A practical approach to the E-IMD patient registry (WP4) (Deliverable #6, milestones #5-7)

Major aims of the registry (1) To describe the natural history and outcome of OADs and UCDs (2) To describe and evaluate the efficacy and safety of current treatment strategies (3) To compare the diagnosis, treatment and management of affected individuals in Europe (4) To identify the major impact of a rare inherited disease for patients and their families on quality of life

Organic acidurias Disease panel Methylmalonic aciduria (MMA) mut 0, mut -, cbla, cblb, cblc, cbld (including variants 1 and 2), cblf Propionic aciduria (PA) Isovaleric aciduria (IVA) Glutaric aciduria type 1 (GA1) Urea cycle defects N-Acetylglutamate synthase (NAGS) deficiency Carbamylphosphate synthetase 1 (CPS1) deficiency Ornithine transcarbamylase (OTC) deficiency Citrullinemia type 1 / Argininosuccinate synthetase (ASS) deficiency Argininosuccinate lyase (ASL) deficiency Arginase 1 (ARG1) deficiency Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome/ mitochondrial ornithine transporter 1 (ORNT1) deficiency

Technical aspects and data protection

Hardware APACHE server (external server used for studies, locked, entry only for employees, restricted access via two ports, firewall etc) HTTPS (hypertext transfer protocol secure): provides encrypted communication and secure identification of a network web server. Data backup: Daily backups are stored for 30 days; all data are also saved on a second server located in another building (URZ, university computing centre)

Database MySQL (www.mysql.com): Most popular (6 million installations, 64,000 downloads per day) relational database management system Structured in a way that the database management system can organise several databases in parallel A characteristic application area of MySQL are web-based databases, usually in combination with an APACHE server

Software TYPO3 (www.typo3.org): A free and open source content management system Runs on several web servers such as APACHE, on top of many operating systems (Linux, MS Windows...) 4500 pluggable extensions are available for TYPO3, most of them written by third party developers (available for free)

Data protection Accessibility via two open ports Firewall Password protection HTTPS encrypted communication, secure identification Locked room, entry restricted to employees

Pseudonymisation of entered data All entered data are pseudonymised: Number for study centre (e.g. 001 ) + number for patient (e.g 003 ) unique pseudonym ( 001-003 ) Pseudonymisation allows each study centre but not the central office (UKL-HD) to identify study patients followed by this study centre Only study centres know the definite link between a patient and his/her pseudonym Each study centre is responsible to keep this definite link (key list) in a safe place

Ethical issues Central office (UKL-HD) Data protection concept of E-IMD Ethics approval of local IRB Preparation of ethics template in English Clinical partners Translation of ethics template, application according to local/national standards Written informed consent obtained from all patients before starting data entry. 9 (of 37) clinical partners in 8 (of 19) countries have already received ethics approval: Czech Republic Croatia Denmark Germany Greece Spain Poland Portugal

Visits and items

Types of visits 1. Baseline visit Once at the beginning for a new study patient Missing data, e.g. results of pending analyses should be completed asap 2. Regular visit Scheduled visits (inpatient or outpatient) At least once yearly 3. Emergency (or any other unscheduled) visit All unscheduled visits (inpatient or outpatient) Due to (impending) metabolic decompensation or another significant health problems

Visits and (electronic and printed) forms FORMS Baseline visit Regular (annual) visit Emergency / unscheduled visit Fatal disease course (of a registered patient) Fatal disease course (of a previously unregistered patient) Eligibility (form 0) X X Baseline assessment (form A) X X Medical history (form B) X (X)* Physical / neurological examination (form C) X X Dietary treatment (form E) X X Drug and other treatment (form F) X X Neuropsychological development (form H) Part I Questionnaire on behaviour (parent report, self report) Part II Tests (BSID-II or III, Denver-II, WPPSI-III, WISC-IV, WAIS-IV according to the E-IMD schedule) Quality of life (form I) PedsQL, WHOQOL-BREF (according to the E-IMD schedule) MRI / MRS assessment (form J) (X) (X) (X) Laboratory analysis (form K) X X X Emergency / unscheduled visit (form D) Emergency treatment (form G) Fatal disease form (form L) X X (X) (X) X** X** X X * only if update is required ** at least once during the course of the project In brackets, optional tasks for visits

Types of items 1. Tick boxes, pull down menus (e.g. clinical presentation, medical history) Choose answers from a predefined list 2. Input boxes (e.g. treatment, lab results) Fill in digits and/or characters Please take care using the correct (SI) unit Calculators are provided to convert units 3. Free text boxes (to add important information) Use only if necessary Length of information is restricted to 150 characters

First steps

How to start? Written ethics approval received and scanned document sent Personalised access data (username, password) received User manual read carefully before first use Profile activated (change your password before first use) https://www.eimd-registry.org/

Password Note: After the first login to the password-protected area, you are asked to change your password. The new (secure) password must contain 8-15 characters and at least 2 variations (capital letters, digits). If the new password does not meet these formal requirements, you will not be able to save it. Example (for a correct password): Example (for an incorrect password): Murakami1Q84 winniepooh Please note that the new password only not known to you! Keep it in a safe place!

How to add a new patient? Click on Patient registry and Add a new patient to the registry Fill in the Eligibility form The following criteria needs to be fulfilled: 1) Written informed consent obtained 2) Diagnosis of OAD or UCD is confirmed or highly likely 3) No exclusion criteria are known (metabolic derangement due to other IEM, no unrelated serious comorbidities) If the form is correctly filled Patient basic data form

Patient basic data Example: correctly filled form before saving 01/04/2011 Female 05/1995 Mixed France France Gambia None After saving pseudonym is generated automatically, the patient is added to your list and the status of the form changes to completed Only you will know the combination of patient-id and patient name!! Note: the items gender, date of birth and ethnic background cannot be changed after saving

Click on a pseudonym in your list Baseline visit Choose Baseline visit from the box Add a visit for this patient..., press Add A new window opens providing you with all electronic forms required for this visit type Select an electronic form from the list Note: Choose a correct visit date!! Visit date cannot be before the date of written informed consent has been obtained!!

Other visit types Only after completion of the baseline visit, other visit types can be added 1) Regular (annual) visit, emergency 2) Unscheduled visit 3) Fatal disease course visit While getting closer to the date of the next regular visit, the colour changes from grey to orange to red.

Loss to follow-up and data transfer Reasons for loss to follow-up: 1) Informed consent withdrawn 2) Patient has moved to another centre 2a) to another centre NOT involved in E-IMD 2b) to another E-IMD partner ( data transfer) Except for option 2b, loss to follow-up results in factual anonymisation of previously entered patient data; to enter new data will become impossible.

Use of the online forms Step-by-step approach: not all parameters are visible from the beginning; the form develops sequentially by choosing certain options Example: Baseline assessment

Validation Missing data: are highlighted by a question mark in the same line Outliers and invalid data: input boxes for numeric data have been set up with a predefined range. Outliers and invalid data (e.g. comma instead of a dot) will receive a warning note. You are able to save outliers (if correct), but not invalid data.

Formulas and calculators Formulas Body mass index Dosages (in mg or g/kg per day) Schwartz formula (creatinine clearance for patients < 18 years) MDRD formula (creatinine clearance for patients > 18 years) Note that proper function requires correct and complete basic data! Calculators Helps to convert lab results in appropriate units

Additional functions and tools Data extraction tool All entered centre-specific patient data can be extracted Two.csv files (1. table with patient basic data, 2. follow-data) Files can be used with standard statistical programmes Printing tool Filled electronic forms can be printed Single forms or all forms of one visit of one patient Download tool User manual Word forms matching electronic forms

Trouble shooting, fault management and training If anything fails, don t get angry. We will try to help you!!