al., 2004) specific job titles were subdivided into four groups: 1.  work at the camp mainly indoors (35%) 2.  outdoor operations in delimited areas with transport mainly by foot

(54%)

3.  outdoor operations over large areas with transport by convoy (7%)

4.  personnel engaged in mine or ammunition clearance (4%) •  Feasibility in the context of the Italian studies is uncertain

•  one variable in the data-base refers to the job performed during the mission

•  missing data = 25%

•  vagueness of information recorded (e.g. “operating task” = 27% of non-missing data)

•  Mortality and incidence rates among members of the Balkan cohort compared to

– rates experienced by the N-D soldiers (Cox proportional hazard model)

– general population rates (SMR / SIR analyses)

May 2007 Project illustrated to the Scientific Committee

Sept 2007 Finalised study protocol Feb 2008 Received data-base including eligible subjects

data cleaning Nov 2007 Protocol approved by the ISS Ethical

Committee March 2008 Project included in the “National Program for

Biomedical Research” May 2008 Notification to the “Authority for Personal Data

Protection” (GPDP) June 2008 GPDP identifies critical aspects requiring

revision

Current activities 1/3

•  Huge amount of data cleaning (still in progress) –  “Multi-purpose” data-base provided by the Defence Health

service •  Used to record data from different surveillance systems (a.

personnel involved in missions in the Balkans; b. forms filled in by soldiers participating in the voluntary surveillance ex Law 27/2001; c. monitoring of cancer cases)

•  Access d-b with multiple tables –  “Persons” –  “Missions” –  “Follow-up

•  Lack of ID code loss of between-tables referential integrity (multiple records per subject; equivocal correspondence of records relating to the same individual)

–  Missing data –  Non-standardised recording of free-text fields (i.e. Municipalities

of birth and residence; Country and Place of deployment; Battalion/Brigade/Detachment; Rank…)

Current activities 2/3

•  Clearance from the Privacy Authority still pending –  The Italian regulation does not foresee any form of

exempt or expedited review for record-linkage studies –  Research projects included in the National Program

for Biomedical Research are exempt from the obligation to obtain an informed consent from study participants

•  Voluntary participation may involve bias in effect estimates –  Research projects included in the NPBMR, however,

are not free from the obligation to provide each study participant with a detailed information concerning the use of his/her personal data for research purposes

Current activities 3/3

– When the “ad personam” information report requires efforts out of proportion to the protected rights or proves to be impossible to carry out, other information modalities are allowed (e.g. advertisements on news paper or in the web)

•  In facts, an address is available for 10% of study subjects •  Many (still not quantified) Balkan veterans were not

permanently employed in the Armed Forces (discharged soon after deployment)

–  The Privacy Authority is waiting for an official response from the Defence Health Service

–  The start of field work is not allowed at the moment

Current activities 3/3

– When the “ad personam” information report requires efforts out of proportion to the protected rights or proves to be impossible to carry out, other information modalities are allowed (e.g. advertisements on news paper or in the web)

•  In facts, an address is available for 10% of study subjects •  Many (still not quantified) Balkan veterans were not

permanently employed in the Armed Forces (discharged soon after deployment)

–  The Privacy Authority is waiting for an official response from the Defence Health Service

–  The start of field work is not allowed at the moment

 “Accurate exposure information is critical”

  “Study of biomarker data (e.g. urinary uranium concentration) is a necessary first step in characterizing DU exposure for epidemiologic studies”

  “Other approaches, such as questionnaires and review of military-activity records, are unlikely to yield as accurate an assessment of exposure because of recall bias and exposure misclassification”

Conclusions

•  In respects to the previous analysis carried out by the Committee of Enquire, the improvements in the follow-up and the case ascertainment methods will allow a more reliable evaluation of possible increases in cancer risk experienced by the Italian military personnel deployed to Bosnia and Kosovo

•  However, due to their sub-optimal study size and the poor exposure assessment, the planned epidemiologic studies will not permit sound inferences about the relationship between DU exposure and subsequent cancer risk