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SN Comprehensive Clinical Medicine

, Volume 1, Issue 2, pp 123–133 | Cite as

A Guide to Total Quality Management System (TQMS) in Molecular Diagnostics from Experiences in Seeking Accreditation and Implementation

  • Seetha DayakarEmail author
  • Heera R. Pillai
  • Sanughosh Kalpathodi
  • Ganesan Jeya Chandran
  • Radhakrishnan R. NairEmail author
Medicine
  • 213 Downloads
Part of the following topical collections:
  1. Topical Collection on Medicine

Abstract

The molecular diagnostic laboratories in developing countries are progressively improving and attaining international accreditation. Hence, understanding and implementing the concept of quality are the needs of the hour. Total quality management system (TQMS) in a diagnostic laboratory is an integrated program involving all laboratory staff aiming for integration, consistency, and increase in efficiency. A comprehensive understanding of such a system is unfortunately only through practice. Our endeavors in establishment of TQMS for laboratory accreditation has helped us gain comprehensive understanding of the process and have compelled us to share the knowledge with the community engaged in such diagnostics. A number of accreditation bodies have put forth guidelines for laboratories seeking accreditation; however, such documents can be overwhelming at times leading to confusion and difficulty in implementation. We aim to present to the reader a lucid script of basic reasoning behind such accreditation guidelines in conjunction with thorough and practical generalized workflows for TQMS implementation. The goal of TQMS is to provide the best possible care for patients; and to achieve top-notch quality, there should be a continuous drive for improvement. The clinical vignettes presented in this paper illustrate the value of applying select ISO 15189:2012 recommendations in a molecular diagnostic laboratory to efficiently ensure quality through TQMS and a basic understanding of nuances for its practical implementation. Implementation of TQMS in a diagnostic setting enables seamless flow of laboratory results and instills confidence in clinicians regarding disease interpretation and treatment.

Keywords

Molecular diagnostics Total quality management system Next-generation sequencing Real-time PCR/PCR ISO15189:2012 Accreditation 

Introduction

At present, globally, healthcare management relies on a battery of molecular diagnostic tests that help clinicians to take highly informed decisions for better prognosis of disease. It is a dynamic area leading to insights in research and treatment that are revolutionizing health care. Molecular diagnostics detect and measure the presence of genetic material or proteins associated with a specific health condition. It helps to uncover the underlying mechanisms of disease and also enables clinicians to individualize therapy, thus facilitating the practice of personalized medicine. These tests cover an array of diseases and contribute to early and precise diagnosis of the disease aiding in preventing disease progression [1••]. Molecular diagnostics gained wide acceptance and attention owing to its quick turnaround time and reliability [2•]. Though there has been a steep increase in the number of laboratories performing such tests on clinical samples for disease diagnosis, the documentation or guidelines for efficient functioning of such laboratories are often tabooed as complicated and incomprehensible for use in regular practice. Nonetheless, it does not diminish the fact that these labs must strictly abide by uniform guidelines globally so that the results generated are reproducible across centers [3]. Till recently, molecular testing was offered only by specialized reference laboratories possessing appropriate resources and technical expertise. The European conformity (CE) marking for in vitro diagnostic (IVD) devices and food and drug administration (FDA)–labeled commercial certified assays allow routine clinical laboratories to offer molecular analysis without large investments [4••, 5]. The approach to new molecular assays in a clinical laboratory requires expert selection of the appropriate biological specimen and suitable test by clinicians. It is necessary to evaluate performance of the pre-analytical and analytical phases of the test and to generate clinically useful patient reports [6••]. This requires proper training to laboratory personnel and clinicians to add value and robustness to the tests performed on precious clinical specimens [7••, 8••, 9••]. Thus, national and international accreditations help the laboratories to establish and maintain a total quality management system (TQMS). It improves the effectiveness in accordance with the requirements of the International Organization for Standardization (ISO) [10, 11]. In India, the National Accreditation Board for testing and calibration Laboratories (NABL) provides guidelines and accreditation to such laboratories in accordance with international standards [12••].

In this review, we focus on development and implementation of a quality management system which improves effectiveness of molecular diagnostic laboratories. We aim to go beyond the complexities of available quality manuals in presenting the concept of TQMS to laboratory personnel undertaking routine molecular tests. Our experience in implementing TQMS procedures in human genetic (somatic/familial) and infectious disease testing has been enlightening in the rigor of following these guidelines and also in its adaptability to most other testing’s with slight modifications. ISO 15189:2012 is a standard document that provides the specific requirements for quality and competence of medical laboratories performing molecular testing. This standard promotes global harmonization of medical practices and overall workflow of molecular diagnostic tests. It also protects the health and safety of both patients and healthcare providers. Thus, it supports efficient exchange of information and protection of data in improving the quality of patient care. Molecular diagnostic laboratories need to have a comprehensive quality manual (QM) and quality system procedure (QSP) to cover many critical areas of testing such as equipment selection, procurement, maintenance, and plan for breakdown. It also helps to check the competency of technical staff, internal quality control (IQC), proficiency testing (PT), external quality assurance service (EQAS), inter laboratory comparison (ILC), and the outlier management [13]. A properly designed quality manual, as per ISO15189:2012 and NABL 112, has to be developed in each facility for proper management of medical laboratories.

TQMS provides integration of all processes required to fulfill quality policy and objectives to meet the needs of the users. It ensures the best clinical care by using processes, methods, and technology that are consistent with the best practices [14, 15, 16]. A detailed description of manuals comprising the TQMS is given in the sections below.

The Total Quality Management System Essentials

The TQMS process and interactions in the molecular diagnostics lab are detailed in Fig. 1a. And the model starts with the collection of the most appropriate samples from patients or public health institutions for each diagnostic test and ends with the release of results according to ISO 15189:2012. The TQMS should present clear guidelines to address general problems; especially in case of nonconformance with laboratories’ own policies and procedures, quality program guidelines should encourage scientific and laboratory staff to regularly discuss quality issues.
Fig. 1

a Total quality management system process and interactions in molecular diagnostics. b Overview of next-generation sequencing. c unidirectional workflow of PCR and quality checkpoints

The Quality Manual

According to the ISO notion, quality is the ability to satisfy customer’s expectations. Quality manual is a document based on description, assignment of responsibilities, and documentation of all processes related to quality management. In India, NABL requires establishment of a Quality manual (QM), which should describe the TQMS to be followed by the organization/laboratory looking for accreditation [17••]. QM documents for NABL accreditation following ISO guidance 15189 should comply with documents NABL 160 and 112, and a detailed workflow should be embedded in the manual.

Quality System Procedure

Quality system procedure addresses all the quality system essentials consistent with overall policy of an organization to ensure accurate, reliable, and timely laboratory results, and to have quality throughout the laboratory operations. Strictly complying with QSP yields results with high quality and helps in detecting errors and prevents them from recurring. To satisfy the ISO guidelines, each laboratory is expected to develop QSPs based on their needs (Fig. 1a).

Molecular diagnostic laboratories following such QSPs should show evidence of monitoring of their reagents, primers, sequencing chemistries, and platforms for regular quality check.

This documentation can be organized at four levels for convenience. The apex document or level A document is the manual which includes quality policy and objectives to be followed for implementation of various elements of ISO 15189. Level B documents are QSPS, which describe detailed procedures of the activities of individual functional units needed to implement management system. All procedures are cross-referred in the quality manual. Management system procedures are further supplemented with detailed work instructions—standard operating procedures (SOPs) termed as level C1 documents and brief work desk instructions termed as level C2 documents. Forms and formats constitute level D1 documents. The reports comprised of registers (a), filed reports (b), and data in data base (c) that are grouped as level D2 documents.

Internal Audit and Management Review

Management and internal reviews of TQMS at planned intervals help to address continued adequacy and effectiveness of a diagnostic laboratory. Internal audits have to be completed once in 12 months with trained unbiased auditors, when systems are in place and should include pre- and post-examination and can then be extended to all elements of the TQMS (Fig. 1a). The laboratory shall take necessary action for nonconformities raised by auditors. Corrective actions should be taken without delay to resolve raised nonconformities.

Laboratory director is expected to inform well in advance and accommodate the management and technical team (including instrumentation and information technology divisions) for the management review conducted yearly. The management review includes periodic review of requests for sample requirements, assessment of user feedback, staff suggestions, internal audits, risk management, use of quality indicators, and review by external referral laboratories. It also helps in assessing the results of proficiency testing, monitoring of complaint resolutions, performance of suppliers, and identification and control of nonconformities.

Competence of Personnel and Training

The laboratory should be headed by the laboratory director/authorized signatory with a M.D. or Ph.D. degree in the respective discipline and have accomplished a post-doctoral training in this field and subsequently has at least 4 years of experience. The laboratory team has to be comprised of trained and dedicated research technologists.

Due to technical nature of many molecular methods, the training requirements are often extensive and highly complex. All technical and laboratory staff is expected to be well versed with technical and management requirements of the laboratory. The competence assessment must be carried out by allowing them to participate in mock testing of laboratory procedures including waste management and personal safety procedures.

Equipment Calibration and Testing/Maintenance

The laboratory needs to be spacious enough to carry out molecular biology procedures. All instruments have to be calibrated by appropriate accredited service agencies. Information of manufacturer’s name, model, serial number, and contact information of the supplier; date of manufacturing/receiving; and the schedule for preventive maintenance should be on display on the instrument.

Molecular methods using PCR may require the use of bio safety cabinets in a diagnostic laboratory for protecting integrity of clinical samples to avoid errors and for personal safety. These cabinets consist of a high efficiency particulate air (HEPA) combination of heating, ventilation, and air-conditioning (HVAC) control system to prevent sustained positive pressurization of the laboratory. The PCR workstation is a UV sterilization cabinet to decontaminate reagents and equipment prior to carrying out PCR reactions. These cabinets have to be serviced and calibrated as recommended by the supplier. Wipe tests and culture using blood agar plates have to be performed regularly to check for background cross contamination. Typically, cabinets are cleaned before and after each use. A detailed cleaning protocol must be attached to the QSP.

Pipettes used for molecular methods require sophisticated calibration and generally tend to use much smaller volumes than those used in other areas. Internal calibration schemes do not suffice for such minute volume calibrations accurately. A six-point (decimal place) weighing balance is required for accurate gravimetric calibration of such small volumes. In common practice, laboratories prefer sending pipettes to external agencies for calibration, which may significantly increase the cost of calibration compared to in-house methods. However, choice of in-house or external calibration must comply with the acceptable precision and accuracy tolerances required in the laboratory as per ISO 8655 guidelines. Thorough retrospective analysis of all laboratory results should be carried out if pipettes are found to have performed poorly during calibration checks.

Centrifuge maintenance and speed verification are assessed across a range of speeds using a calibrated tachometer or stroboscope. Platinum resistance thermometer (PRT) with digital indicator and timing devices in high-speed centrifuges is use to calibrate temperature. It is recommended to have annual maintenance contracts inclusive of checking the condition of centrifuges twice a year.

Temperature-controlled equipment such as water baths, incubators, ovens, refrigerators, and deep freezers must be verified for accuracy and performance (with calibrated temperature-recording devices) for the intended temperature required. Refrigerators and deep freezers requiring critical and continuous temperature control must be fitted with 24 × 7 temperature recorders/data loggers. Daily temperature logs should be maintained for storage freezers to account for temperature fluctuations due to mechanical or other faults that can lead to damage of sensitive reagents and may eventually affect the test results. Temperature must be monitored with calibrated recording devices at multiple points with the doors shut. All records must be documented and filed for future reference.

Purchasing and Inventory

The laboratory needs to identify critical support services it requires to operate user-defined criteria for each critical supply and service. It is imperative for the laboratory’s management to collaborate with the organization purchasing unit to ensure a continuous supply of materials and proper logistics. All processes, from raising a purchasing order to receipt and storage of purchased items, should be documented. Selection criteria of vendors shall be decided by a logical scoring system taking in account their current turn over, reliability, cost, communication, and support capabilities.

Quality Assurance, Proficiency Testing, and Measuring Uncertainty

ISO/IEC (International Electrotechnical Commission) 170 Guide 43:2010 has guidelines for development, selection, and use of proficiency testing by laboratory accreditation bodies [18••, 19]. All laboratories operating under such accreditation should follow these guidelines which encompass most testing parameters performed in such molecular diagnostic setups.

However, a number of laboratories using next-generation sequencing (NGS) face a major obstacle due to absence of established proficiency testing (PT) system for NGS, which causes lack of error identification, missing indications of QC problems as well as verification of test performance in laboratories. Therefore, there is a scope for the development of national-level Next-Generation Sequencing - Standardization of Clinical Testing (NGS-SCT) workgroups to provide recommendations for NGS-PT program. Such NGS-SCT groups should propose PT opportunities for both wet and dry laboratory pipelines covering the entire NGS workflow [20].

Internal quality assurance (IQA) is necessary to ensure high assay reproducibility, performance, and enable detection of errors in daily practice. Assays can be performed according to standard operating procedures (SOP) with appropriate positive, negative, and internal quality controls [21, 22]. Implementation of new tests requires a verification and validation procedure using predefined parameters [23, 24].

External quality assurance (EQA) involves use of results of many laboratories analyzing same specimen of known composition and value, supplied by the external agencies for quality control purposes [25•, 26••, 27, 28••].

Quality control procedures need to be designed to detect errors in a manner that does not generate false alarms and periodic review of it is essential. The use of the Westgard rules is a useful approach to identify QC violations as shown in Table 1 [29•, 30••].
Table 1

Westgard rules is an interpretation and action of QC violation

Rule

Interpretation

Action

1 2s

One control observation exceeding the mean ± 2s.

It is used only as a “warning” rule that initiates testing of the control data by other control rules.

1 3s

One control data observation exceeding the mean ± 3s.

Rejection. Method is primarily sensitive to random error.

2 2s

Two consecutive control observations exceeding the same mean + 2s or mean – 2s limit.

Rejection. Method is sensitive to systematic error.

R 4s

One control observation exceeding the mean + 2s and another exceeding the mean – 2s in one run with two level control

Rejection. Method is sensitive to random error.

4 1s

Four consecutive observations exceeding the mean + 1s or mean – 1s

Rejection. Sensitive to systematic error

10x

10 consecutive control observations falling on one side of the mean (above or below, with no other requirement on size of deviations)

Rejection. Sensitive to systematic error. This rule may not be used.

Measurement uncertainty (MU) estimation is critical for overall quality assurance of diagnostic setups and should be performed as recommended in ISO 15189. MU reporting should be evaluated with respect to different test purposes like comparison with reference intervals and thresholds for clinical decision limits [31••].

Environmental Conditions

The laboratory ambient temperature must be maintained at 22–26 °C. Work surfaces should be made of inert materials that can be thoroughly decontaminated after every use. Molecular diagnosis laboratories have to be conscious of directional movement of samples and nucleic acids. Unidirectional workflows in molecular diagnostic labs prevent amplicon contamination of unprocessed samples and laboratory reagents (Fig. 1c). It is also recommended that monthly check for monitoring any such contamination be conducted by wipe test and sterility check using blood agar for the entire laboratory. Waste should be properly segregated and disposed by following standard local pollution control board recommendations or WHO guidelines [32].

Standard Operating Procedure Manual

The Standard Operating Procedure Manual (SOPM) is a tool that laboratory technologist’s use for safe and efficient guidance through a specific procedure. A poorly designed SOP can result in misdiagnosis. This can also result in QA failures and regulatory lapses. Laboratory personnel have to be trained in all aspects of SOPs. The SOP has to be reviewed periodically and revised as needed and should be supervised by two qualified personnel and signed by the laboratory director. Methods, reagents, instruments, instrument software, and versions used have to be documented. Development of SOP for NGS assays and target-enrichment protocols, regarding captured regions, must be documented.

Next-Generation Sequencing and Real-Time PCR/Conventional PCR

NGS techniques are increasingly impacting research and diagnostics, especially for complex genetic/infectious diseases. NGS in diagnostics allows for unbiased screening of samples with a higher throughput and eventually will result in obtaining results faster and make diagnostics much more cost effective by eliminating multiple testing on samples [33••, 34•]. The general NGS workflow is elaborated in Fig. 1b [35••]. NGS produces enormous amounts of data and can unravel findings that can be pivotal for disease diagnostics. However, these results must be interpreted with caution, and further evaluation must be carried out using other gold-standard techniques in case of discrepancies.

The concept of use of NGS techniques in diagnostics is apparently new in developing countries and thus prevalent TQMS procedures do not suffice for its complete QM. In order to change this, the standardization and simplification of NGS workflows are a central requirement, involving QMA methods.

The American College for Medical Genetics and Genomics has published detailed NGS diagnostic lab standards for patient care [36•]. Furthermore, the College of American Pathologists has developed an NGS checklist for accreditation of molecular laboratories [37••]. Currently, no clinical NGS-based infectious disease testing (laboratory-developed tests) is yet approved by the US Food and Drug Administration (FDA). Nevertheless, the FDA has published detailed clinical application and validation approaches for regulatory clearances of NGS diagnostic for clinical microbiology [38••].

Molecular diagnostic laboratories currently heavily rely upon the use of methods like real-time PCR for quick turnaround times from sample to pathogen detection with high reliability. Real-time PCR functions by measuring the fluorescence of DNA/RNA intercalating dyes and fluorescent probes added to the PCR mixture prior to amplification [39••]. Using mixtures of compounds that emit fluorescence at different wavelengths, real-time PCR has evolved to quantify multiple targets simultaneously from a single sample. Compared to conventional PCR’s, real-time assays provide a more sensitive limit of detection (LOD) and faster results [40••]. Also, chances of sample cross contamination are minimal for real-time PCR. Also, an overall cost reduction strongly supports the routine use of real-time PCR assays and other rapid molecular assays in clinical diagnostics [41•].

The molecular laboratory has to ensure high degree of quality which includes availability of a suitable biological starting material, best strategy to use to fit the purpose and choice of quality control programs [42] (Fig. 1c).

Safe Disposal of Infectious Laboratory Waste

Universal/local precautions applicable to clinical labs must be followed to minimize occupational hazards of personnel working in the laboratory. Safety measures like maintaining first aid facilities and general safety precautions of the laboratory (hand washing, eyewash, spill management, needle stick injury, and fire safety) should be meticulously observed (Table 2). Every individual performing laboratory procedure must undergo proper training in safe-handling and disposal of hazardous materials. They also must be vaccinated against all recommended pathogens for prevention of unwanted accidental infection, and antibody titers should be monitored regularly. Laboratory operations should be designed in a way that minimizes personnel risk [43••, 44•].
Table 2

Personnel protective equipment (PPE) used in molecular diagnostics

Type of PPE you would wear in an infectious disease (molecular biology) lab

Gown

Mask or respirator

Goggles or face shield

Wash hands

Gloves

Sample preparation

✔*

Isolation of nucleic acids

✔*

Master mix preparation

✔*

Template room

✔*

Real-time PCR room

×

✔*

×

Post amplification

×

✔*

Centrifugation

✔**

Autoclave room

✔*

Spill management (biological and chemical)

Sitting at desk and working with computers

×

×

×

×

×

✔ - compulsory; ✔* - optional; ✔** - UV protected; × - not needed

All wastes generated in the lab are segregated and disposed in bags which are color coded. Red bags are used for plastic tubes, plastic containers, infected gloves, and syringes (without needles). Green bags are used for general wastes like paper and stationery. Sharp containers are used for needles, blades, broken glass, and other sharps [45•, 46•].

Information System Management

The laboratory information system is used for collection, processing, recording, reporting, storage, and retrieval of information within the laboratory. It is the black box for the laboratory and enhances quality management through robust traceability. It is also used between the laboratory and external agencies to monitor test results and ensure quality. The clinical laboratory deals with private and confidential information; thus, the handling of information must be secure at all times and should be in compliance with the national or international requirements regarding data protection.

Difficulties and Bottlenecks in TQMS Implementation

Poor quality management due to improper staff training, lack of use of proper test controls, inefficient or lack of result verification process, non-implementation of regular quality control assessment, use of non-validated tests, understaffing, and inadequate attention to detail in ILC and EQAS lead to difficulty in implementing a robust quality management process.

EQAS and proficiency testing for PCR-based tests are not available in most molecular diagnostic laboratories leading to high cost of performing external agency testing. This results in most laboratories refraining from EQAS testing which can potentially lead to serious lapses in quality management. This can be effectively addressed by engaging more domestic laboratories for EQAS/PT/ILC testing through national policies on clinical diagnostics.

Preparation of clinical samples for downstream analysis and careful assessment of results while accounting for data from control reactions are few of the critical components that could derail the functioning of diagnostic laboratories if not implemented properly. Inhibition by chemicals found in clinical samples can be a major hurdle, but with the use of commercially available nucleic acid extraction kits, these issues can be efficiently managed.

Also, external and internal quality control assays must be performed simultaneously during sample processing. An effective example of this is the use of an internal amplification control (IAC) and external amplification control (EAC) during PCR-based testing of clinical specimens. This helps in accurate determination of specificity and sensitivity of each test performed and helps establish true negatives by estimating poor performance due to sample handling.

An IAC is a non-target nucleic acid sequence that is co-amplified simultaneously with the target sequence [47]. A negative response (no signal) in a molecular test can sometimes be due to inhibition of the whole reaction by some sample generated contaminants giving a false-negative result. Thus, the use of IAC along with the target-specific probes will always generate a control signal irrespective of the status of the target, ensuring completion of the reaction.

Similarly, EAC is a more specific amplification control that is mostly identical to the target nucleic acid sequence. Thus, two separate reactions are carried out for each test and control reaction under identical conditions to further ensure reliability of test results [48]. If the above strategy is carefully optimized, it represents a highly comprehensive and fail-safe approach in molecular testing.

Laboratory Accreditation

Pre-assessment is the initial step for any laboratory seeking accreditation, and it is a comprehensive review carried out on-site by the accreditation body in accordance with ISO15189:2012. Reviews are carried out for legal identity of the laboratory, list of personnel working, their qualifications, the list of equipment, structure of laboratory organogram for efficient work management, availability of referral external documents, internal auditor training certificates of all laboratory personnel, and list of authorized signatories. It also includes assessment of documents pertaining to monitoring of laboratory EQAS/ILC and personnel technical skills and details of certificate of biomedical waste disposal from the local pollution control board and the agency that collects biological wastes from the lab. In case of referral laboratories, the memorandum of understanding (MoU) with clinical partners should also be assessed.

This is followed by a final assessment by the accreditation body where assessors, after verifying all documents, will raise any nonconformities according to the ISO15189:2012 checklist. The laboratory has to propose corrective action within a stipulated time following which the assessors will provide their final recommendation to the accreditation board for the final approval.

Once accreditation is granted, the laboratory accreditation enlists a set of specified fields for testing valid till the next evaluation period. It is mandatory for the accredited lab to comply with the requirements of the quality management as ascertained for the accreditation for all parameters throughout the entire accreditation period. The laboratories’ accreditation status will be dependent on surveillance and re-assessment process which mainly accounts for rigor in maintenance of quality parameters and deviations from laid-down laboratory SOPs during the course of the previous accredited time frame.

Conclusions

The major challenge for a molecular diagnostic laboratory is to select high-performing technological methodologies that enable reliable detection of all requests at a high sensitivity, with a limited amount of specimen and short turnaround time at low costs. Efficient molecular testing could bring reduction of inappropriate therapeutic prescriptions leading to better and faster prognosis and economical clinical care. Thus, a thorough quality management system is critical for the success and growth of molecular diagnostics taking into account the induction of new diagnostic tools and ensuring reliability of generated results.

Developing countries in the South American, African, and Indian sub-continents with a high burden of chronic and infectious diseases constantly battle a number of challenges to ensure quality standards in a molecular diagnostic laboratory. This includes but is not exclusive to high expenses for procurement of quality reagents, non-availability of reference standards, lack of awareness/training, minimalistic local guidelines, and difficulty in transportation of biological substances.

This review is a summary of anticipated pathways and hurdles during the accreditation process of a clinical molecular diagnostic laboratory in developing countries. Our review brings to light critical elements of the process in addition to overall guidelines. We believe this will be of help for laboratories seeking such accreditation in resource-limited settings. The experience we had undergone during this process could be of immense benefit to others.

Notes

Acknowledgements

We acknowledge and thank the lab members Karthika, Jayalakshmi, Vineetha, Ashique, Sumaja, Rose, Sruthi, Vinod, Lekshmy and special thanks to Ms B Padmavathi Amma, Medical Laboratory Service her constant support to get accreditation.

Funding Information

Medical

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Seetha Dayakar
    • 1
    Email author
  • Heera R. Pillai
    • 2
  • Sanughosh Kalpathodi
    • 2
  • Ganesan Jeya Chandran
    • 3
  • Radhakrishnan R. Nair
    • 1
    Email author
  1. 1.Laboratory Medicine and Molecular Diagnostics, Bio-Innovation CenterRajiv Gandhi Center for Biotechnology, KINFRA Film & Video ParkThiruvananthapuramIndia
  2. 2.Srinivasa Ramanujan Institute for Basic SciencesThiruvananthapuramIndia
  3. 3.Department of BiochemistryPSG Institute of Medical Sciences and ResearchCoimbatoreIndia

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