Patent Application
20240310394
The present application relates to quantifying errors in sample handling sequences, and particularly to quantifying and reducing errors accumulated in the course of multi-step sample handling sequences in a laboratory.
Sample preparation and their analysis in a laboratory typically involve multi-step protocols during which multiple laboratory devices are needed. Such protocols may necessitate accurate determination of for example sample weight, sample volume and sample composition.
In liquid handling applications, typically several liquid handling devices for different liquid volumes and multiple dispensing steps are used in order to complete the desired application or workflow. Examples of such liquid handling applications include preparation of a dilution series and a multi-step kit. In addition to liquid handling steps also other handling and measuring methods, such as weighing, may be used in the same workflow.
Such multi-step and multi-device workflows are susceptible to accumulation of experimental error, which may seriously affect the accuracy of the ultimate result of the workflow. For example, if in a 5-step liquid dispensing sequence each dispensing step involves an experimental error of 10%, the total amount of liquid dispensed after the five steps will be in the range 59% to 161% of the targeted amount 100%.
It is known to reduce random and systematic experimental error in sample handling by calibrating the devices used and by striving to reduce any random variations in the sample handling procedure.
The invention is defined by the features of the independent claims. Some specific embodiments are defined in the dependent claims.
According to a first aspect of the present invention, there is provided a method comprising: quantifying a total experimental error of a multi-step sample handling and/or analysis sequence comprising at least two steps, including quantifying respective individual experimental errors of said at least two steps; and presenting said total experimental error and/or an output value derived from said total experimental error by an output device.
According to a second aspect of the present invention, there is provided a sample handling device comprising means for performing the method according to the first aspect, comprising: a computing device configured to quantify said total experimental error, and an output device configured to present said total experimental error and/or said output value.
Various embodiments of the first aspect or the second aspect may comprise one or more features from the following bulleted list:
Embodiments of the present invention aim at improving the known methods of reducing experimental error in sample handling processes.
At least some embodiments enable handling of experimental errors and their accumulation more effectively, particularly in the case of multi-step sample handling and analysis processes in which a plurality of laboratory devices and/or a plurality of users are involved.
An advantage of an embodiment is that a user may immediately react to accumulation of error and adjust or interrupt the ongoing sample handling process.
An advantage of an embodiment is that confirmed or predicted sources of error in sample handling may be indicated to a user during said sample handling.
An advantage of an embodiment is that a user is informed on error or error accumulation during or at sequential steps of sample handling. This enables the user to carry out particular actions or protocol amendments or even protocol interruption to reduce experimental error in a sample handling protocol and/or to avoid execution of protocols in which total experimental error would be unacceptably large.
An advantage of an embodiment is that a user may receive information of previous errors accumulated during earlier steps in a sample handling protocol and/or errors in the current and forthcoming steps.
An advantage of an embodiment is that unnecessary process steps may be avoided as the user may be informed of the uncertainty level in the sample handling and/or analysis sequence in the course of said sequence, and for example before beginning a particular step thereof.
An advantage of an embodiment is that accuracy and reproducibility particularly in multi-step and/or multi-device sample handling protocols may be improved.
In the present context, the term “experimental error” refers to random and/or systematic experimental or observational error.
In the present context, the term “sample handling device” may refer to any device, typically a laboratory device, which is intended for handling a sample, for example a sample analysis device, a liquid handling device or a sample weighing device.
Typically, the term “laboratory device” refers to a sample handling device.
Typically, the term “sample handling” comprises sample handling and/or analysis.
In the present context, the term “display” may refer to any display which may be part of, or connected or integrated to a laboratory device, such as a sample handling device, in the course of a sample handling task or sequence.
It has been surprisingly observed that accuracy and/or reproducibility of sample handling in a laboratory may be significantly improved by the present method in which accumulation of experimental error during a sample handling protocol is quantified and presented to a user in the course of or even already in the beginning of execution of said protocol.
The experimental error to be quantified may comprise errors from various sources. The sources of experimental error may include instrumental, environmental, procedural, and human sources. The experimental error may comprise random and/or systematic error. Typically, experimental error comprises experimental error in sample handling and/or sample analysis.
In one embodiment, the present invention provides a method comprising: quantifying a total experimental error of a sample handling and/or analysis sequence, which sequence comprises at least two steps and respective individual experimental errors; presenting said total experimental error and/or presenting a parameter and/or an instruction and/or a recommendation derived from said total experimental error, to a user carrying out a step of said sample handling and/or analysis sequence.
The sample handing sequence typically comprises at least two sample handling steps or tasks.
A sample handling step or task may be a liquid pipetting task or a sample weighing task.
In one embodiment, the sample handling sequence comprises at least one liquid handling task or a liquid handling sequence.
The sample handling sequence may comprise a pipetting sequence involving multiple liquid aspirating and dispensing steps.
In one embodiment, the sample handling sequence comprises one or more of the following tasks: liquid handling, such as liquid aspiration, liquid dispensing or liquid pipetting; or sample handling, such as sample weighing or sample analysis, preferably at least liquid pipetting.
In one embodiment, said sample handling sequence may be performed using one or more of the following devices: a hand-held pipette, a liquid handling robot, a scale, an air pressure sensor, a temperature sensor, a humidity sensor, a spectrometer, a sample analysis device.
Individual experimental errors in the use of these sample handling devices may be quantified. A total experimental error may be calculated from the individual experimental errors and presented to a user.
Experimental error may be quantified and presented as an absolute error or a relative error or both.
For example, the total error may take account of experimental error in a current sample handling and/or analysis step to be executed by the user and/or experimental error in previous and/or forthcoming sample handling and analysis steps of the same sample.
Taking account of previous sample handling steps when quantifying a total experimental error to be presented provides the advantage that the user may decide not to execute the next step at all if the already accumulated error is unacceptably large.
Taking account of current and forthcoming sample handling steps when quantifying a total experimental error to be presented provides the advantage that the user may adjust the execution to avoid accumulation of too large total experimental error. In this way it may be possible to complete the entire multi-step sample handling protocol with an acceptable experimental error.
Experimental errors in use of one or more devices in the course of a sample handling sequence, which devices may be called sample handling devices, may contribute to the total experimental error to be quantified. The one or more sample handling devices may comprise at least one of the following: a hand-held pipette, a liquid handling robot, a scale, an air pressure sensor, a temperature sensor, a humidity sensor, a spectrometer, or a sample analysis device.
For example, a hand-held pipette may cause errors based on its settings, control, use, process phase, and so on. A liquid handling robot may cause errors based on its settings, control, program, process phase, and so on. An air pressure sensor, a temperature sensor, and/or a humidity sensor may cause errors based on their settings, calibration, use, and so on. The sensors may cause errors to other devices, readings, results, or samples to be handled. A spectrometer and/or a sample analysis device may cause errors based on their settings, control, use, used process or process phase, calibration, and so on. A scale on any of the mentioned and/or calibration of scales may cause errors. Any errors may be caused directly from a source, use of it, selection of a used source, its scale, settings, control, and so on.
The experimental error may relate to the accuracy of the sample handling device, to the action of sample handling and/or to the object of handling (the sample itself).
In some embodiments, the error quantification takes account of one or more experimental errors during a sample handling sequence. The one or more experimental errors may comprise at least one of the following: pipetting errors, weighing errors, sample analysis errors, and errors in concentrations of chemical or biological compounds.
In some embodiments the quantified error is reported or fed back to a sample handling or analysis device the use of which forms part of the sample handling task or sequence and thus contributes to accumulation of total experimental error.
For example, on the basis of the quantified error, it is possible to calculate a correction factor, such as a slope, and send it for use of a laboratory device used in a previous step or in a forthcoming step. A change of temperature between steps may be a source of systematic error which can be taken into account and corrected in this way.
The total error may be quantified by means of an empirically trained algorithm.
The algorithm may be a parameterized algorithm or a learning algorithm.
Empirical data may be based on measurement results and/or on certain values and/or ranges. Values and/or ranges may relate to used devices or processes, like predefined settings, regulations, timings, control, and so on. Empirical data may be used to train an executable program. For example, machine learning and neural networks may use empirical data as an input. Inputted empirical data may lead to output derived from any of inputted empirical data or combinations of such. Output may be a parameter, which may indicate a deviation from a predetermined range or value. Output may be an instruction for correcting an error, for example by adjusting or changing a device or settings of the device, or correcting a phase of a previous or forthcoming handling process. In response to receiving an instruction, the device may be adjusted automatically based on the received instruction. Output may be a recommendation for adjusting, changing and/or controlling devices, settings, a process and/or phases of it.
The total error may be quantified by calculating from individual errors related to individual steps in a multi-step sample handling sequence.
The quantifying may comprise for example: calculating a sum of individual errors, possibly after giving individual weights or probabilities to the errors to be added together, or possibly after quantizing the individual errors to be added together.
The means for quantifying the error may comprise a computing device, typically integrated to a sample handling device, such as a hand-held sample handling device. Said computing device is preferably configured to quantify an accumulated error from individual experimental errors in steps or stages of a sample handling sequence, which sample handling sequence may include a liquid handling task carried out by a liquid handling device.
In some embodiments, the computing device has been integrated into a liquid handling device, such as a hand-held liquid handling device or an automated liquid handling station, preferably into a hand-held liquid handling device.
By means of quantifying and presenting the total experimental error, the embodiments provide information on current status of the sample handling and/or possible estimations for the further steps. This enables the user to follow-up and understand the effect of accumulation of experimental error and in this way to improve reliability of results.
The method may comprise presenting the quantified error(s). The method may alternatively or additionally comprise presenting an output value or values derived from the error(s).
The type of output values may be tailored for example on the basis of the user and/or on the basis of error accumulation speed.
Educated users may benefit from directly receiving error information, whereas non-educated users may prefer receiving output values comprising concrete or practical instructions.
As an example, if the total error is accumulating slowly, the output values may comprise more general instructions than in a case where a sudden increase of total error is being observed.
The method preferably comprises showing an output value by an output device, such as a display, based on assessment of the individual experimental errors and the total experimental error.
The method preferably comprises showing an instruction and/or a recommendation to the user, for example by an output device, such as a display. The display may be part of, or connected or integrated to a laboratory device, such as a sample handling device, in the course of a sample handling task or sequence. Said instruction and/or said recommendation preferably guides the user to reduce said quantified error in execution of the sample handling task in the current step or the forthcoming steps of the sample handling and/or analysis sequence.
Said recommendation may relate to a step or device in which adjustments have the largest potential to reduce the total error.
Said recommendation may relate to a step or device in which adjustments are not susceptible of increasing errors in other steps or other devices.
Said recommendation may comprise recommending use of a particular liquid handling device in a liquid handling task and/or a particular tip in a liquid handling device during execution of the current step or a forthcoming step of said sample handling and/or analysis sequence.
For example, the selection of a tip volume may be a source of systematic error, particularly with tips for automated liquid handling robots.
Further, if the same tip is being used for a long time, a systematic error may begin to accumulate.
In air displacement pipettes, it may be possible to detect errors that are typical or specific for their use, for example if the user has not pre-wetted the tip or does not work at temperature equilibrium. Such errors may be indicated to the user. It may also be possible to take account of these errors by applying a correction factor.
Said recommendation may comprises recommending use of a particular liquid handling parameter, such as liquid volume to be dispensed, in a liquid handling task.
Preferably said recommendation guides a user to actions that are adapted to reduce experimental error in the current and/or any of the forthcoming steps of a sample handling procedure. Said recommendation may guide a user to actions that are adapted to reduce total experimental error of an entire sample handling procedure. Said action may comprise continuing the current procedure with adjusted parameters or adjusted equipment. Said action may comprise interrupting and relaunching of the current sample handling step or the entire sample handling and/or analysis sequence.
In some embodiments, such interrupting or relaunching may be avoided by reporting, as an output value, a parameter, such as a correction factor, to a forthcoming step.
In an embodiment, an output value is based on the experimental error of the current step.
In an embodiment, an output value is based on accumulated error, i.e. the experimental error of the current step and the experimental error of at least one previous step, preferably all previous steps.
In an embodiment, an output value is based on accumulated error and estimated forthcoming error, i.e. the experimental error of the current step, all previous steps and all forthcoming steps.
In an embodiment, if a threshold value for the error is approached or exceeded, an output value is generated.
The threshold value may be a predetermined threshold value or it may be a learning threshold, such as a threshold determined by a learning algorithm.
The threshold value may be a threshold value for an error of an individual step or a threshold value for an error accumulated during several steps.
In one embodiment, the recommendation comprises recommending use of a particular combination of laboratory devices, such as liquid handling devices, to minimize the total experimental error.
Said combination may comprise a combination of at least two sample handling devices, which may be the same or different.
Said combination may comprise a combination of at least three sample handling devices, such as at least four sample handling devices.
Said combination may comprise at least an automated liquid handling station or a hand-held pipette. For example, said combination may comprise a hand-held pipette and an automated liquid handling station. As another example, said combination may comprise an automated liquid handling station and a scale. As another example, said combination may comprise a hand-held pipette and an automated liquid handling station.
In an embodiment, the recommendation comprises recommending use of an electronic pipette, an automated liquid handling station, a mechanically actuated pipette or any combination thereof.
In an embodiment, the recommendation comprises recommending optimal dispensing volumes in the preparation of a dilution series: for example, whether to prepare a 1:30 dilution by first diluting 1:3 and thereafter 1:3, or alternatively by diluting twice about 1:5.47.
In an embodiment, the recommendation comprises recommending use of a tip by a particular tip manufacturer.
In an embodiment, the recommendation comprises recommending change of tip.
In an embodiment, the recommendation comprises recommending change of liquid handling equipment or sample weighing equipment.
In an embodiment, the recommendation comprises recommending interrupting and re-execution of the sample handling sequence, for example by using a different liquid handling device or a different scale or different pipetting parameters.
The error is presented by an output device, such as an electronic output device. Typically, the output device is a display.
In an embodiment, the presenting is carried out by an output device of a laboratory device which is operable by the user, and/or which is used for the sample handling and/or sequence analysis.
Preferably, the error is presented in a hand-held device. The hand-held device may be a hand-held laboratory device that the user may operate to execute the sample handling sequence.
Most preferably, the error is presented on a display of a hand-held laboratory device.
In an embodiment, the presenting is carried out by a display integrated to a liquid handling device, such as an electronic pipette or an automated liquid handling station.
In an embodiment, the presenting is carried out by a display of a sample handling device used in the sample handling sequence.
In some embodiments, the presenting may be carried out by any suitable means or an output device, such as by visual means, by audio-visual means, or by audio means. Use of visual means enables that more information, particularly alphanumerical information, can be presented to the user about the magnitude and nature of an error. The advantage of audio means is that the user need not observe any display.
In an embodiment, the presenting comprises vibrating of the hand-held laboratory device.
Preferably, the presenting is carried out via a device held by or worn by or located in the sight of a user who is executing a sample handling and/or analysis task to which the presented experimental error relates. The device for presenting may be connected or integrated to the sample handling device, or to a control device of such.
In an embodiment, the presenting is carried out by an output device of a mobile device that is available to the user during execution of the sample handling sequence. The mobile device may be a mobile phone, a laptop or a tablet. The mobile device may be able to receive information to be presented (output) via a wireless or wired connection.
Said presenting may be provided via wireless or wired connection via a mobile application or a tablet software or a web-based service, or via a software integrated to a sample handling device.
Said presenting may comprise showing one or more charts, graphical symbols and/or alphanumeric symbols on a display of a sample handling device.
Said presenting may comprise presenting a variable-size graphical symbol, such as an arrow or a circle, on a display of sample handling device.
Preferably said presenting comprises presenting a numerical uncertainty factor to a user for example on a display of a sample handling device, which may be a hand-held device.
In an embodiment, said uncertainty factor may be derived from a total experimental error of an entire sample handling and/or analysis sequence.
In an embodiment, said uncertainty factor may be derived from an experimental error of an individual sample handling step.
In an embodiment, said uncertainty factor may be derived from accumulated experimental error.
In an embodiment, said uncertainty factor may be derived from estimated experimental error of the current step and/or the forthcoming steps.
The method may comprise automated locking of one or more functions of a sample handling device, for example temporarily. The advantage is that execution of the protocol and accumulation of error is automatically stopped without having to rely on the user's reaction to the presented information.
The present invention also provides a system configured to perform the method.
The system may comprise one or more of the following devices: a hand-held pipette, a liquid handling robot, a scale, an air pressure sensor, a temperature sensor, a humidity sensor, a spectrometer, a sample analysis device, preferably at least a hand-held device, such as a pipette. In addition the system may comprise a device for controlling or operating the system, or liquid handling execution, which may include sample handling and/or sequence analysis. The device for controlling may be called a controller. The controller may be a computer or a mobile device.
Said devices may be connected to each other by means of a wireless connection, such as a Bluetooth connection. In this way it is possible to transmit data, such as error data, such as the quantified total error, between the devices, for example in cases where the total error is quantified by a device that is not the same as the device that will be presenting the error to the user.
In an embodiment, the total experimental error is calculated by a hand-held liquid handling device, and said error is presented by the hand-held liquid handling device.
In an embodiment, the total experimental error is calculated by an automated liquid handling station, and said error is presented by a hand-held liquid handling device.
In an embodiment, the total experimental error is calculated by an automated sample analysis device or station, and said error is presented by a hand-held liquid handling device.
In some embodiments, data retrieved from one or more laboratory devices may be shown on the display of a hand-held pipette. Such data may comprise experimental errors and/or output values derived therefrom. The display of the pipette may thus present a combination of errors and/or output values. In this way it is possible to illustrate to the user the accumulation and sources of errors in previous steps in detail and in good time, for example in a situation where the total error slowly accumulates and approaches the set thresholds.
The present invention may also provide a sample handling device comprising means for performing the method. In an embodiment the sample handling device comprises: a computing device configured to quantify said total experimental error, and an output device, such as a display, configured to present said total experimental error.
If the Steps 1, 2 and 3 are different, such as performed by different types of devices or involving different type of sample handling actions, it may be preferable to carry out quantization of the errors before adding them together.
In one example, the sample handling and/or analysis sequence comprises a programmed pipetting sequence. The pipette is configured to follow accumulation of experimental error and to estimate the total experimental error of the entire programmed sequence. Thus the pipette quantifies or determines experimental errors of past steps, calculates the accumulated error, optionally compares to respective threshold values, estimates forthcoming errors, and calculates (estimates) the total error of the entire sequence. The estimate may change or be updated as the sequence progresses. The pipette presents the accumulated experimental error and/or the estimated total experimental error to the user. The user is able to assess whether it is possible to complete the programmed sequence with an acceptable level of uncertainty. Alternatively, the pipette may automatically generate such assessment and present it to the user.
In one example, one or more of the following are taken into account when quantifying the total experimental error in a liquid handling sequence: tip, liquid to be dispensed, number of doses to be dispensed, user, air humidity, ambient temperature. A threshold value or an acceptable value may be associated with each individual source of error.
Handling of solvents in the same space in which other sample handling and/or analysis procedures are carried out increases experimental error in said procedures. In one example, a volatile organic compound (VOC) sensor is used to detect concentrations of volatile organic compounds in the air of a laboratory. The detected concentrations are taken into account when quantifying the total experimental error in said sample handling and/or analysis procedure.
In one example, the sample handling and/or analysis sequence includes a liquid handling task, a polymerase chain reaction (PCR) analysis task and a protein separation task. Accumulation of experimental error is presented to the user during the execution of said steps, for example as an uncertainty factor. In this way the user is able to assess on the basis of the magnitude of the uncertainty factor whether it is grounded to continue the execution of said tasks and for example to proceed from one task to the next task. In addition or alternatively, a recommendation is presented. The recommendation may comprise an indication based on the determined uncertainty factor. The indication may refer to an error source, and optionally to an adjustment to be made in order to bring the uncertainty factor of the error source to an acceptable level. The acceptable level refers to an error level which is not considered detrimental for continuation of the execution of the tasks.
It is to be understood that the embodiments of the invention disclosed are not limited to the particular structures, process steps, or materials disclosed herein, but are extended to equivalents thereof as would be recognized by those ordinarily skilled in the relevant arts. It should also be understood that terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting.
Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment.
As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary. In addition, various embodiments and example of the present invention may be referred to herein along with alternatives for the various components thereof. It is understood that such embodiments, examples, and alternatives are not to be construed as de facto equivalents of one another, but are to be considered as separate and autonomous representations of the present invention.
Furthermore, the described features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. In the following description, numerous specific details are provided, such as examples of lengths, widths, shapes, etc., to provide a thorough understanding of embodiments of the invention. One skilled in the relevant art will recognize, however, that the invention can be practiced without one or more of the specific details, or with other methods, components, materials, etc. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the invention.
While the forgoing examples are illustrative of the principles of the present invention in one or more particular applications, it will be apparent to those of ordinary skill in the art that numerous modifications in form, usage and details of implementation can be made without the exercise of inventive faculty, and without departing from the principles and concepts of the invention. Accordingly, it is not intended that the invention be limited, except as by the claims set forth below.
The verbs “to comprise” and “to include” are used in this document as open limitations that neither exclude nor require the existence of also un-recited features. The features recited in depending claims are mutually freely combinable unless otherwise explicitly stated. Furthermore, it is to be understood that the use of “a” or “an”, i.e. a singular form, throughout this document does not exclude a plurality.
The present invention is industrially applicable at least in sample handling and/or analysis methods, such as preparation, pipetting, and/or analysis of samples, in a laboratory environment.
| Number | Date | Country | Kind |
|---|---|---|---|
| 23397501.0 | Mar 2023 | EP | regional |
